// ******************************************************************************
   //
   // Title:       Force Field X.
   // Description: Force Field X - Software for Molecular Biophysics.
   // Copyright:   Copyright (c) Michael J. Schnieders 2001-2025.
   //
   // This file is part of Force Field X.
   //
   // Force Field X is free software; you can redistribute it and/or modify it
  // under the terms of the GNU General Public License version 3 as published by
  // the Free Software Foundation.
  //
  // Force Field X is distributed in the hope that it will be useful, but WITHOUT
  // ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS
  // FOR A PARTICULAR PURPOSE. See the GNU General Public License for more
  // details.
  //
  // You should have received a copy of the GNU General Public License along with
  // Force Field X; if not, write to the Free Software Foundation, Inc., 59 Temple
  // Place, Suite 330, Boston, MA 02111-1307 USA
  //
  // Linking this library statically or dynamically with other modules is making a
  // combined work based on this library. Thus, the terms and conditions of the
  // GNU General Public License cover the whole combination.
  //
  // As a special exception, the copyright holders of this library give you
  // permission to link this library with independent modules to produce an
  // executable, regardless of the license terms of these independent modules, and
  // to copy and distribute the resulting executable under terms of your choice,
  // provided that you also meet, for each linked independent module, the terms
  // and conditions of the license of that module. An independent module is a
  // module which is not derived from or based on this library. If you modify this
  // library, you may extend this exception to your version of the library, but
  // you are not obligated to do so. If you do not wish to do so, delete this
  // exception statement from your version.
  //
  // ******************************************************************************
  
  package ffx.potential.extended;
  
  import edu.rit.pj.reduction.SharedDouble;
  import ffx.numerics.Constraint;
  import ffx.numerics.Potential;
  import ffx.potential.ForceFieldEnergy;
  import ffx.potential.MolecularAssembly;
  import ffx.potential.SystemState;
  import ffx.potential.bonded.AminoAcidUtils;
  import ffx.potential.bonded.AminoAcidUtils.AminoAcid3;
  import ffx.potential.bonded.Atom;
  import ffx.potential.bonded.Residue;
  import ffx.potential.constraint.ShakeChargeConstraint;
  import ffx.potential.parameters.ForceField;
  import ffx.potential.parameters.PolarizeType;
  import ffx.potential.parameters.TitrationUtils;
  import ffx.potential.parsers.ESVFilter;
  import ffx.utilities.Constants;
  import ffx.utilities.FileUtils;
  import org.apache.commons.configuration2.CompositeConfiguration;
  import org.apache.commons.io.FilenameUtils;
  
  import java.io.File;
  import java.util.*;
  import java.util.logging.Level;
  import java.util.logging.Logger;
  
  import static ffx.potential.bonded.BondedUtils.hasAttachedAtom;
  import static ffx.utilities.Constants.kB;
  import static java.lang.String.format;
  import static org.apache.commons.math3.util.FastMath.*;
  
  /**
   * ExtendedSystem class.
   *
   * @author Andrew Thiel
   * @since 1.0
   */
  public class ExtendedSystem implements Potential {
  
      private static final double DISCR_BIAS = 1.0; // kcal/mol
      private static final double LOG10 = log(10.0);
      private static final double THETA_FRICTION = 0.5; // psec^-1
      private static final double THETA_MASS = 5.0; //Atomic Mass Units
      private static final int dDiscr_dTautIndex = 6;
      private static final int dDiscr_dTitrIndex = 3;
      private static final int dModel_dTautIndex = 8;
      private static final int dModel_dTitrIndex = 5;
      private static final int dPh_dTautIndex = 7;
      private static final int dPh_dTitrIndex = 4;
      private static final int discrBiasIndex = 0;
      private static final Logger logger = Logger.getLogger(ExtendedSystem.class.getName());
      private static final int modelBiasIndex = 2;
      private static final int pHBiasIndex = 1;
      public final boolean guessTitrState;
      /**
       * Array of AminoAcid3 initialized  to match the number of atoms in the system.
       * Used to know how to apply vdW or electrostatic ESV terms for the atom.
       */
      public final AminoAcid3[] residueNames;
      /**
      * Array of ints that is initialized to match the number of atoms in the molecular assembly.
      * 1 indicates that the tautomer lambda direction is normal.
      * -1 indicates that the tautomer lambda direction is reversed (1-x).
      * 0 indicates that the atom is not a tautomerizing atom.
      */
     public final int[] tautomerDirections;
     private final double[] ASH1toASH2 = new double[4];
     /**
      * Coefficients that define the per residue type Fmod polynomial
      * quadratic * titrationLambda^2 + linear * titrationLambda
      */
     private final double[] ASHFmod = new double[4];
     private final double ASHrestraintConstant;
     /**
      * Descritizer Bias Magnitude. Default is 1 kcal/mol.
      */
     private final double ASHtautBiasMag;
     private final double ASHtitrBiasMag;
     private final double[] CYSFmod = new double[4];
     private final double CYSrestraintConstant;
     /**
      * Descritizer Bias Magnitude. Default is 1 kcal/mol.
      */
     private final double CYStitrBiasMag;
     private final double[] GLH1toGLH2 = new double[4];
     private final double[] GLHFmod = new double[4];
     private final double GLHrestraintConstant;
     /**
      * Descritizer Bias Magnitude. Default is 1 kcal/mol.
      */
     private final double GLHtautBiasMag;
     private final double GLHtitrBiasMag;
     /**
      * Coefficients that define the tautomer component of the bivariate Histidine Fmod
      * quadratic * tautomerLambda^2 + linear * tautomerLambda
      */
     private final double[] HIDFmod = new double[4];
     private final double[] HIDtoHIEFmod = new double[4];
     private final double[] HIEFmod = new double[4];
     private final double HISrestraintConstant;
     /**
      * Descritizer Bias Magnitude. Default is 1 kcal/mol.
      */
     private final double HIStautBiasMag;
     private final double HIStitrBiasMag;
     private final double[] LYSFmod = new double[4];
     private final double LYSrestraintConstant;
     /**
      * Descritizer Bias Magnitude. Default is 1 kcal/mol.
      */
     private final double LYStitrBiasMag;
     private final List<Constraint> constraints;
     public final boolean useTotalChargeCorrection;
     private final boolean doBias;
     private final boolean doElectrostatics;
     private final boolean doPolarization;
     // Controls for turning of certain terms for testing.
     private final boolean doVDW;
     /**
      * 3D array to store the titration and tautomer population states for each ESV
      */
     final private int[][][] esvHistogram;
     private final SharedDouble[] esvIndElecDerivs;
     private final SharedDouble[] esvPermElecDerivs;
     /**
      * Array of ints that is initialized to match the number of atoms in the molecular assembly.
      * Elements correspond to residue index in the tautomerizingResidueList. Only set for tautomerizing residues, -1 otherwise.
      */
     private final SystemState esvState;
     /**
      * Shared double that is initialized to match the number of ESVs in the system.
      * Once reduced, will equal either dU_Titr/dLambda or dU_Taut/dLambda for specific ESV
      */
     private final SharedDouble[] esvVdwDerivs;
     /**
      * Extended Atoms
      */
     private final Atom[] extendedAtoms;
     /**
      * Array of lambda values that matches residues in extendedResidueList
      */
     private final double[] extendedLambdas;
     /**
      * Extended Molecules
      */
     private final int[] extendedMolecules;
     /**
      * Concatenated list of titrating residues + tautomerizing residues.
      */
     private final List<Residue> extendedResidueList;
     /**
      * ForceField Energy Instance. This instance is only used for Potential implementations for grabbing the energy components.
      */
     private final ForceFieldEnergy forceFieldEnergy;
     /**
      * Array of booleans that is initialized to match the number of atoms in the molecular assembly
      * noting whether the atom is tautomerizing. Note that any side chain atom that belongs to a tautomerizing residue
      * will be flagged as tautomerizing for purposes of scaling electrostatic parameters.
      */
     private final boolean[] isTautomerizing;
     /**
      * Array of booleans that is initialized to match the number of atoms in the molecular assembly
      * noting whether the atom is titrating. Note that any side chain atom that belongs to a titrating residue
      * will be flagged as titrating for purposes of scaling electrostatic parameters.
      */
     private final boolean[] isTitrating;
     /**
      * Array of booleans that is initialized to match the number of atoms in the assembly to note whether an atom is
      * specifically a heavy atom with changing polarizability (CYS SG, ASP OD1/OD2, GLU OE1/OE2).
      */
     private final boolean[] isTitratingHeavy;
     /**
      * Array of booleans that is initialized to match the number of atoms in the assembly to note whether an atom is
      * specifically a titrating hydrogen.
      */
     private final boolean[] isTitratingHydrogen;
     /**
      * Boolean similar to fixTitrationState/fixTautomerState but is even more restrictive in that set methods
      * are not allowed to change lambda values from their initialized values.
      * Mainly used when evaluating archive snapshots at different initialized lambda values.
      * If not set to true the archive and esv files set the lambdas automatically.
      */
     private final boolean lockStates;
     /**
      * Number of atoms in the molecular assembly. Since all protons are instantiated at start, this int will not change.
      */
     private final int nAtoms;
     /**
      * Number of ESVs attached to the molecular assembly. This number is the sum of tautomerizing + titrating ESVs.
      */
     private final int nESVs;
     /**
      * Number of titrating ESVs attached to the molecular assembly.
      */
     private final int nTitr;
     private final ArrayList<Double> specialInitTautomer;
     private final ArrayList<Double> specialInitTitration;
     private final ArrayList<Double> specialResiduePKAs;
     private final ArrayList<Double> specialResidues;
     private final int[] tautomerIndexMap;
     /**
      * Array of doubles that is initialized to match the number of atoms in the molecular assembly.
      * Only elements that match a tautomerizing atom will have their lambda updated.
      */
     private final double[] tautomerLambdas;
     /**
      * List of tautomerizing residues.
      */
     private final List<Residue> tautomerizingResidueList;
     /**
      * Friction for the ESV system
      */
     private final double thetaFriction;
     /**
      * The system defined theta mass of the fictional particle. Used to fill theta mass array.
      */
     private final double thetaMass;
     /**
      * List of titrating residues.
      */
     private final List<Residue> titratingResidueList;
     /**
      * Array of ints that is initialized to match the number of atoms in the molecular assembly.
      * Elements correspond to residue index in the titratingResidueList. Only set for titrating residues, -1 otherwise.
      */
     private final int[] titrationIndexMap;
     /**
      * Array of doubles that is initialized to match the number of atoms in the molecular assembly.
      * Only elements that match a titrating atom will have their lambda updated.
      */
     private final double[] titrationLambdas;
     /**
      * Titration Utils instance. This instance is the master copy that will be distributed to electrostatics classes
      * when an Extended System is attached.
      */
     private final TitrationUtils titrationUtils;
     private final boolean useChargeConstraint;
     /**
      * Dynamics restart file.
      */
     File restartFile;
     /**
      * Boolean to keep the lambdas from updating over the course of dynamics. Useful for running dynamics
      * with extended system variables at fixed windows (i.e. BAR)
      */
     private boolean fixTautomerState;
     private boolean fixTitrationState;
     /**
      * Filter to parse the dynamics restart file.
      */
     private ESVFilter esvFilter = null;
     /**
      * System PH.
      */
     private double constantSystemPh = 7.4;
     /**
      * Target system temperature.
      */
     private double currentTemperature = Constants.ROOM_TEMPERATURE;
 
     /**
      * Construct extended system with the provided configuration.
      *
      * @param mola a {@link MolecularAssembly} object.
      */
     public ExtendedSystem(MolecularAssembly mola, double pH, final File esvFile) {
         extendedAtoms = mola.getAtomArray();
         extendedMolecules = mola.getMoleculeNumbers();
         setConstantPh(pH);
         ForceField forceField = mola.getForceField();
         forceFieldEnergy = mola.getPotentialEnergy();
         if (forceFieldEnergy == null) {
             logger.severe("No potential energy found?");
         }
         CompositeConfiguration properties = mola.getProperties();
         titrationUtils = new TitrationUtils(forceField);
 
         doVDW = properties.getBoolean("esv.vdW", true);
         doElectrostatics = properties.getBoolean("esv.elec", true);
         doBias = properties.getBoolean("esv.bias", true);
         doPolarization = properties.getBoolean("esv.polarization", true);
         useTotalChargeCorrection = properties.getBoolean("esv.total.charge.correction", false);
         thetaFriction = properties.getDouble("esv.friction", ExtendedSystem.THETA_FRICTION);
         thetaMass = properties.getDouble("esv.mass", ExtendedSystem.THETA_MASS);
 
         lockStates = properties.getBoolean("lock.esv.states", false); // Prevents setTitrationLambda/setTautomerLambda
         double initialTitrationLambda = properties.getDouble("lambda.titration.initial", 0.5);
         double initialTautomerLambda = properties.getDouble("lambda.tautomer.initial", 0.5);
         guessTitrState = properties.getBoolean("guess.titration.state", false);
         specialResidues = getPropertyList(properties, "esv.special.residues");
         specialResiduePKAs = getPropertyList(properties, "esv.special.residues.pka");
         specialInitTautomer = getPropertyList(properties, "esv.special.residues.tautomer");
         specialInitTitration = getPropertyList(properties, "esv.special.residues.titration");
         initSpecialResidues(specialResidues, specialResiduePKAs, specialInitTautomer, specialInitTitration, mola);
 
         fixTitrationState = properties.getBoolean("fix.titration.lambda", false);
         fixTautomerState = properties.getBoolean("fix.tautomer.lambda", false);
         useChargeConstraint = properties.getBoolean("esv.charge.constraint", false);
         int totalCharge = properties.getInt("esv.charge.constraint.value", 0);
 
 
         ASHFmod[3] = properties.getDouble("ASH.cubic", TitrationUtils.Titration.ASHtoASP.cubic);
         ASHFmod[2] = properties.getDouble("ASH.quadratic", TitrationUtils.Titration.ASHtoASP.quadratic);
         ASHFmod[1] = properties.getDouble("ASH.linear", TitrationUtils.Titration.ASHtoASP.linear);
         ASHFmod[0] = TitrationUtils.Titration.ASHtoASP.offset;
         ASH1toASH2[3] = properties.getDouble("ASH1toASH2.cubic", TitrationUtils.Titration.ASH1toASH2.cubic);
         ASH1toASH2[2] = properties.getDouble("ASH1toASH2.quadratic", TitrationUtils.Titration.ASH1toASH2.quadratic);
         ASH1toASH2[1] = properties.getDouble("ASH1toASH2.linear", TitrationUtils.Titration.ASH1toASH2.linear);
         ASH1toASH2[0] = TitrationUtils.Titration.ASH1toASH2.offset;
         ASHtitrBiasMag = properties.getDouble("ASH.titration.bias.magnitude", DISCR_BIAS);
         ASHtautBiasMag = properties.getDouble("ASH.tautomer.bias.magnitude", DISCR_BIAS);
         ASHrestraintConstant = properties.getDouble("ASH.restraint.constant", 0.0);
 
         GLHFmod[3] = properties.getDouble("GLH.cubic", TitrationUtils.Titration.GLHtoGLU.cubic);
         GLHFmod[2] = properties.getDouble("GLH.quadratic", TitrationUtils.Titration.GLHtoGLU.quadratic);
         GLHFmod[1] = properties.getDouble("GLH.linear", TitrationUtils.Titration.GLHtoGLU.linear);
         GLHFmod[0] = TitrationUtils.Titration.GLHtoGLU.offset;
         GLH1toGLH2[3] = properties.getDouble("GLH1toGLH2.cubic", TitrationUtils.Titration.GLH1toGLH2.cubic);
         GLH1toGLH2[2] = properties.getDouble("GLH1toGLH2.quadratic", TitrationUtils.Titration.GLH1toGLH2.quadratic);
         GLH1toGLH2[1] = properties.getDouble("GLH1toGLH2.linear", TitrationUtils.Titration.GLH1toGLH2.linear);
         GLH1toGLH2[0] = TitrationUtils.Titration.GLH1toGLH2.offset;
         GLHtitrBiasMag = properties.getDouble("GLH.titration.bias.magnitude", DISCR_BIAS);
         GLHtautBiasMag = properties.getDouble("GLH.tautomer.bias.magnitude", DISCR_BIAS);
         GLHrestraintConstant = properties.getDouble("GLH.restraint.constant", 0.0);
 
         LYSFmod[3] = properties.getDouble("LYS.cubic", TitrationUtils.Titration.LYStoLYD.cubic);
         LYSFmod[2] = properties.getDouble("LYS.quadratic", TitrationUtils.Titration.LYStoLYD.quadratic);
         LYSFmod[1] = properties.getDouble("LYS.linear", TitrationUtils.Titration.LYStoLYD.linear);
         LYSFmod[0] = TitrationUtils.Titration.LYStoLYD.offset;
         LYStitrBiasMag = properties.getDouble("LYS.titration.bias.magnitude", DISCR_BIAS);
         LYSrestraintConstant = properties.getDouble("LYS.restraint.constant", 0.0);
 
         CYSFmod[3] = properties.getDouble("CYS.cubic", TitrationUtils.Titration.CYStoCYD.cubic);
         CYSFmod[2] = properties.getDouble("CYS.quadratic", TitrationUtils.Titration.CYStoCYD.quadratic);
         CYSFmod[1] = properties.getDouble("CYS.linear", TitrationUtils.Titration.CYStoCYD.linear);
         CYSFmod[0] = TitrationUtils.Titration.CYStoCYD.offset;
         CYStitrBiasMag = properties.getDouble("CYS.titration.bias.magnitude", DISCR_BIAS);
         CYSrestraintConstant = properties.getDouble("CYS.restraint.constant", 0.0);
 
         HIDFmod[3] = properties.getDouble("HID.cubic", TitrationUtils.Titration.HIStoHID.cubic);
         HIDFmod[2] = properties.getDouble("HID.quadratic", TitrationUtils.Titration.HIStoHID.quadratic);
         HIDFmod[1] = properties.getDouble("HID.linear", TitrationUtils.Titration.HIStoHID.linear);
         HIDFmod[0] = TitrationUtils.Titration.HIStoHID.offset;
         HIEFmod[3] = properties.getDouble("HIE.cubic", TitrationUtils.Titration.HIStoHIE.cubic);
         HIEFmod[2] = properties.getDouble("HIE.quadratic", TitrationUtils.Titration.HIStoHIE.quadratic);
         HIEFmod[1] = properties.getDouble("HIE.linear", TitrationUtils.Titration.HIStoHIE.linear);
         HIEFmod[0] = TitrationUtils.Titration.HIStoHIE.offset;
         HIDtoHIEFmod[3] = properties.getDouble("HIDtoHIE.cubic", TitrationUtils.Titration.HIDtoHIE.cubic);
         HIDtoHIEFmod[2] = properties.getDouble("HIDtoHIE.quadratic", TitrationUtils.Titration.HIDtoHIE.quadratic);
         HIDtoHIEFmod[1] = properties.getDouble("HIDtoHIE.linear", TitrationUtils.Titration.HIDtoHIE.linear);
         HIDtoHIEFmod[0] = TitrationUtils.Titration.HIDtoHIE.offset;
         HIStitrBiasMag = properties.getDouble("HIS.titration.bias.magnitude", DISCR_BIAS);
         HIStautBiasMag = properties.getDouble("HIS.tautomer.bias.magnitude", DISCR_BIAS);
         HISrestraintConstant = properties.getDouble("HIS.restraint.constant", 0.0);
 
         // Log all of the titration bias magnitudes for each titratable residue.
         logger.info("\n Titration bias magnitudes:");
         logger.info(" Lysine titration bias magnitude: " + LYStitrBiasMag);
         logger.info(" Cysteine titration bias magnitude: " + CYStitrBiasMag);
         logger.info(" Histidine titration bias magnitude: " + HIStitrBiasMag);
         logger.info(" Glutamic acid titration bias magnitude: " + GLHtitrBiasMag);
         logger.info(" Aspartic acid titration bias magnitude: " + ASHtitrBiasMag);
 
         // Log all of the tautomer bias magnitudes for each tautomerizable residue.
         logger.info("\n Tautomer bias magnitudes:");
         logger.info(" Aspartic acid tautomer bias magnitude: " + ASHtautBiasMag);
         logger.info(" Glutamic acid tautomer bias magnitude: " + GLHtautBiasMag);
         logger.info(" Histidine tautomer bias magnitude: " + HIStautBiasMag);
 
         // Log all of  th cubic, quadratic, and linear terms for all of the amino acid terms
         logger.info("\n Titration bias terms:");
         logger.info(" Lysine cubic term: " + LYSFmod[3]);
         logger.info(" Lysine quadratic term: " + LYSFmod[2]);
         logger.info(" Lysine linear term: " + LYSFmod[1]);
         logger.info(" Cysteine cubic term: " + CYSFmod[3]);
         logger.info(" Cysteine quadratic term: " + CYSFmod[2]);
         logger.info(" Cysteine linear term: " + CYSFmod[1]);
         logger.info(" Histidine cubic term: " + HIDFmod[3]);
         logger.info(" HID quadratic term: " + HIDFmod[2]);
         logger.info(" HID linear term: " + HIDFmod[1]);
         logger.info(" HIE cubic term: " + HIEFmod[3]);
         logger.info(" HIE quadratic term: " + HIEFmod[2]);
         logger.info(" HIE linear term: " + HIEFmod[1]);
         logger.info(" HID-HIE cubic term: " + HIDtoHIEFmod[3]);
         logger.info(" HID-HIE quadratic term: " + HIDtoHIEFmod[2]);
         logger.info(" HID-HIE linear term: " + HIDtoHIEFmod[1]);
         logger.info(" Glutamic acid cubic term: " + GLHFmod[3]);
         logger.info(" Glutamic acid quadratic term: " + GLHFmod[2]);
         logger.info(" Glutamic acid linear term: " + GLHFmod[1]);
         logger.info(" Aspartic acid cubic term: " + ASHFmod[3]);
         logger.info(" Aspartic acid quadratic term: " + ASHFmod[2]);
         logger.info(" Aspartic acid linear term: " + ASHFmod[1]);
 
         titratingResidueList = new ArrayList<>();
         tautomerizingResidueList = new ArrayList<>();
         extendedResidueList = new ArrayList<>();
         // Initialize atom arrays with the existing assembly.
         Atom[] atoms = mola.getAtomArray();
         nAtoms = atoms.length;
         isTitrating = new boolean[nAtoms];
         isTitratingHydrogen = new boolean[nAtoms];
         isTitratingHeavy = new boolean[nAtoms];
         isTautomerizing = new boolean[nAtoms];
         titrationLambdas = new double[nAtoms];
         tautomerLambdas = new double[nAtoms];
         titrationIndexMap = new int[nAtoms];
         tautomerIndexMap = new int[nAtoms];
         tautomerDirections = new int[nAtoms];
         residueNames = new AminoAcid3[nAtoms];
 
         Arrays.fill(isTitrating, false);
         Arrays.fill(isTitratingHydrogen, false);
         Arrays.fill(isTitratingHeavy, false);
         Arrays.fill(isTautomerizing, false);
         Arrays.fill(titrationLambdas, 1.0);
         Arrays.fill(tautomerLambdas, 0.0);
         Arrays.fill(titrationIndexMap, -1);
         Arrays.fill(tautomerIndexMap, -1);
         Arrays.fill(tautomerDirections, 0);
         Arrays.fill(residueNames, AminoAcid3.UNK);
 
         // Cycle through each residue to determine if it is titratable or tautomerizing.
         // If a residue is one of these, add to titration or tautomer lists.
         // Next, loop through all atoms and check to see if the atom belongs to this residue.
         // If the atom does belong to this residue, set all corresponding variables in the respective titration or tautomer array (size = numAtoms).
         // Store the index of the residue in the respective list into a map array (size = numAtoms).
         List<Residue> residueList = mola.getResidueList();
         //logger.info(residueList.toString());
         List<Residue> preprocessList = new ArrayList<>(residueList);
         for (Residue residue : preprocessList) {
             List<Atom> atomList = residue.getSideChainAtoms();
             for (Atom atom : atomList) {
                 //Detect disulfide sulfurs, so we can exclude these when setting up titrating residues.
                 if (atom.getAtomicNumber() == 16) {
                     if (hasAttachedAtom(atom, 16)) {
                         residueList.remove(residue);
                     }
                 }
             }
         }
         //logger.info(residueList.toString());
         // Use only a list that contains AminoAcid residues so remove Nucleic Acid residues
         residueList.removeIf(residue -> (residue.getResidueType() == Residue.ResidueType.NA));
         for (Residue residue : residueList) {
             if (isTitratable(residue)) {
                 titratingResidueList.add(residue);
                 List<Atom> atomList = residue.getSideChainAtoms();
                 for (Atom atom : atomList) {
                     int atomIndex = atom.getArrayIndex();
                     residueNames[atomIndex] = residue.getAminoAcid3();
                     isTitrating[atomIndex] = true;
                     titrationLambdas[atomIndex] = initialTitrationState(residue, initialTitrationLambda, guessTitrState);
                     int titrationIndex = titratingResidueList.indexOf(residue);
                     titrationIndexMap[atomIndex] = titrationIndex;
                     isTitratingHydrogen[atomIndex] = TitrationUtils.isTitratingHydrogen(residue.getAminoAcid3(), atom);
                     isTitratingHeavy[atomIndex] = TitrationUtils.isTitratingHeavy(residue.getAminoAcid3(), atom);
                     // Average out pdamp values of the atoms with changing polarizability which will then be used as fixed values throughout simulation.
                     // When testing end state energies don't average pdamp.
                     // Default pdamp is set from protonated polarizability, so it must be changed when testing deprotonated end state (Titration lambda = 0.0.)
                     if (isTitratingHeavy(atomIndex)) {
                         //If polarization is turned off atom.getPolarizeType() will return null
                         if (atom.getPolarizeType() != null) {
                             double deprotPolar = titrationUtils.getPolarizability(atom, 0.0, 0.0, atom.getPolarizeType().polarizability);
                             double protPolar = titrationUtils.getPolarizability(atom, 1.0, 1.0, atom.getPolarizeType().polarizability);
                             double avgPolar = 0.5 * deprotPolar + 0.5 * protPolar;
                             PolarizeType esvPolarizingHeavyAtom = new PolarizeType(atom.getType(), avgPolar, atom.getPolarizeType().thole,
                                     atom.getPolarizeType().ddp, atom.getPolarizeType().polarizationGroup);
                             atom.setPolarizeType(esvPolarizingHeavyAtom);
                         }
                     }
                 }
                 // If is a tautomer, it must also be titrating.
                 if (isTautomer(residue)) {
                     tautomerizingResidueList.add(residue);
                     for (Atom atom : atomList) {
                         int atomIndex = atom.getArrayIndex();
                         if (isTitratingHydrogen[atomIndex]) {
                             logger.info("Residue: " + residue + " Atom: " + atom + " atomType: " +
                                     atom.getAtomType().type + " " + atom.getAtomType().atomClass);
                         }
                         isTautomerizing[atomIndex] = true;
                         double resNum = residue.getResidueNumber();
                         tautomerLambdas[atomIndex] = specialResidues.contains(resNum) && !specialInitTautomer.isEmpty() &&
                                 Math.abs(specialInitTitration.get(specialResidues.indexOf(resNum)) + 1) > 1e-4
                                 ? specialInitTitration.get(specialResidues.indexOf(resNum)) : initialTautomerLambda;
                         int tautomerIndex = tautomerizingResidueList.indexOf(residue);
                         tautomerIndexMap[atomIndex] = tautomerIndex;
                         tautomerDirections[atomIndex] = TitrationUtils.getTitratingHydrogenDirection(residue.getAminoAcid3(), atom);
                     }
                 }
                 // Test the multipole frames during unit testing.
                 assert (titrationUtils.testResidueTypes(residue));
             }
         }
 
         //Concatenate titratingResidueList and tautomerizingResidueList
         extendedResidueList.addAll(titratingResidueList);
         extendedResidueList.addAll(tautomerizingResidueList);
         //Arrays that are sent to integrator are based on extendedResidueList size
         nESVs = extendedResidueList.size();
         nTitr = titratingResidueList.size();
         extendedLambdas = new double[nESVs];
         esvState = new SystemState(nESVs);
         //thetaPosition = new double[nESVs];
         //thetaVelocity = new double[nESVs];
         //thetaAccel = new double[nESVs];
         //thetaMassArray = new double[nESVs];
         esvHistogram = new int[nTitr][10][10];
         esvVdwDerivs = new SharedDouble[nESVs];
         esvPermElecDerivs = new SharedDouble[nESVs];
         esvIndElecDerivs = new SharedDouble[nESVs];
         for (int i = 0; i < nESVs; i++) {
             esvVdwDerivs[i] = new SharedDouble(0.0);
             esvPermElecDerivs[i] = new SharedDouble(0.0);
             esvIndElecDerivs[i] = new SharedDouble(0.0);
         }
         if (useChargeConstraint) {
             constraints = new ArrayList<>();
             ShakeChargeConstraint chargeConstraint = new ShakeChargeConstraint(nTitr, totalCharge, 0.001);
             constraints.add(chargeConstraint);
         } else {
             constraints = Collections.emptyList();
         }
 
         //Theta masses should always be the same for each ESV
         Arrays.fill(esvState.getMass(), thetaMass);
 
         for (int i = 0; i < nESVs; i++) {
             if (i < nTitr) {
                 Residue residue = extendedResidueList.get(i);
                 double initialTitrLambda = initialTitrationState(residue, initialTitrationLambda, guessTitrState);
                 initializeThetaArrays(i, initialTitrLambda);
             } else {
                 double resNum = extendedResidueList.get(i).getResidueNumber();
                 initialTautomerLambda = specialResidues.contains(resNum) && !specialInitTautomer.isEmpty() &&
                         Math.abs(specialInitTitration.get(specialResidues.indexOf(resNum)) + 1) > 1e-4
                         ? specialInitTitration.get(specialResidues.indexOf(resNum)) : initialTautomerLambda;
                 initializeThetaArrays(i, initialTautomerLambda);
             }
         }
         if (esvFilter == null) {
             esvFilter = new ESVFilter(mola.getName());
         }
         if (esvFile == null) {
             String firstFileName = FilenameUtils.removeExtension(mola.getFile().getAbsolutePath());
             restartFile = new File(firstFileName + ".esv");
         } else {
             double[] thetaPosition = esvState.x();
             double[] thetaVelocity = esvState.v();
             double[] thetaAccel = esvState.a();
             if (!esvFilter.readESV(esvFile, thetaPosition, thetaVelocity, thetaAccel, esvHistogram)) {
                 String message = " Could not load the restart file - dynamics terminated.";
                 logger.log(Level.WARNING, message);
                 throw new IllegalStateException(message);
             } else {
                 restartFile = esvFile;
                 updateLambdas();
             }
         }
     }
 
     /**
      * Initialize special residues specified in the key file
      */
     private void initSpecialResidues(ArrayList<Double> specialResidues, ArrayList<Double> specialResiduePKAs, ArrayList<Double> specialInitTautomer, ArrayList<Double> specialInitTitration, MolecularAssembly mola) {
         if ((specialResidues.size() != specialResiduePKAs.size() && !specialResiduePKAs.isEmpty())
                 || (specialResidues.size() != specialInitTautomer.size() && !specialInitTautomer.isEmpty())
                 || (specialResidues.size() != specialInitTitration.size() && !specialInitTitration.isEmpty())
         ) {
             logger.severe("The number of special residues and their associated values do not match.");
         } else if (!specialResidues.isEmpty()) {
             logger.info("\nSpecial residues and their associated values:");
             for (int i = 0; i < specialResidues.size(); i++) {
                 int resNum = (int) (double) specialResidues.get(i) - mola.getResidueList().get(0).getResidueNumber(); // Shift pdb index by first residue number
                 if (!specialResiduePKAs.isEmpty()) {
                     logger.info("Residue: " + specialResidues.get(i) + "-" +
                             mola.getResidueList().get(resNum).getName()
                             + " Pka: " + specialResiduePKAs.get(i));
                 }
                 if (!specialInitTautomer.isEmpty()) {
                     logger.info("Residue: " + specialResidues.get(i) + "-" +
                             mola.getResidueList().get(resNum).getName()
                             + " Tautomer: " + specialInitTautomer.get(i));
                 }
                 if (!specialInitTitration.isEmpty()) {
                     logger.info("Residue: " + specialResidues.get(i) + "-" +
                             mola.getResidueList().get(resNum).getName()
                             + " Titration: " + specialInitTitration.get(i));
                 }
             }
             logger.info(" ");
         }
         logger.info("Special residues: " + specialResidues);
         logger.info("Special residues pKa: " + specialResiduePKAs);
         logger.info("Special residues titration: " + specialInitTitration);
         logger.info("Special residues tautomer: " + specialInitTautomer);
         for (Residue res : mola.getResidueList()) {
             if (!isTitratable(res) && specialResidues.contains((double) res.getResidueNumber())) {
                 logger.severe("Given special residue: " + res + " is not titratable.");
             }
         }
     }
 
     /**
      * Returns the titratibility of the passed residue
      */
     public boolean isTitratable(Residue residue) {
         if (residue.getResidueType() == Residue.ResidueType.NA) {
             return false;
         }
         AminoAcidUtils.AminoAcid3 AA3 = residue.getAminoAcid3();
         return AA3.isConstantPhTitratable;
     }
 
     // Method that takes in properties, a string.
     private ArrayList<Double> getPropertyList(CompositeConfiguration properties, String s) {
         ArrayList<Double> list = new ArrayList<>();
         String[] split = properties.getString(s, "").trim()
                 .replace("[", "")
                 .replace("]", "")
                 .replace(",", " ")
                 .split(" ");
         for (String s1 : split) {
             if (s1.isEmpty()) {
                 continue;
             }
             list.add(Double.parseDouble(s1));
         }
         return list;
     }
 
     /**
      * During constructor, initialize arrays that will hold theta positions, velocities, and accelerations.
      * Positions determined from starting lambda.
      * Velocities randomly set according to Maxwell Boltzmann Distribution based on temperature.
      * Accelerations determined from initial forces.
      *
      * @param index  index of ExtendedResidueList for which to set these values.
      * @param lambda starting lambda value for each ESV.
      */
     private void initializeThetaArrays(int index, double lambda) {
         extendedLambdas[index] = lambda;
         double[] thetaPosition = esvState.x();
         double[] thetaVelocity = esvState.v();
         double[] thetaAccel = esvState.a();
         thetaPosition[index] = Math.asin(Math.sqrt(lambda));
         //Perform unit analysis carefully
         Random random = new Random();
         thetaVelocity[index] = random.nextGaussian() * sqrt(kB * 298.15 / thetaMass);
         double dUdL = getDerivatives()[index];
         double dUdTheta = dUdL * sin(2 * thetaPosition[index]);
         thetaAccel[index] = -Constants.KCAL_TO_GRAM_ANG2_PER_PS2 * dUdTheta / thetaMass;
         //logger.info(format("Index: %d, dU/dL: %6.8f, dU/dTheta: %6.8f Theta Accel: %6.8f, Theta Velocity: %6.8f", index, -Constants.KCAL_TO_GRAM_ANG2_PER_PS2*dUdL, -Constants.KCAL_TO_GRAM_ANG2_PER_PS2*dUdTheta, thetaAccel[index], thetaVelocity[index]));
     }
 
     /**
      * get array of dU/dL for each titrating residue
      *
      * @return esvDeriv a double[]
      */
     public double[] getDerivatives() {
         double[] esvDeriv = new double[nESVs];
         double[] biasDerivComponents = new double[9];
 
         for (Residue residue : titratingResidueList) {
             int resTitrIndex = titratingResidueList.indexOf(residue);
             //Bias Terms
             if (doBias) {
                 getBiasTerms(residue, biasDerivComponents);
                 //Sum up titration bias derivs
                 esvDeriv[resTitrIndex] += biasDerivComponents[dDiscr_dTitrIndex] + biasDerivComponents[dPh_dTitrIndex] + biasDerivComponents[dModel_dTitrIndex];
                 //Sum up tautomer bias derivs
                 if (isTautomer(residue)) {
                     int resTautIndex = tautomerizingResidueList.indexOf(residue) + nTitr;
                     esvDeriv[resTautIndex] += biasDerivComponents[dDiscr_dTautIndex] + biasDerivComponents[dPh_dTautIndex] + biasDerivComponents[dModel_dTautIndex];
                 }
             }
 
             if (doVDW) {
                 esvDeriv[resTitrIndex] += getVdwDeriv(resTitrIndex);
                 //Sum up tautomer bias derivs
                 if (isTautomer(residue)) {
                     int resTautIndex = tautomerizingResidueList.indexOf(residue) + nTitr;
                     esvDeriv[resTautIndex] += getVdwDeriv(resTautIndex);
                 }
             }
 
             if (doElectrostatics) {
                 esvDeriv[resTitrIndex] += getPermElecDeriv(resTitrIndex);
                 //Sum up tautomer bias derivs
                 if (isTautomer(residue)) {
                     int resTautIndex = tautomerizingResidueList.indexOf(residue) + nTitr;
                     esvDeriv[resTautIndex] += getPermElecDeriv(resTautIndex);
                 }
                 if (doPolarization) {
                     esvDeriv[resTitrIndex] += getIndElecDeriv(resTitrIndex);
                     if (isTautomer(residue)) {
                         int resTautIndex = tautomerizingResidueList.indexOf(residue) + nTitr;
                         esvDeriv[resTautIndex] += getIndElecDeriv(resTautIndex);
                     }
                 }
             }
         }
         return esvDeriv;
     }
 
     /**
      * Collect respective pH, model, and discr bias terms and their derivatives for each titrating residue.
      */
     private void getBiasTerms(Residue residue, double[] biasEnergyAndDerivs) {
         AminoAcidUtils.AminoAcid3 AA3 = residue.getAminoAcid3();
         double titrationLambda = getTitrationLambda(residue);
         double titrationLambdaSquared = titrationLambda * titrationLambda;
         double titrationLambdaCubed = titrationLambdaSquared * titrationLambda;
         double discrBias;
         double pHBias;
         double modelBias;
         double dDiscr_dTitr;
         double dDiscr_dTaut;
         double dPh_dTitr;
         double dPh_dTaut;
         double dMod_dTitr;
         double dMod_dTaut;
         //If bias terms shouldn't be computed, set AA3 to UNK so that default case executes and all terms are set to zero.
         if (!doBias) {
             AA3 = AminoAcid3.UNK;
         }
         switch (AA3) {
             case ASD:
             case ASH:
             case ASP:
                 // Discr Bias & Derivs
                 double tautomerLambda = getTautomerLambda(residue);
                 discrBias = -4.0 * ASHtitrBiasMag * (titrationLambda - 0.5) * (titrationLambda - 0.5);
                 discrBias += -4.0 * ASHtautBiasMag * (tautomerLambda - 0.5) * (tautomerLambda - 0.5);
                 dDiscr_dTitr = -8.0 * ASHtitrBiasMag * (titrationLambda - 0.5);
                 dDiscr_dTaut = -8.0 * ASHtautBiasMag * (tautomerLambda - 0.5);
 
                 // pH Bias & Derivs
                 double pKa1 = TitrationUtils.Titration.ASHtoASP.pKa;
                 double pKa2 = pKa1;
                 pHBias = LOG10 * Constants.R * currentTemperature * (1.0 - titrationLambda)
                         * (tautomerLambda * (pKa1 - constantSystemPh) + (1.0 - tautomerLambda) * (pKa2 - constantSystemPh));
                 dPh_dTitr = LOG10 * Constants.R * currentTemperature * -1.0
                         * (tautomerLambda * (pKa1 - constantSystemPh) + (1.0 - tautomerLambda) * (pKa2 - constantSystemPh));
                 dPh_dTaut = LOG10 * Constants.R * currentTemperature * (1.0 - titrationLambda)
                         * ((pKa1 - constantSystemPh) - (pKa2 - constantSystemPh));
 
                 // pH restraint to add to pH Bias
                 double restraint = ASHrestraintConstant;
                 double pHSignedSquared = (pKa1 - constantSystemPh) * Math.abs(pKa1 - constantSystemPh);
                 // x*abs(x) is quadratic-like but sign is preserved
                 pHBias += restraint * (1.0 - titrationLambda) * pHSignedSquared;
                 dPh_dTitr += restraint * -1.0 * pHSignedSquared;
 
                 // Model Bias & Derivs
                 double coeffA0 = ASH1toASH2[3];
                 double coeffA1 = ASH1toASH2[2];
                 double coeffA2 = ASH1toASH2[1];
                 double coeffB0 = ASHFmod[3];
                 double coeffB1 = ASHFmod[2];
                 double coeffB2 = ASHFmod[1];
                 double coeffC0 = ASHFmod[3];
                 double coeffC1 = ASHFmod[2];
                 double coeffC2 = ASHFmod[1];
                 double tautomerLambdaSquared = tautomerLambda * tautomerLambda;
                 double tautomerLambdaCubed = tautomerLambdaSquared * tautomerLambda;
                 double oneMinusTitrationLambda = (1.0 - titrationLambda);
                 double oneMinusTautomerLambda = (1.0 - tautomerLambda);
                 double coeffBSum = coeffB0 + coeffB1 + coeffB2;
                 double coeffCSum = coeffC0 + coeffC1 + coeffC2;
                 modelBias = titrationLambda * (coeffA0 * tautomerLambdaCubed + coeffA1 * tautomerLambdaSquared + coeffA2 * tautomerLambda) +
                         tautomerLambda * (coeffB0 * titrationLambdaCubed + coeffB1 * titrationLambdaSquared + coeffB2 * titrationLambda) +
                         oneMinusTautomerLambda * (coeffC0 * titrationLambdaCubed + coeffC1 * titrationLambdaSquared + coeffC2 * titrationLambda) +
                         //Enforce that HIS(titration==1) state is equal energy no matter tautomer value
                         oneMinusTitrationLambda * (coeffCSum - coeffBSum) * tautomerLambda;
                 dMod_dTitr = (coeffA0 * tautomerLambdaCubed + coeffA1 * tautomerLambdaSquared + coeffA2 * tautomerLambda) +
                         tautomerLambda * (3.0 * coeffB0 * titrationLambdaSquared + 2.0 * coeffB1 * titrationLambda + coeffB2) +
                         oneMinusTautomerLambda * (3.0 * coeffC0 * titrationLambdaSquared + 2.0 * coeffC1 * titrationLambda + coeffC2) +
                         -tautomerLambda * (coeffCSum - coeffBSum);
                 dMod_dTaut = titrationLambda * (3.0 * coeffA0 * tautomerLambdaSquared + 2.0 * coeffA1 * tautomerLambda + coeffA2) +
                         (coeffB0 * titrationLambdaCubed + coeffB1 * titrationLambdaSquared + coeffB2 * titrationLambda) +
                         -1.0 * (coeffC0 * titrationLambdaCubed + coeffC1 * titrationLambdaSquared + coeffC2 * titrationLambda) +
                         oneMinusTautomerLambda * (coeffCSum - coeffBSum);
                 break;
             case GLD:
             case GLH:
             case GLU:
                 // Discr Bias & Derivs
                 tautomerLambda = getTautomerLambda(residue);
                 discrBias = -4.0 * GLHtitrBiasMag * (titrationLambda - 0.5) * (titrationLambda - 0.5);
                 discrBias += -4.0 * GLHtautBiasMag * (tautomerLambda - 0.5) * (tautomerLambda - 0.5);
                 dDiscr_dTitr = -8.0 * GLHtitrBiasMag * (titrationLambda - 0.5);
                 dDiscr_dTaut = -8.0 * GLHtautBiasMag * (tautomerLambda - 0.5);
 
                 // pH Bias & Derivs
                 pKa1 = TitrationUtils.Titration.GLHtoGLU.pKa;
                 pKa2 = pKa1;
                 pHBias = LOG10 * Constants.R * currentTemperature * (1.0 - titrationLambda)
                         * (tautomerLambda * (pKa1 - constantSystemPh) + (1.0 - tautomerLambda) * (pKa2 - constantSystemPh));
                 dPh_dTitr = LOG10 * Constants.R * currentTemperature * -1.0
                         * (tautomerLambda * (pKa1 - constantSystemPh) + (1.0 - tautomerLambda) * (pKa2 - constantSystemPh));
                 dPh_dTaut = LOG10 * Constants.R * currentTemperature * (1.0 - titrationLambda)
                         * ((pKa1 - constantSystemPh) - (pKa2 - constantSystemPh));
 
                 // pH restraint to add to pH Bias
                 restraint = GLHrestraintConstant;
                 pHSignedSquared = (pKa1 - constantSystemPh) * Math.abs(pKa1 - constantSystemPh);
                 // x*abs(x) is quadratic-like but sign is preserved
                 pHBias += restraint * (1.0 - titrationLambda) * pHSignedSquared;
                 dPh_dTitr += restraint * -1.0 * pHSignedSquared;
 
                 // Model Bias & Derivs
                 coeffA0 = GLH1toGLH2[3];
                 coeffA1 = GLH1toGLH2[2];
                 coeffA2 = GLH1toGLH2[1];
                 coeffB0 = GLHFmod[3];
                 coeffB1 = GLHFmod[2];
                 coeffB2 = GLHFmod[1];
                 coeffC0 = GLHFmod[3];
                 coeffC1 = GLHFmod[2];
                 coeffC2 = GLHFmod[1];
                 tautomerLambdaSquared = tautomerLambda * tautomerLambda;
                 tautomerLambdaCubed = tautomerLambdaSquared * tautomerLambda;
                 oneMinusTitrationLambda = (1.0 - titrationLambda);
                 oneMinusTautomerLambda = (1.0 - tautomerLambda);
                 coeffBSum = coeffB0 + coeffB1 + coeffB2;
                 coeffCSum = coeffC0 + coeffC1 + coeffC2;
                 modelBias = titrationLambda * (coeffA0 * tautomerLambdaCubed + coeffA1 * tautomerLambdaSquared + coeffA2 * tautomerLambda) +
                         tautomerLambda * (coeffB0 * titrationLambdaCubed + coeffB1 * titrationLambdaSquared + coeffB2 * titrationLambda) +
                         oneMinusTautomerLambda * (coeffC0 * titrationLambdaCubed + coeffC1 * titrationLambdaSquared + coeffC2 * titrationLambda) +
                         //Enforce that HIS(titration==1) state is equal energy no matter tautomer value
                         oneMinusTitrationLambda * (coeffCSum - coeffBSum) * tautomerLambda;
                 dMod_dTitr = (coeffA0 * tautomerLambdaCubed + coeffA1 * tautomerLambdaSquared + coeffA2 * tautomerLambda) +
                         tautomerLambda * (3.0 * coeffB0 * titrationLambdaSquared + 2.0 * coeffB1 * titrationLambda + coeffB2) +
                         oneMinusTautomerLambda * (3.0 * coeffC0 * titrationLambdaSquared + 2.0 * coeffC1 * titrationLambda + coeffC2) +
                         -tautomerLambda * (coeffCSum - coeffBSum);
                 dMod_dTaut = titrationLambda * (3.0 * coeffA0 * tautomerLambdaSquared + 2.0 * coeffA1 * tautomerLambda + coeffA2) +
                         (coeffB0 * titrationLambdaCubed + coeffB1 * titrationLambdaSquared + coeffB2 * titrationLambda) +
                         -1.0 * (coeffC0 * titrationLambdaCubed + coeffC1 * titrationLambdaSquared + coeffC2 * titrationLambda) +
                         oneMinusTautomerLambda * (coeffCSum - coeffBSum);
                 break;
             case HIS:
             case HID:
             case HIE:
                 // Discr Bias & Derivs
                 tautomerLambda = getTautomerLambda(residue);
 
                 discrBias = -4.0 * HIStitrBiasMag * (titrationLambda - 0.5) * (titrationLambda - 0.5);
                 discrBias += -4.0 * HIStautBiasMag * (tautomerLambda - 0.5) * (tautomerLambda - 0.5);
                 dDiscr_dTitr = -8.0 * HIStitrBiasMag * (titrationLambda - 0.5);
                 dDiscr_dTaut = -8.0 * HIStautBiasMag * (tautomerLambda - 0.5);
 
                 // pH Bias & Derivs
                 // At tautomerLambda=1 HIE is fully on.
                 pKa1 = TitrationUtils.Titration.HIStoHIE.pKa;
                 // At tautomerLambda=0 HID is fully on.
                 pKa2 = TitrationUtils.Titration.HIStoHID.pKa;
                 pHBias = LOG10 * Constants.R * currentTemperature * (1.0 - titrationLambda)
                         * (tautomerLambda * (pKa1 - constantSystemPh) + (1.0 - tautomerLambda) * (pKa2 - constantSystemPh));
                 dPh_dTitr = LOG10 * Constants.R * currentTemperature * -1.0
                         * (tautomerLambda * (pKa1 - constantSystemPh) + (1.0 - tautomerLambda) * (pKa2 - constantSystemPh));
                 dPh_dTaut = LOG10 * Constants.R * currentTemperature * (1.0 - titrationLambda)
                         * ((pKa1 - constantSystemPh) - (pKa2 - constantSystemPh));
 
                 // pH restraint to add to pH Bias
                 restraint = HISrestraintConstant;
                 double pH1SignedSquared = (pKa1 - constantSystemPh) * Math.abs(pKa1 - constantSystemPh);
                 double pH2SignedSquared = (pKa2 - constantSystemPh) * Math.abs(pKa2 - constantSystemPh);
                 // x*abs(x) is quadratic-like but sign is preserved
                 pHBias += restraint * (1.0 - titrationLambda)
                         * (tautomerLambda * pH1SignedSquared + (1.0 - tautomerLambda) * pH2SignedSquared);
                 dPh_dTitr += restraint * -1.0
                         * (tautomerLambda * pH1SignedSquared + (1.0 - tautomerLambda) * pH2SignedSquared);
                 dPh_dTaut += restraint * (1.0 - titrationLambda)
                         * (pH1SignedSquared - pH2SignedSquared);
                 // Model Bias & Derivs
 
                 coeffA0 = HIDtoHIEFmod[3];
                 coeffA1 = HIDtoHIEFmod[2];
                 coeffA2 = HIDtoHIEFmod[1];
                 coeffB0 = HIEFmod[3];
                 coeffB1 = HIEFmod[2];
                 coeffB2 = HIEFmod[1];
                 coeffC0 = HIDFmod[3];
                 coeffC1 = HIDFmod[2];
                 coeffC2 = HIDFmod[1];
                 tautomerLambdaSquared = tautomerLambda * tautomerLambda;
                 tautomerLambdaCubed = tautomerLambdaSquared * tautomerLambda;
                 oneMinusTitrationLambda = (1.0 - titrationLambda);
                 oneMinusTautomerLambda = (1.0 - tautomerLambda);
                 coeffBSum = coeffB0 + coeffB1 + coeffB2;
                 coeffCSum = coeffC0 + coeffC1 + coeffC2;
                 modelBias = oneMinusTitrationLambda * (coeffA0 * tautomerLambdaCubed + coeffA1 * tautomerLambdaSquared + coeffA2 * tautomerLambda) +
                         tautomerLambda * (coeffB0 * titrationLambdaCubed + coeffB1 * titrationLambdaSquared + coeffB2 * titrationLambda) +
                         oneMinusTautomerLambda * (coeffC0 * titrationLambdaCubed + coeffC1 * titrationLambdaSquared + coeffC2 * titrationLambda) +
                         //Enforce that HIS(titration==1) state is equal energy no matter tautomer value
                         titrationLambda * (coeffCSum - coeffBSum) * tautomerLambda;
                 dMod_dTitr = -(coeffA0 * tautomerLambdaCubed + coeffA1 * tautomerLambdaSquared + coeffA2 * tautomerLambda) +
                         tautomerLambda * (3.0 * coeffB0 * titrationLambdaSquared + 2.0 * coeffB1 * titrationLambda + coeffB2) +
                         oneMinusTautomerLambda * (3.0 * coeffC0 * titrationLambdaSquared + 2.0 * coeffC1 * titrationLambda + coeffC2) +
                         tautomerLambda * (coeffCSum - coeffBSum);
                 dMod_dTaut = oneMinusTitrationLambda * (3.0 * coeffA0 * tautomerLambdaSquared + 2.0 * coeffA1 * tautomerLambda + coeffA2) +
                         (coeffB0 * titrationLambdaCubed + coeffB1 * titrationLambdaSquared + coeffB2 * titrationLambda) +
                         -1.0 * (coeffC0 * titrationLambdaCubed + coeffC1 * titrationLambdaSquared + coeffC2 * titrationLambda) +
                         titrationLambda * (coeffCSum - coeffBSum);
 
                 break;
             case LYS:
             case LYD:
                 // Discr Bias & Derivs
                 discrBias = -4.0 * LYStitrBiasMag * (titrationLambda - 0.5) * (titrationLambda - 0.5);
                 dDiscr_dTitr = -8.0 * LYStitrBiasMag * (titrationLambda - 0.5);
                 dDiscr_dTaut = 0.0;
 
                 // pH Bias & Derivs
                 pKa1 = TitrationUtils.Titration.LYStoLYD.pKa;
                 pHBias = LOG10 * Constants.R * currentTemperature * (1.0 - titrationLambda) * (pKa1 - constantSystemPh);
                 dPh_dTitr = LOG10 * Constants.R * currentTemperature * -1.0 * (pKa1 - constantSystemPh);
                 dPh_dTaut = 0.0;
 
                 // pH restraint to add to pH Bias
                 restraint = LYSrestraintConstant;
                 pHSignedSquared = (pKa1 - constantSystemPh) * Math.abs(pKa1 - constantSystemPh);
                 // x*abs(x) is quadratic-like but sign is preserved
                 pHBias += restraint * (1.0 - titrationLambda) * pHSignedSquared;
                 dPh_dTitr += restraint * -1.0 * pHSignedSquared;
 
                 // Model Bias & Derivs
                 double cubic = LYSFmod[3];
                 double quadratic = LYSFmod[2];
                 double linear = LYSFmod[1];
                 modelBias = cubic * titrationLambdaCubed + quadratic * titrationLambdaSquared + linear * titrationLambda;
                 dMod_dTitr = 3 * cubic * titrationLambdaSquared + 2 * quadratic * titrationLambda + linear;
                 dMod_dTaut = 0.0;
                 break;
             case CYS:
             case CYD:
                 // Discr Bias & Derivs
                 discrBias = -4.0 * CYStitrBiasMag * (titrationLambda - 0.5) * (titrationLambda - 0.5);
                 dDiscr_dTitr = -8.0 * CYStitrBiasMag * (titrationLambda - 0.5);
                 dDiscr_dTaut = 0.0;
 
                 // pH Bias & Derivs
                 pKa1 = TitrationUtils.Titration.CYStoCYD.pKa;
                 pHBias = LOG10 * Constants.R * currentTemperature * (1.0 - titrationLambda) * (pKa1 - constantSystemPh);
                 dPh_dTitr = LOG10 * Constants.R * currentTemperature * -1.0 * (pKa1 - constantSystemPh);
                 dPh_dTaut = 0.0;
 
                 // pH restraint to add to pH Bias
                 restraint = CYSrestraintConstant;
                 pHSignedSquared = (pKa1 - constantSystemPh) * Math.abs(pKa1 - constantSystemPh);
                 // x*abs(x) is quadratic-like but sign is preserved
                 pHBias += restraint * (1.0 - titrationLambda) * pHSignedSquared;
                 dPh_dTitr += restraint * -1.0 * pHSignedSquared;
 
 
                 // Model Bias & Derivs
                 cubic = CYSFmod[3];
                 quadratic = CYSFmod[2];
                 linear = CYSFmod[1];
                 modelBias = cubic * titrationLambdaCubed + quadratic * titrationLambdaSquared + linear * titrationLambda;
                 dMod_dTitr = 3 * cubic * titrationLambdaSquared + 2 * quadratic * titrationLambda + linear;
                 dMod_dTaut = 0.0;
                 break;
             default:
                 discrBias = 0.0;
                 pHBias = 0.0;
                 modelBias = 0.0;
                 dDiscr_dTitr = 0.0;
                 dDiscr_dTaut = 0.0;
                 dPh_dTitr = 0.0;
                 dPh_dTaut = 0.0;
                 dMod_dTitr = 0.0;
                 dMod_dTaut = 0.0;
                 break;
         }
         biasEnergyAndDerivs[0] = discrBias;
         biasEnergyAndDerivs[1] = pHBias;
         biasEnergyAndDerivs[2] = -modelBias;
         biasEnergyAndDerivs[3] = dDiscr_dTitr;
         biasEnergyAndDerivs[4] = dPh_dTitr;
         biasEnergyAndDerivs[5] = -dMod_dTitr;
         biasEnergyAndDerivs[6] = dDiscr_dTaut;
         biasEnergyAndDerivs[7] = dPh_dTaut;
         biasEnergyAndDerivs[8] = -dMod_dTaut;
     }
 
     /**
      * Gets the titration lambda for the input residue if the residue is titrating
      *
      * @param residue a titrating residue
      * @return the titration lambda for the residue
      */
     public double getTitrationLambda(Residue residue) {
         if (titratingResidueList.contains(residue)) {
             int resIndex = titratingResidueList.indexOf(residue);
             return extendedLambdas[resIndex];
         } else {
             return 1.0;
         }
     }
 
     /**
      * Gets the tautomer lambda for the input residue if the residue is tautomerizing
      *
      * @param residue a tautomer residue
      * @return the tautomer lambda for the residue
      */
     public double getTautomerLambda(Residue residue) {
         if (tautomerizingResidueList.contains(residue)) {
             int resIndex = tautomerizingResidueList.indexOf(residue);
             return extendedLambdas[nTitr + resIndex];
         } else {
             return 1.0;
         }
     }
 
     /**
      * get total dUvdw/dL for the selected extended system variable
      */
     private double getVdwDeriv(int esvID) {
         return esvVdwDerivs[esvID].get();
     }
 
     /**
      * get total dUpermElec/dL for the selected extended system variable.
      */
     private double getPermElecDeriv(int esvID) {
         return esvPermElecDerivs[esvID].get();
     }
 
     /**
      * get total dUindElec/dL for the selected extended system variable
      */
     private double getIndElecDeriv(int esvID) {
         return esvIndElecDerivs[esvID].get();
     }
 
     /**
      * Returns the tautomerizibility of a residue
      */
     public boolean isTautomer(Residue residue) {
         if (residue.getResidueType() == Residue.ResidueType.NA) {
             return false;
         }
         AminoAcidUtils.AminoAcid3 AA3 = residue.getAminoAcid3();
         return AA3.isConstantPhTautomer;
     }
 
     /**
      * Update all theta (lambda) positions after each move from the Stochastic integrator
      */
     private void updateLambdas() {
         //If lockStates is true, then the titration and tautomer states are permanently locked.
         if (lockStates) {
             return;
         }
         double[] thetaPosition = esvState.x();
         //This will prevent recalculating multiple sinTheta*sinTheta that are the same number.
         for (int i = 0; i < nESVs; i++) {
             //Check to see if titration/tautomer lambdas are to be fixed
             if ((!fixTitrationState && i < nTitr) || (!fixTautomerState && i >= nTitr)) {
                 double sinTheta = Math.sin(thetaPosition[i]);
                 extendedLambdas[i] = sinTheta * sinTheta;
             }
         }
         for (int i = 0; i < nAtoms; i++) {
             int mappedTitrationIndex = titrationIndexMap[i];
             int mappedTautomerIndex = tautomerIndexMap[i] + nTitr;
             if (isTitrating(i) && mappedTitrationIndex != -1) {
                 titrationLambdas[i] = extendedLambdas[mappedTitrationIndex];
             }
             if (isTautomerizing(i) && mappedTautomerIndex >= nTitr) {
                 tautomerLambdas[i] = extendedLambdas[mappedTautomerIndex];
             }
         }
         setESVHistogram();
     }
 
     /**
      * Returns whether an atom is titrating
      */
     public boolean isTitrating(int atomIndex) {
         return isTitrating[atomIndex];
     }
 
     /**
      * Returns whether an atom is tautomerizing
      */
     public boolean isTautomerizing(int atomIndex) {
         return isTautomerizing[atomIndex];
     }
 
     /**
      * Goes through residues updates the ESV histogram based on the residues current state
      */
     private void setESVHistogram() {
         for (Residue residue : titratingResidueList) {
             int index = titratingResidueList.indexOf(residue);
             if (residue.getAminoAcid3().equals(AminoAcid3.LYS)) { // TODO: Add support for CYS? by adding "|| residue.getAminoAcid3().equals(AminoAcid3.CYS))"
                 double titrLambda = getTitrationLambda(residue);
                 esvHistogram(index, titrLambda);
             } else {
                 double titrLambda = getTitrationLambda(residue);
                 double tautLambda = getTautomerLambda(residue);
                 esvHistogram(index, titrLambda, tautLambda);
             }
         }
     }
 
     /**
      * Updates the ESV histogram of the passed residue at the given lambda
      *
      * @param esv    the index of the esv to be updated
      * @param lambda the lambda value to be updated
      */
     private void esvHistogram(int esv, double lambda) {
         int value = (int) (lambda * 10.0);
         //Cover the case where lambda could be exactly 1.0
         if (value == 10) {
             value = 9;
         }
         esvHistogram[esv][value][0]++;
     }
 
     /**
      * Updates the ESV histogram of the passed residue at the given titr and taut state
      *
      * @param esv        the index of the esv to be updated
      * @param titrLambda the titration lambda coordinate to be updated
      * @param tautLambda the tautomer lambda coordinate to be updated
      */
     private void esvHistogram(int esv, double titrLambda, double tautLambda) {
         int titrValue = (int) (titrLambda * 10.0);
         //Cover the case where lambda could be exactly 1.0
         if (titrValue == 10) {
             titrValue = 9;
         }
         int tautValue = (int) (tautLambda * 10.0);
         if (tautValue == 10) {
             tautValue = 9;
         }
         esvHistogram[esv][titrValue][tautValue]++;
     }
 
     /**
      * Naive guess as to what the best starting state should be based purely on the acidostat term.
      */
     private double initialTitrationState(Residue residue, double initialLambda, boolean guessTitrState) {
         AminoAcid3 AA3 = residue.getAminoAcid3();
         double residueNumber = residue.getResidueNumber();
         double initialTitrationLambda = 0.0;
         if (specialResidues.contains(residueNumber)) { // If we set a special residue for this state
             if (!specialResiduePKAs.isEmpty()) {
                 initialTitrationLambda =
                         (constantSystemPh < specialResiduePKAs.get(specialResidues.indexOf(residueNumber))) ? 1.0 : 0.0;
             }
             if (!specialInitTitration.isEmpty()) { // Override the pKa value if we have a special initial titration state
                 double value = specialInitTitration.get(specialResidues.indexOf(residueNumber));
                 if (Math.abs(value + 1) > 1e-4) { // If the value is not -1
                     initialTitrationLambda = value;
                 }
             }
         } else if (!guessTitrState) { // If we do not want to guess the titration state but instead use the value
             // passed in via the initialLambda parameter.
             initialTitrationLambda = initialLambda;
         } else { // Guess titration state
             initialTitrationLambda = switch (AA3) {
                 case ASD -> (constantSystemPh < TitrationUtils.Titration.ASHtoASP.pKa) ? 1.0 : 0.0;
                 case GLD -> (constantSystemPh < TitrationUtils.Titration.GLHtoGLU.pKa) ? 1.0 : 0.0;
                 case HIS -> (constantSystemPh < TitrationUtils.Titration.HIStoHID.pKa) ? 1.0 : 0.0;
                 case LYS -> (constantSystemPh < TitrationUtils.Titration.LYStoLYD.pKa) ? 1.0 : 0.0;
                 case CYS -> (constantSystemPh < TitrationUtils.Titration.CYStoCYD.pKa) ? 1.0 : 0.0;
                 default -> initialLambda;
             };
         }
         return initialTitrationLambda;
     }
 
     /**
      * Questions whether the current non-hydrogen atom's polarizability is changing in response to lambda being updated.
      * Only affects carboxylic oxygen and sulfur.
      *
      * @param atomIndex
      * @return
      */
     public boolean isTitratingHeavy(int atomIndex) {
         return isTitratingHeavy[atomIndex];
     }
 
     // Getter for specialResidues
     public ArrayList<Double> getSpecialResidueList() {
         return specialResidues;
     }
 
     /**
      * Does not allow for changes to the tautomer states of tautomerizing residues
      */
     public void setFixedTautomerState(boolean fixTautomerState) {
         this.fixTautomerState = fixTautomerState;
     }
 
     /**
      * Does not allow for changes to the tautomer states of titrating residues
      */
     public void setFixedTitrationState(boolean fixTitrationState) {
         this.fixTitrationState = fixTitrationState;
     }
 
     /**
      * Reset initialized lambdas to a naive guess based on the model pKa for each extended residue
      */
     public void reGuessLambdas() {
         logger.info(" Reinitializing lambdas to match RepEx window pH");
         for (Residue residue : titratingResidueList) {
             double lambda = initialTitrationState(residue, 1.0, guessTitrState);
             setTitrationLambda(residue, lambda);
             double resNum = residue.getResidueNumber();
             double tautomerLambda = specialResidues.contains(resNum) && !specialInitTautomer.isEmpty() &&
                     Math.abs(specialInitTitration.get(specialResidues.indexOf(resNum)) + 1) > 1e-4
                     ? specialInitTitration.get(specialResidues.indexOf(resNum)) : (int) Math.round(random());
             setTautomerLambda(residue, tautomerLambda);
         }
     }
 
     /**
      * Set the tautomer lambda of a residue and update corresponding theta
      *
      * @param residue
      * @param lambda
      */
     public void setTautomerLambda(Residue residue, double lambda) {
         setTautomerLambda(residue, lambda, true);
     }
 
     /**
      * Set the tautomer lambda of a residue and update corresponding theta if desired
      *
      * @param residue      residue to set the lambda of
      * @param lambda       value to set the residue to
      * @param changeThetas whether to change the theta positions ~comes with information loss~
      */
     public void setTautomerLambda(Residue residue, double lambda, boolean changeThetas) {
         double[] thetaPosition = esvState.x();
         if (tautomerizingResidueList.contains(residue) && !lockStates) {
             // The correct index in the theta arrays for tautomer coordinates is after the titration list.
             // So titrationList.size() + tautomerIndex should match with appropriate spot in thetaPosition, etc.
             int index = tautomerizingResidueList.indexOf(residue) + nTitr;
             extendedLambdas[index] = lambda;
             if (changeThetas) {
                 thetaPosition[index] = Math.asin(Math.sqrt(lambda));
             }
             List<Atom> currentAtomList = residue.getSideChainAtoms();
             for (Atom atom : currentAtomList) {
                 int atomIndex = atom.getArrayIndex();
                 tautomerLambdas[atomIndex] = lambda;
             }
         } /*else {
             logger.warning(format("This residue %s does not have any titrating tautomers.", residue.getName()));
         }*/
     }
 
     /**
      * Set the titration lambda of a residue and update corresponding theta
      *
      * @param residue residue to set the lambda of
      * @param lambda  value to set the residue to
      */
     public void setTitrationLambda(Residue residue, double lambda) {
         setTitrationLambda(residue, lambda, true);
     }
 
     /**
      * Set the titration lambda of a residue and update corresponding theta if desired
      *
      * @param residue      residue to set the lambda of
      * @param lambda       value to set the residue to
      * @param changeThetas whether to change the theta positions ~comes with information loss~
      */
     public void setTitrationLambda(Residue residue, double lambda, boolean changeThetas) {
         double[] thetaPosition = esvState.x();
         if (titratingResidueList.contains(residue) && !lockStates) {
             int index = titratingResidueList.indexOf(residue);
             extendedLambdas[index] = lambda;
             if (changeThetas) {
                 thetaPosition[index] = Math.asin(Math.sqrt(lambda));
             }
             List<Atom> currentAtomList = residue.getSideChainAtoms();
             for (Atom atom : currentAtomList) {
                 int atomIndex = atom.getArrayIndex();
                 titrationLambdas[atomIndex] = lambda;
             }
         }
     }
 
     /**
      * Overwrites the histogram passed into it and returns the new one out ~output never used?~
      *
      * @param histogram 2D histogram list with the tautomer and titration states compressed to a 1D array
      * @return another compressed histogram
      */
     public int[][] getESVHistogram(int[][] histogram) {
         for (int i = 0; i < titratingResidueList.size(); i++) {
             int h = 0;
             for (int j = 0; j < 10; j++) {
                 for (int k = 0; k < 10; k++) {
                     histogram[i][h++] = esvHistogram[i][j][k];
                 }
             }
         }
         return histogram;
     }
 
     /**
      * Changes this ESV's histogram to equal the one passed
      *
      * @param histogram histogram to set this ESV histogram to
      */
     public void copyESVHistogramTo(int[][] histogram) {
         for (int i = 0; i < titratingResidueList.size(); i++) {
             int h = 0;
             for (int j = 0; j < 10; j++) {
                 for (int k = 0; k < 10; k++) {
                     esvHistogram[i][j][k] = histogram[i][h++];
                 }
             }
         }
     }
 
     /**
      * Zero out each array element of the vdW ESV array
      */
     public void initEsvVdw() {
         for (int i = 0; i < nESVs; i++) {
             esvVdwDerivs[i].set(0.0);
         }
     }
 
     /**
      * Zero out each array element of the permElec ESV array
      */
     public void initEsvPermElec() {
         for (int i = 0; i < nESVs; i++) {
             esvPermElecDerivs[i].set(0.0);
         }
     }
 
     /**
      * Zero out each array element of the indElec ESV array
      */
     public void initEsvIndElec() {
         for (int i = 0; i < nESVs; i++) {
             esvIndElecDerivs[i].set(0.0);
         }
     }
 
     /**
      * get Titration Lambda for an extended atom
      *
      * @param atomIndex
      * @return titrationLambdas[atomIndex]
      */
     public double getTitrationLambda(int atomIndex) {
         return titrationLambdas[atomIndex];
     }
 
     /**
      * get the index of the extended residue list that corresponds to this atom
      *
      * @param i
      * @return titrationIndexMap[i]
      */
     public int getTitrationESVIndex(int i) {
         return titrationIndexMap[i];
     }
 
     /**
      * get Tautomer Lambda for an extended atom
      *
      * @param atomIndex
      * @return tautomerLambdas[atomIndex]
      */
     public double getTautomerLambda(int atomIndex) {
         return tautomerLambdas[atomIndex];
     }
 
     public int getTautomerESVIndex(int i) {
         return tautomerIndexMap[i];
     }
 
     /**
      * Return the List of Titrating Residues
      *
      * @return titratingResidueList
      */
     public List<Residue> getTitratingResidueList() {
         return titratingResidueList;
     }
 
     /**
      * Return the List of Tautomerizing Residues
      *
      * @return tautomerizingResidueList
      */
     public List<Residue> getTautomerizingResidueList() {
         return tautomerizingResidueList;
     }
 
     /**
      * Return the List of Extended Residues which = TitratingResidueList + TautomerizingResidueList
      *
      * @return extendedResidueList
      */
     public List<Residue> getExtendedResidueList() {
         return extendedResidueList;
     }
 
     public double getThetaMass() {
         return thetaMass;
     }
 
     public double getThetaFriction() {
         return thetaFriction;
     }
 
     /**
      * Gets a copy of the array of doubles that matches the nESVs correspoding to each titration and tautomer lambda
      *
      * @return double array of length nESVs
      */
     public double[] getExtendedLambdas() {
         double[] lambdas = new double[nESVs];
         System.arraycopy(extendedLambdas, 0, lambdas, 0, lambdas.length);
         return lambdas;
     }
 
     /**
      * getLambdaList.
      *
      * @return a {@link String} object.
      */
     public String getLambdaList() {
         if (nESVs < 1) {
             return "";
         }
         StringBuilder sb = new StringBuilder();
         for (int i = 0; i < nESVs; i++) {
             if (i == 0) {
                 sb.append("\n  Titration Lambdas: ");
             }
             if (i > 0) {
                 sb.append(", ");
             }
             if (i == nTitr) {
                 sb.append("\n  Tautomer Lambdas: ");
             }
             sb.append(format("%6.4f", extendedLambdas[i]));
         }
         return sb.toString();
     }
 
     /**
      * All atoms of the fully-protonated system (not just those affected by this system).
      *
      * @return an array of {@link Atom} objects.
      */
     public Atom[] getExtendedAtoms() {
         return extendedAtoms;
     }
 
     /**
      * Companion to getExtendedAtoms() for vdw::setAtoms and pme::setAtoms.
      *
      * @return the molecule ID for each extended atom.
      */
     public int[] getExtendedMolecule() {
         return extendedMolecules;
     }
 
     /**
      * Sum up total bias (Ubias = UpH + Udiscr - Umod)
      *
      * @return totalBiasEnergy
      */
     public double getBiasEnergy() {
         double totalBiasEnergy = 0.0;
         double[] biasEnergyComponents = new double[9];
         //Do not double count residues in tautomer list.
         for (Residue residue : titratingResidueList) {
             getBiasTerms(residue, biasEnergyComponents);
             double biasEnergy = biasEnergyComponents[discrBiasIndex] + biasEnergyComponents[pHBiasIndex] + biasEnergyComponents[modelBiasIndex];
             totalBiasEnergy += biasEnergy;
         }
         return totalBiasEnergy;
     }
 
     /**
      * getBiasDecomposition.
      *
      * @return a {@link String} object.
      */
     public String getBiasDecomposition() {
         double discrBias = 0.0;
         double phBias = 0.0;
         double modelBias = 0.0;
         double[] biasEnergyAndDerivs = new double[9];
         for (Residue residue : titratingResidueList) {
             getBiasTerms(residue, biasEnergyAndDerivs);
             discrBias += biasEnergyAndDerivs[discrBiasIndex];
             phBias += biasEnergyAndDerivs[pHBiasIndex];
             //Reminder: Ubias = UpH + Udiscr - Umod but the Umod terms already have their sign reversed
             modelBias += biasEnergyAndDerivs[modelBiasIndex];
         }
         return format("    %-16s %16.8f\n", "Discretizer", discrBias)
                 + format("    %-16s %16.8f\n", "Acidostat", phBias)
                 + format("    %-16s %16.8f\n", "Fmod", modelBias);
     }
 
     /**
      * Calculate prefactor for scaling the van der Waals based on titration/tautomer state if titrating proton
      */
     public void getVdwPrefactor(int atomIndex, double[] vdwPrefactorAndDerivs) {
         double prefactor = 1.0;
         double titrationDeriv = 0.0;
         double tautomerDeriv = 0.0;
         if (!isTitratingHydrogen(atomIndex) || !doVDW) {
             vdwPrefactorAndDerivs[0] = prefactor;
             vdwPrefactorAndDerivs[1] = titrationDeriv;
             vdwPrefactorAndDerivs[2] = tautomerDeriv;
             return;
         }
         AminoAcid3 AA3 = residueNames[atomIndex];
         switch (AA3) {
             case ASD:
             case GLD:
                 if (tautomerDirections[atomIndex] == 1) {
                     prefactor = titrationLambdas[atomIndex] * tautomerLambdas[atomIndex];
                     titrationDeriv = tautomerLambdas[atomIndex];
                     tautomerDeriv = titrationLambdas[atomIndex];
                 } else if (tautomerDirections[atomIndex] == -1) {
                     prefactor = titrationLambdas[atomIndex] * (1.0 - tautomerLambdas[atomIndex]);
                     titrationDeriv = (1.0 - tautomerLambdas[atomIndex]);
                     tautomerDeriv = -titrationLambdas[atomIndex];
                 }
                 break;
             case HIS:
                 if (tautomerDirections[atomIndex] == 1) {
                     prefactor = (1.0 - titrationLambdas[atomIndex]) * tautomerLambdas[atomIndex] + titrationLambdas[atomIndex];
                     titrationDeriv = -tautomerLambdas[atomIndex] + 1.0;
                     tautomerDeriv = (1 - titrationLambdas[atomIndex]);
                 } else if (tautomerDirections[atomIndex] == -1) {
                     prefactor = (1.0 - titrationLambdas[atomIndex]) * (1.0 - tautomerLambdas[atomIndex]) + titrationLambdas[atomIndex];
                     titrationDeriv = tautomerLambdas[atomIndex];
                     tautomerDeriv = -(1.0 - titrationLambdas[atomIndex]);
                 }
                 break;
             case LYS:
             case CYS:
                 prefactor = titrationLambdas[atomIndex];
                 titrationDeriv = 1.0;
                 tautomerDeriv = 0.0;
                 break;
         }
         vdwPrefactorAndDerivs[0] = prefactor;
         vdwPrefactorAndDerivs[1] = titrationDeriv;
         vdwPrefactorAndDerivs[2] = tautomerDeriv;
     }
 
     /**
      * Questions whether the current hydrogen's polarizability is changing in response to lambda being updated.
      *
      * @param atomIndex
      * @return
      */
     public boolean isTitratingHydrogen(int atomIndex) {
         return isTitratingHydrogen[atomIndex];
     }
 
     /**
      * Add van der Waals deriv to appropriate dU/dL term given the atom index and its contributions.
      *
      * @param atomI
      * @param vdwEnergy
      * @param vdwPrefactorAndDerivI
      * @param vdwPrefactorJ
      */
     public void addVdwDeriv(int atomI, double vdwEnergy, double[] vdwPrefactorAndDerivI, double vdwPrefactorJ) {
         if (!isTitratingHydrogen(atomI)) {
             return;
         }
 
         //Sum up dU/dL for titration ESV if atom i is titrating hydrogen
         //Sum up dU/dL for tautomer ESV if atom i is titrating hydrogen
         int titrationEsvIndex = titrationIndexMap[atomI];
         int tautomerEsvIndex = tautomerIndexMap[atomI] + nTitr;// tautomerIndexMap[atomI] = -1 for non tautomerizing residues
         double dTitr_dLambda;
         double dTaut_dLambda;
 
         dTitr_dLambda = vdwPrefactorAndDerivI[1] * vdwPrefactorJ * vdwEnergy;
         dTaut_dLambda = vdwPrefactorAndDerivI[2] * vdwPrefactorJ * vdwEnergy;
 
         esvVdwDerivs[titrationEsvIndex].addAndGet(dTitr_dLambda);
         if (tautomerEsvIndex >= nTitr) {
             esvVdwDerivs[tautomerEsvIndex].addAndGet(dTaut_dLambda);
         }
     }
 
     /**
      * Add Perm Elec deriv to appropriate dU/dL term given the atom index and its contributions.
      *
      * @param atomI
      * @param titrationEnergy
      * @param tautomerEnergy
      */
     public void addPermElecDeriv(int atomI, double titrationEnergy, double tautomerEnergy) {
         int titrationEsvIndex = titrationIndexMap[atomI];
         int tautomerEsvIndex = tautomerIndexMap[atomI] + nTitr;// tautomerIndexMap[atomI] = -1 for non tautomerizing residues
         esvPermElecDerivs[titrationEsvIndex].addAndGet(titrationEnergy);
         if (tautomerEsvIndex >= nTitr) {
             esvPermElecDerivs[tautomerEsvIndex].addAndGet(tautomerEnergy);
         }
     }
 
     /**
      * Add Induced Elec deriv to appropriate dU/dL term given the atom index and its contributions.
      *
      * @param atomI
      * @param titrationEnergy
      * @param tautomerEnergy
      */
     public void addIndElecDeriv(int atomI, double titrationEnergy, double tautomerEnergy) {
         int titrationEsvIndex = titrationIndexMap[atomI];
         int tautomerEsvIndex = tautomerIndexMap[atomI] + nTitr; // tautomerIndexMap[atomI] = -1 for non tautomerizing residues
         esvIndElecDerivs[titrationEsvIndex].addAndGet(titrationEnergy);
         if (tautomerEsvIndex >= nTitr) {
             esvIndElecDerivs[tautomerEsvIndex].addAndGet(tautomerEnergy);
         }
     }
 
     /**
      * getConstantPh.
      *
      * @return a double.
      */
     public double getConstantPh() {
         return constantSystemPh;
     }
 
     /**
      * setConstantPh.
      *
      * @param pH a double.
      */
     public void setConstantPh(double pH) {
         constantSystemPh = pH;
     }
 
     /**
      * @return titrationUtils master copy from ExtendedSystem.
      */
     public TitrationUtils getTitrationUtils() {
         return titrationUtils;
     }
 
     /**
      * Sets the restartFile field of this extended system to the passed file. This does not read the file, it only
      * determines where the writeRestartFile() will write to.
      *
      * @param esvFile
      */
     public void setRestartFile(File esvFile) {
         restartFile = esvFile;
     }
 
     /**
      * Writes out the current state of the extended system to the specified file without setting the file to that location.
      *
      * @param esvFile file to be written to
      * @return whether the read was successful or not
      */
     public boolean writeESVInfoTo(File esvFile) {
         logger.info("Writing pH Dynamics out to: " + esvFile.getParentFile().getName() + File.separator + esvFile.getName());
         double[] thetaPosition = esvState.x();
         double[] thetaVelocity = esvState.v();
         double[] thetaAccel = esvState.a();
         return esvFilter.writeESV(esvFile, thetaPosition, thetaVelocity, thetaAccel, titratingResidueList, esvHistogram, constantSystemPh);
     }
 
     /**
      * Method overwrites whatever is in the extended system at the time with the read data.
      * <p>
      * CAUTION: If the old data is not written out to file before this is called, the data will be lost.
      *
      * @param esvFile esvFile to read
      * @return whether the read was successful or not
      */
     public boolean readESVInfoFrom(File esvFile) {
         double[] thetaPosition = esvState.x();
         double[] thetaVelocity = esvState.v();
         double[] thetaAccel = esvState.a();
         return esvFilter.readESV(esvFile, thetaPosition, thetaVelocity, thetaAccel, esvHistogram);
     }
 
     /**
      * setTemperature.
      *
      * @param set a double.
      */
     public void setTemperature(double set) {
         currentTemperature = set;
     }
 
     /**
      * Processes lambda values based on propagation of theta value from Stochastic integrator in Molecular dynamics
      */
     public void preForce() {
         updateLambdas();
     }
 
     /**
      * Execute writeESV from esvFilter that is contained within ExtendedSystem
      */
     public void writeRestart() {
         String esvName = FileUtils.relativePathTo(restartFile).toString();
         double[] thetaPosition = esvState.x();
         double[] thetaVelocity = esvState.v();
         double[] thetaAccel = esvState.a();
         if (esvFilter.writeESV(restartFile, thetaPosition, thetaVelocity, thetaAccel, titratingResidueList, esvHistogram, constantSystemPh)) {
             logger.info(" Wrote PhDynamics restart file to " + esvName);
         } else {
             logger.info(" Writing PhDynamics restart file to " + esvName + " failed");
         }
     }
 
     /**
      * Execute writeLambdaHistogrm from esvFilter that is contained within ExtendedSystem
      * Prints the ESV histogram for each titrating residue
      */
     public void writeLambdaHistogram(boolean printHistograms) {
         printProtonationRatios();
         if (printHistograms) {
             logger.info(esvFilter.getLambdaHistogram(titratingResidueList, esvHistogram, constantSystemPh));
         }
     }
 
     /**
      * Calculate the Deprotonation Fraction from the ESV histogram
      */
     public void printProtonationRatios() {
         for (int i = 0; i < esvHistogram.length; i++) {
             int[] rowSums = new int[esvHistogram[i].length];
             for (int j = 0; j < esvHistogram[i].length; j++) {
                 for (int k = 0; k < esvHistogram[i][j].length; k++) {
                     rowSums[j] += esvHistogram[i][j][k];
                 }
             }
             int i1 = rowSums[0] + rowSums[rowSums.length - 1];
             double buf = i1 == 0 ? 0.0 : .001;
             logger.info(" " + extendedResidueList.get(i).toString() + " Deprotonation Fraction at pH " + constantSystemPh + ": " + (rowSums[0] / (i1 + buf)));
             if (buf == 0.0) {
                 logger.info(" Buffer required to avoid division by 0");
             }
         }
     }
 
     @Override
     public double[] getAcceleration(double[] acceleration) {
         return getThetaAccel();
     }
 
     public double[] getThetaAccel() {
         return esvState.a();
     }
 
     @Override
     public double energyAndGradient(double[] x, double[] g) {
         double[] thetaPosition = esvState.x();
         System.arraycopy(x, 0, thetaPosition, 0, thetaPosition.length);
         updateLambdas();
         fillESVgradient(g);
         return energy(x);
     }
 
     @Override
     public List<Constraint> getConstraints() {
         return constraints.isEmpty() ? Collections.emptyList() : new ArrayList<>(constraints);
     }
 
     @Override
     public STATE getEnergyTermState() {
         return null;
     }
 
     private double[] fillESVgradient(double[] g) {
         double[] gradESV = postForce();
         System.arraycopy(gradESV, 0, g, 0, g.length);
         return g;
     }
 
     @Override
     public void setEnergyTermState(STATE state) {
 
     }
 
     @Override
     public double[] getMass() {
         return getThetaMassArray();
     }
 
     /**
      * Applies a chain rule term to the derivative to account for taking a derivative of lambda = sin(theta)^2
      *
      * @return dE/dL a double[]
      */
     public double[] postForce() {
         double[] thetaPosition = esvState.x();
         double[] dEdL = ExtendedSystem.this.getDerivatives();
         double[] dEdTheta = new double[dEdL.length];
         for (int i = 0; i < nESVs; i++) {
             dEdTheta[i] = dEdL[i] * sin(2 * thetaPosition[i]);
             //logger.info("dEdL["+i+"]: "+dEdL[i]);
         }
         return dEdTheta;
     }
 
     public double[] getThetaMassArray() {
         return esvState.getMass();
     }
 
     @Override
     public double[] getPreviousAcceleration(double[] previousAcceleration) {
         return new double[0];
     }
     @Override
     public double energy(double[] x) {
         double[] coords = new double[forceFieldEnergy.getNumberOfVariables()];
         forceFieldEnergy.getCoordinates(coords);
         return forceFieldEnergy.energy(coords);
     }
 
     @Override
     public VARIABLE_TYPE[] getVariableTypes() {
         return new VARIABLE_TYPE[0];
     }
 
     @Override
     public double[] getVelocity(double[] velocity) {
         return getThetaVelocity();
     }
 
     public double[] getThetaVelocity() {
         return esvState.v();
     }
 
     @Override
     public void setAcceleration(double[] acceleration) {
     }
 
     @Override
     public double[] getCoordinates(double[] parameters) {
         return getThetaPosition();
     }
 
   @Override
   public void setCoordinates(double[] parameters) {
     throw new UnsupportedOperationException("Not supported yet.");
   }
 
     @Override
     public void setPreviousAcceleration(double[] previousAcceleration) {
 
     }
 
     @Override
     public void setVelocity(double[] velocity) {
 
     }
 
     public SystemState getState() {
         return esvState;
     }
 
     public double[] getThetaPosition() {
         return esvState.x();
     }
 
     @Override
     public int getNumberOfVariables() {
         return nESVs;
     }
 
     @Override
     public double[] getScaling() {
         double[] scaling = new double[nESVs];
         Arrays.fill(scaling, 1.0);
         return scaling;
     }
 
     @Override
     public void setScaling(double[] scaling) {
 
     }
 
     @Override
     public double getTotalEnergy() {
         return 0;
     }
 
 }