// ******************************************************************************
   //
   // Title:       Force Field X.
   // Description: Force Field X - Software for Molecular Biophysics.
   // Copyright:   Copyright (c) Michael J. Schnieders 2001-2024.
   //
   // 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.parameters;
  
  import ffx.numerics.Potential;
  import ffx.numerics.optimization.LBFGS;
  import ffx.numerics.optimization.LineSearch;
  import ffx.numerics.optimization.OptimizationListener;
  import ffx.potential.bonded.AminoAcidUtils.AminoAcid3;
  import ffx.potential.bonded.Angle;
  import ffx.potential.bonded.AngleTorsion;
  import ffx.potential.bonded.Atom;
  import ffx.potential.bonded.Bond;
  import ffx.potential.bonded.ImproperTorsion;
  import ffx.potential.bonded.OutOfPlaneBend;
  import ffx.potential.bonded.PiOrbitalTorsion;
  import ffx.potential.bonded.Residue;
  import ffx.potential.bonded.Rotamer;
  import ffx.potential.bonded.StretchBend;
  import ffx.potential.bonded.StretchTorsion;
  import ffx.potential.bonded.Torsion;
  import ffx.potential.bonded.TorsionTorsion;
  import ffx.potential.bonded.UreyBradley;
  import ffx.potential.parameters.MultipoleType.MultipoleFrameDefinition;
  import ffx.potential.parameters.SoluteType.SOLUTE_RADII_TYPE;
  import ffx.utilities.Constants;
  
  import java.util.Arrays;
  import java.util.HashMap;
  import java.util.List;
  import java.util.logging.Level;
  import java.util.logging.Logger;
  
  import static ffx.potential.bonded.AminoAcidUtils.AA_CB;
  import static ffx.potential.bonded.AminoAcidUtils.AminoAcid3.ASH;
  import static ffx.potential.bonded.AminoAcidUtils.AminoAcid3.ASP;
  import static ffx.potential.bonded.AminoAcidUtils.AminoAcid3.CYD;
  import static ffx.potential.bonded.AminoAcidUtils.AminoAcid3.CYS;
  import static ffx.potential.bonded.AminoAcidUtils.AminoAcid3.GLH;
  import static ffx.potential.bonded.AminoAcidUtils.AminoAcid3.GLU;
  import static ffx.potential.bonded.AminoAcidUtils.AminoAcid3.HID;
  import static ffx.potential.bonded.AminoAcidUtils.AminoAcid3.HIE;
  import static ffx.potential.bonded.AminoAcidUtils.AminoAcid3.HIS;
  import static ffx.potential.bonded.AminoAcidUtils.AminoAcid3.LYD;
  import static ffx.potential.bonded.AminoAcidUtils.AminoAcid3.LYS;
  import static ffx.potential.bonded.BondedUtils.findAtomType;
  import static ffx.potential.parameters.MultipoleType.assignAxisAtoms;
  import static java.lang.String.format;
  import static org.apache.commons.math3.util.FastMath.log;
  
  /**
   * Utilities for interpolating between Amino Acid protonation and tautomer states.
   *
   * @author Michael Schnieders
   * @author Andrew Thiel
   * @since 1.0
   */
  public class TitrationUtils {
  
    private static final Logger logger = Logger.getLogger(TitrationUtils.class.getName());
  
    private static final double LOG10 = log(10.0);
  
    private static final MultipoleType aspZeroMultipoleType = new MultipoleType(MultipoleType.zeroM,
       new int[] {0, 140, 139}, MultipoleFrameDefinition.ZTHENX, false);
   private static final MultipoleType ashZeroMultipoleType = new MultipoleType(MultipoleType.zeroM,
       new int[] {0, 144, 143}, MultipoleFrameDefinition.ZTHENX, false);
 
   private static final MultipoleType gluZeroMultipoleType = new MultipoleType(MultipoleType.zeroM,
       new int[] {0, 158, 157}, MultipoleFrameDefinition.ZTHENX, false);
   private static final MultipoleType glhZeroMultipoleType = new MultipoleType(MultipoleType.zeroM,
       new int[] {0, 164, 163}, MultipoleFrameDefinition.ZTHENX, false);
 
   private static final MultipoleType hieZeroMultipoleType = new MultipoleType(MultipoleType.zeroM,
       new int[] {0, 130, 129}, MultipoleFrameDefinition.ZTHENX, false);
   private static final MultipoleType hidZeroMultipoleType = new MultipoleType(MultipoleType.zeroM,
       new int[] {0, 126, 124}, MultipoleFrameDefinition.ZTHENX, false);
 
   private static final MultipoleType lydZeroMultipoleType = new MultipoleType(MultipoleType.zeroM,
       new int[] {0, 200, 198}, MultipoleFrameDefinition.ZTHENX, false);
 
   private static final MultipoleType cydZeroMultipoleType = new MultipoleType(MultipoleType.zeroM,
       new int[] {0, 49, 43}, MultipoleFrameDefinition.ZTHENX, false);
 
   private static final PolarizeType zeroPolarizeType = new PolarizeType(0, 0.0, 0.39, 0.0,
       new int[] {0});
 
   private static final SoluteType zeroSoluteType = new SoluteType(0, 1.0);
 
   private static final AtomType dummyHydrogenAtomType = new AtomType(0, 0, "H", "\"Dummy Hydrogen\"",
       1, 1.0080, 1);
 
   private static final BondType zeroBondType = new BondType(new int[] {0, 0}, 0.0, 1.0);
   private static final AngleType zeroAngleType = new AngleType(new int[] {0, 0, 0}, 0.0,
       new double[] {0.0});
   private static final StretchBendType zeroStretchBendType = new StretchBendType(new int[] {0, 0, 0},
       new double[] {0.0, 0.0});
   private static final OutOfPlaneBendType zeroOutOfPlaneBendType = new OutOfPlaneBendType(
       new int[] {0, 0, 0, 0}, 0.0);
   private static final TorsionType zeroTorsionType = new TorsionType(new int[] {0, 0, 0, 0},
       new double[] {0.0}, new double[] {0.0}, new int[] {0});
   private static final PiOrbitalTorsionType zeroPiOrbitalTorsionType = new PiOrbitalTorsionType(
       new int[] {0, 0}, 0.0);
 
   private double proteinDielectric;
   private boolean tanhCorrection = false;
 
   enum AspStates {
     ASP, ASH1, ASH2
   }
 
   /** Constant <code>AspartateAtomNames</code> */
   private enum AspartateAtomNames {
     CB(0, 0, 0, 0), HB2(1, 1, 1, 0), HB3(1, 1, 1, 0), CG(2, 2, 2, 0), OD1(3, 4, 3, 0), OD2(3, 3, 4,
         0), HD1(-1, 5, -1, 1), HD2(-1, -1, 5, -1);
 
     /**
      * Biotype offset relative to the CB biotype for charged aspartate (ASP).
      */
     private final int offsetASP;
 
     /**
      * Biotype offset relative to the CB biotype for neutral aspartic acid protonated on OD1 (ASH1).
      * <p>
      * This is set to negative -1 for the OD2 hydrogen.
      */
     private final int offsetASH1;
 
     /**
      * Biotype offset relative to the CB biotype for neutral aspartic acid protonated on OD2 (ASH2).
      * <p>
      * This is set to negative -1 for the OD1 hydrogen.
      */
     private final int offsetASH2;
 
     private final int tautomerDirection;
 
     public int getOffset(AspStates state) {
       if (state == AspStates.ASP) {
         return offsetASP;
       } else if (state == AspStates.ASH1) {
         return offsetASH1;
       } else {
         return offsetASH2;
       }
     }
 
     /**
      * Init the Histidine atom names.
      *
      * @param offsetASP Biotype relative to the CB biotype for ASP.
      * @param offsetASH1 Biotype relative to the CB biotype for ASH.
      * @param offsetASH2 Biotype relative to the CB biotype for ASH.
      */
     AspartateAtomNames(int offsetASP, int offsetASH1, int offsetASH2, int tautomerDirection) {
       this.offsetASP = offsetASP;
       this.offsetASH1 = offsetASH1;
       this.offsetASH2 = offsetASH2;
       this.tautomerDirection = tautomerDirection;
     }
   }
 
   enum GluStates {
     GLU, GLH1, GLH2
   }
 
   /** Constant <code>GlutamateAtomNames</code> */
   private enum GlutamateAtomNames {
     CB(0, 0, 0, 0), HB2(1, 1, 1, 0), HB3(1, 1, 1, 0), CG(2, 2, 2, 0), HG2(3, 3, 3, 0), HG3(3, 3, 3,
         0), CD(4, 4, 4, 0), OE1(5, 6, 5, 0), OE2(5, 5, 6, 0), HE1(-1, 7, -1, 1), HE2(-1, -1, 7, -1);
 
     /**
      * Biotype offset relative to the CB biotype for charged Glutamate (GLU).
      */
     private final int offsetGLU;
 
     /**
      * Biotype offset relative to the CB biotype for neutral Glutamate acid protonated on OE1
      * (GLU1).
      * <p>
      * This is set to negative -1 for the OE2 hydrogen.
      */
     private final int offsetGLH1;
 
     /**
      * Biotype offset relative to the CB biotype for neutral Glutamate acid protonated on OE2
      * (GLU2).
      * <p>
      * This is set to negative -1 for the OE1 hydrogen.
      */
     private final int offsetGLH2;
 
     private final int tautomerDirection;
 
     public int getOffset(GluStates state) {
       if (state == GluStates.GLU) {
         return offsetGLU;
       } else if (state == GluStates.GLH1) {
         return offsetGLH1;
       } else {
         return offsetGLH2;
       }
     }
 
     /**
      * Init the Glutamate atom names.
      *
      * @param offsetGLU Biotype relative to the CB biotype for GLU.
      * @param offsetGLH1 Biotype relative to the CB biotype for GLH.
      * @param offsetGLH2 Biotype relative to the CB biotype for GLH.
      */
     GlutamateAtomNames(int offsetGLU, int offsetGLH1, int offsetGLH2, int tautomerDirection) {
       this.offsetGLU = offsetGLU;
       this.offsetGLH1 = offsetGLH1;
       this.offsetGLH2 = offsetGLH2;
       this.tautomerDirection = tautomerDirection;
     }
   }
 
   public enum LysStates {
     LYD, LYS
   }
 
   /** Constant <code>lysineAtoms</code> */
   public enum LysineAtomNames {
     CB(0, 0), HB2(1, 1), HB3(1, 1), CG(2, 2), HG2(3, 3), HG3(3, 3), CD(4, 4), HD2(5, 5), HD3(5,
         5), CE(6, 6), HE2(7, 7), HE3(7, 7), NZ(8, 8), HZ1(9, 9), HZ2(9, 9), HZ3(9, -1);
 
     /**
      * Biotype offset relative to the CB biotype for LYS.
      */
     private final int offsetLYS;
 
     /**
      * Biotype offset relative to the CB biotype for LYD.
      */
     private final int offsetLYD;
 
     public int getOffsetLYS(LysStates state) {
       if (state == LysStates.LYS) {
         return offsetLYS;
       } else {
         return offsetLYD;
       }
     }
 
     /**
      * Init the Lysine atom names.
      *
      * @param offsetLYS Biotype offset relative to the CB biotype for LYS.
      * @param offsetLYD Biotype offset relative to the CB biotype for LYD.
      */
     LysineAtomNames(int offsetLYS, int offsetLYD) {
       this.offsetLYS = offsetLYS;
       this.offsetLYD = offsetLYD;
     }
   }
 
   public enum HisStates {
     HIS, HID, HIE
   }
 
   /** Constant <code>HistidineAtoms</code> */
   public enum HistidineAtomNames {
     // HIS, HID, HIE
     CB(0, 0, 0, 0), HB2(1, 1, 1, 0), HB3(1, 1, 1, 0), CG(2, 2, 2, 0), ND1(3, 3, 3,
         0), // No HD1 proton for HIE; HIE HD1 offset is -1.
     HD1(4, 4, -1, -1), CD2(5, 5, 4, 0), HD2(6, 6, 5, 0), CE1(7, 7, 6, 0), HE1(8, 8, 7, 0), NE2(9, 9,
         8, 0), // No HE2 proton for HID; HID HE2 offset is -1
     HE2(10, -1, 9, 1);
 
     /**
      * Biotype offset relative to the CB biotype for charged histidine (HIS).
      */
     private final int offsetHIS;
 
     /**
      * Biotype offset relative to the CB biotype for neutral histidine protonated on the delta
      * nitrogren (HID).
      * <p>
      * This is set to negative -1 for the epsilon hydrogen.
      */
     private final int offsetHID;
 
     /**
      * Biotype offset relative to the CB biotype for neutral histidine protonated the epsilon
      * nitrogen (HIE).
      * <p>
      * This is set to negative -1 for the delta hydrogen.
      */
     private final int offsetHIE;
 
     private final int tautomerDirection;
 
     public int getOffsetHIS(HisStates state) {
       if (state == HisStates.HIS) {
         return offsetHIS;
       } else if (state == HisStates.HID) {
         return offsetHID;
       } else {
         return offsetHIE;
       }
     }
 
     /**
      * Init the Histidine atom names.
      *
      * @param offsetHIS Biotype relative to the CB biotype for HIS.
      * @param offsetHID Biotype relative to the CB biotype for HID.
      * @param offsetHIE Biotype relative to the CB biotype for HIE.
      */
     HistidineAtomNames(int offsetHIS, int offsetHID, int offsetHIE, int tautomerDirection) {
       this.offsetHIS = offsetHIS;
       this.offsetHID = offsetHID;
       this.offsetHIE = offsetHIE;
       this.tautomerDirection = tautomerDirection;
     }
   }
 
   public enum CysStates {
     CYS, CYD
   }
 
   /** Constant <code>CysteineAtoms</code> */
   public enum CysteineAtomNames {
     CB(0, 0), HB2(1, 1), HB3(1, 1), SG(2, 2), HG(3, -1);
 
     /**
      * Biotype offset relative to the CB biotype for neutral cysteine (CYS).
      */
     private final int offsetCYS;
 
     /**
      * Biotype offset relative to the CB biotype for negatively charged cysteine (CYD).
      * <p>
      * This is set to negative -1 for the gamma hydrogen.
      */
     private final int offsetCYD;
 
     public int getOffsetCYS(CysStates state) {
       if (state == CysStates.CYS) {
         return offsetCYS;
       } else {
         return offsetCYD;
       }
     }
 
     /**
      * Init the Cysteine atom names.
      *
      * @param offsetCYS Biotype relative to the CB biotype for CYS.
      * @param offsetCYD Biotype relative to the CB biotype for CYD.
      */
     CysteineAtomNames(int offsetCYS, int offsetCYD) {
       this.offsetCYS = offsetCYS;
       this.offsetCYD = offsetCYD;
     }
   }
 
   /**
    * Lysine atom types.
    */
   private final int nLysAtomNames = LysineAtomNames.values().length;
   private final int nLysStates = LysStates.values().length;
   private final AtomType[][] lysAtomTypes = new AtomType[nLysAtomNames][nLysStates];
   private final MultipoleType[][] lysMultipoleTypes = new MultipoleType[nLysAtomNames][nLysStates];
   private final PolarizeType[][] lysPolarizeTypes = new PolarizeType[nLysAtomNames][nLysStates];
   private final VDWType[][] lysVDWTypes = new VDWType[nLysAtomNames][nLysStates];
   private final SoluteType[][] lysSoluteTypes = new SoluteType[nLysAtomNames][nLysStates];
 
   /**
    * Histidine atom types.
    */
   private final int nHisAtomNames = HistidineAtomNames.values().length;
   private final int nHisStates = HisStates.values().length;
   private final AtomType[][] hisAtomTypes = new AtomType[nHisAtomNames][nHisStates];
   private final MultipoleType[][] hisMultipoleTypes = new MultipoleType[nHisAtomNames][nHisStates];
   private final PolarizeType[][] hisPolarizeTypes = new PolarizeType[nHisAtomNames][nHisStates];
   private final VDWType[][] hisVDWTypes = new VDWType[nHisAtomNames][nHisStates];
   private final SoluteType[][] hisSoluteTypes = new SoluteType[nHisAtomNames][nHisStates];
 
   /**
    * Aspartic acid atom types.
    */
   private final int nAspAtomNames = AspartateAtomNames.values().length;
   private final int nAspStates = AspStates.values().length;
   private final AtomType[][] aspAtomTypes = new AtomType[nAspAtomNames][nAspStates];
   private final MultipoleType[][] aspMultipoleTypes = new MultipoleType[nAspAtomNames][nAspStates];
   private final PolarizeType[][] aspPolarizeTypes = new PolarizeType[nAspAtomNames][nAspStates];
   private final VDWType[][] aspVDWTypes = new VDWType[nAspAtomNames][nAspStates];
   private final SoluteType[][] aspSoluteTypes = new SoluteType[nAspAtomNames][nAspStates];
 
   /**
    * Glutamic acid atom types.
    */
   private final int nGluAtomNames = GlutamateAtomNames.values().length;
   private final int nGluStates = GluStates.values().length;
   private final AtomType[][] gluAtomTypes = new AtomType[nGluAtomNames][nGluStates];
   private final MultipoleType[][] gluMultipoleTypes = new MultipoleType[nGluAtomNames][nGluStates];
   private final PolarizeType[][] gluPolarizeTypes = new PolarizeType[nGluAtomNames][nGluStates];
   private final VDWType[][] gluVDWTypes = new VDWType[nGluAtomNames][nGluStates];
   private final SoluteType[][] gluSoluteTypes = new SoluteType[nGluAtomNames][nGluStates];
 
   /**
    * Cystine atom types.
    */
   private final int nCysAtomNames = CysteineAtomNames.values().length;
   private final int nCysStates = CysStates.values().length;
   private final AtomType[][] cysAtomTypes = new AtomType[nCysAtomNames][nCysStates];
   private final MultipoleType[][] cysMultipoleTypes = new MultipoleType[nCysAtomNames][nCysStates];
   private final PolarizeType[][] cysPolarizeTypes = new PolarizeType[nCysAtomNames][nCysStates];
   private final VDWType[][] cysVDWTypes = new VDWType[nCysAtomNames][nCysStates];
   private final SoluteType[][] cysSoluteTypes = new SoluteType[nCysAtomNames][nCysStates];
 
   private final ForceField forceField;
   private final SOLUTE_RADII_TYPE soluteRadiiType;
   private final boolean updateBondedTerms;
 
   private final HashMap<AminoAcid3, Double> rotamerPhBiasMap = new HashMap<>();
 
   public TitrationUtils(ForceField forceField) {
     this.forceField = forceField;
 
     String gkRadius = forceField.getString("GK_RADIUS", "SOLUTE");
     SOLUTE_RADII_TYPE tempType;
     try {
       tempType = SOLUTE_RADII_TYPE.valueOf(gkRadius.trim().toUpperCase());
     } catch (Exception e) {
       tempType = SOLUTE_RADII_TYPE.SOLUTE;
     }
     soluteRadiiType = tempType;
 
     updateBondedTerms = forceField.getBoolean("TITRATION_UPDATE_BONDED_TERMS", true);
 
     // Populate the Lysine types.
     constructLYSState(AA_CB[LYS.ordinal()], LysStates.LYS);
     constructLYSState(AA_CB[LYD.ordinal()], LysStates.LYD);
     checkParameterTypes("LYS", lysAtomTypes, lysPolarizeTypes, lysMultipoleTypes, lysVDWTypes);
 
     // Populate the Histidine types.
     constructHISState(AA_CB[HIS.ordinal()], HisStates.HIS);
     constructHISState(AA_CB[HID.ordinal()], HisStates.HID);
     constructHISState(AA_CB[HIE.ordinal()], HisStates.HIE);
     checkParameterTypes("HIS", hisAtomTypes, hisPolarizeTypes, hisMultipoleTypes, hisVDWTypes);
 
     // Populate the Aspartic acid types.
     constructASPState(AA_CB[ASP.ordinal()], AspStates.ASP);
     constructASPState(AA_CB[ASH.ordinal()], AspStates.ASH1); // First ASH Tautomer
     constructASPState(AA_CB[ASH.ordinal()], AspStates.ASH2); // Second ASH Tautomer
     checkParameterTypes("ASP", aspAtomTypes, aspPolarizeTypes, aspMultipoleTypes, aspVDWTypes);
 
     // Populate the Glutamic acid types.
     constructGLUState(AA_CB[GLU.ordinal()], GluStates.GLU);
     constructGLUState(AA_CB[GLH.ordinal()], GluStates.GLH1); // First GLH Tautomer
     constructGLUState(AA_CB[GLH.ordinal()], GluStates.GLH2); // Second GLH Tautomer
     checkParameterTypes("GLU", gluAtomTypes, gluPolarizeTypes, gluMultipoleTypes, gluVDWTypes);
 
     // Populate the Cystine types.
     constructCYSState(AA_CB[CYS.ordinal()], CysStates.CYS);
     constructCYSState(AA_CB[CYD.ordinal()], CysStates.CYD);
     checkParameterTypes("CYS", cysAtomTypes, cysPolarizeTypes, cysMultipoleTypes, cysVDWTypes);
   }
 
   public TitrationUtils(ForceField forceField, double proteinDielectric, boolean tanhCorrection){
     this(forceField);
     this.proteinDielectric = proteinDielectric;
     this.tanhCorrection = tanhCorrection;
     //String fModA = forceField.getProperties().getString("fModA");
     //this.fModA = Double.parseDouble(fModA);
     //logger.info("ASP fMOD = " + fModA);
     //String fModG = forceField.getProperties().getString("fModG");
     //this.fModG = Double.parseDouble(fModG);
     //String fModL = forceField.getProperties().getString("fModL");
     //this.fModL = Double.parseDouble(fModL);
     //String fModHE = forceField.getProperties().getString("fModHE");
     //this.fModHE = Double.parseDouble(fModHE);
     //String fModHD = forceField.getProperties().getString("fModHD");
     //this.fModHD = Double.parseDouble(fModHD);
   }
 
   public boolean testResidueTypes(Residue residue) {
 
     boolean testPassed = true;
     int nStates = 1;
     AminoAcid3 aminoAcid3 = residue.getAminoAcid3();
     switch (aminoAcid3) {
       case ASP, ASH, ASD, GLU, GLH, GLD, HIS, HID, HIE -> nStates = 3;
       case CYS, CYD, LYS, LYD -> nStates = 2;
       default -> logger.info(format(" Only one state for atom %s.", aminoAcid3));
     }
 
     List<Atom> atomList = residue.getSideChainAtoms();
     int nAtoms = atomList.size();
     int[][][] axisAtomIndices = new int[nAtoms][nStates][];
     AtomType[][] atomTypes = new AtomType[nAtoms][nStates];
     MultipoleType[][] multipoleTypes = new MultipoleType[nAtoms][nStates];
 
     AtomType[] initialAtomTypes = new AtomType[nAtoms];
     MultipoleType[] initialMultipoleTypes = new MultipoleType[nAtoms];
     // Store initial state
     for (int i = 0; i < nAtoms; i++) {
       Atom atom = atomList.get(i);
       initialAtomTypes[i] = atom.getAtomType();
       initialMultipoleTypes[i] = atom.getMultipoleType();
     }
 
     // Load information for each state.
     for (int state = 0; state < nStates; state++) {
       // Load AtomType and MultipoleType instances for each atom for this state.
       for (int i = 0; i < nAtoms; i++) {
         Atom atom = atomList.get(i);
         String atomName = atom.getName();
         switch (aminoAcid3) {
           case ASP:
           case ASH:
           case ASD:
             int index = AspartateAtomNames.valueOf(atomName).ordinal();
             atom.setAtomType(aspAtomTypes[index][state]);
             atom.setMultipoleType(aspMultipoleTypes[index][state]);
             break;
           case CYS:
           case CYD:
             index = CysteineAtomNames.valueOf(atomName).ordinal();
             atom.setAtomType(cysAtomTypes[index][state]);
             atom.setMultipoleType(cysMultipoleTypes[index][state]);
             break;
           case GLU:
           case GLH:
           case GLD:
             index = GlutamateAtomNames.valueOf(atomName).ordinal();
             atom.setAtomType(gluAtomTypes[index][state]);
             atom.setMultipoleType(gluMultipoleTypes[index][state]);
             break;
           case HIS:
           case HID:
           case HIE:
             index = HistidineAtomNames.valueOf(atomName).ordinal();
             atom.setAtomType(hisAtomTypes[index][state]);
             atom.setMultipoleType(hisMultipoleTypes[index][state]);
             break;
           case LYS:
           case LYD:
             index = LysineAtomNames.valueOf(atomName).ordinal();
             atom.setAtomType(lysAtomTypes[index][state]);
             atom.setMultipoleType(lysMultipoleTypes[index][state]);
             break;
           default:
             logger.info(format(" Only one state for atom %s.", atom));
         }
         atomTypes[i][state] = atom.getAtomType();
         multipoleTypes[i][state] = atom.getMultipoleType();
       }
       // Assign axis atoms for each atom for this state.
       for (int i = 0; i < nAtoms; i++) {
         Atom atom = atomList.get(i);
         assignAxisAtoms(atom);
         axisAtomIndices[i][state] = atom.getAxisAtomIndices();
       }
     }
 
     // Check the local multipole frames.
     for (int i = 0; i < nAtoms; i++) {
       Atom atom = atomList.get(i);
       int[] referenceIndices = axisAtomIndices[i][0];
       AtomType referenceAtomType = atomTypes[i][0];
       MultipoleType referenceMultipoleType = multipoleTypes[i][0];
       for (int state = 1; state < nStates; state++) {
         int[] stateIndices = axisAtomIndices[i][state];
         AtomType stateAtomType = atomTypes[i][state];
         MultipoleType stateMultipoleType = multipoleTypes[i][state];
         if (referenceMultipoleType.frameDefinition != stateMultipoleType.frameDefinition) {
           logger.warning(format(" Local frame definition is inconsistent for atom %s", atom));
           logger.warning(format("  %s\n  %s", referenceAtomType, referenceMultipoleType));
           logger.warning(format("  %s\n  %s", stateAtomType, stateMultipoleType));
           testPassed = false;
           continue;
         }
         if (Arrays.compare(referenceIndices, stateIndices) != 0) {
           // Atom order does not matter for BISECTOR.
           if (referenceMultipoleType.frameDefinition == MultipoleFrameDefinition.BISECTOR) {
             if (referenceIndices[0] == stateIndices[1] && referenceIndices[1] == stateIndices[0]) {
               continue;
             }
           }
           logger.warning(format(" Local frame atom indices are inconsistent for atom %s", atom));
           logger.warning(
               format("  %s %s\n  %s", referenceAtomType, Arrays.toString(referenceIndices),
                   referenceMultipoleType));
           logger.warning(format("  %s %s\n  %s", stateAtomType, Arrays.toString(stateIndices),
               stateMultipoleType));
           testPassed = false;
         }
       }
     }
 
     // Revert initial state
     for (int i = 0; i < nAtoms; i++) {
       Atom atom = atomList.get(i);
       atom.setAtomType(initialAtomTypes[i]);
       atom.setMultipoleType(initialMultipoleTypes[i]);
     }
 
     return testPassed;
   }
 
   /**
    * Update force field parameters for the side-chain atoms of the given residue based on the rotamer
    * amino acid type.
    *
    * @param residue Residue to update.
    * @param rotamer Rotamer that contains the amino acid residue identity.
    */
   public void updateResidueParameters(Residue residue, Rotamer rotamer) {
     if (!rotamer.isTitrating) {
       return;
     }
 
     AminoAcid3 aminoAcid3 = residue.getAminoAcid3();
     switch (aminoAcid3) {
       case ASH, ASP -> {
         // Assume ASP types
         int aspIndex = AspStates.ASP.ordinal();
         if (rotamer.aminoAcid3 == ASH) {
           // Use ASH2 types
           aspIndex = AspStates.ASH2.ordinal();
         }
         for (AspartateAtomNames atomName : AspartateAtomNames.values()) {
           if (atomName.name().equals("HD1")) {
             // Skip the HD1 atom name (used only for ASD during constant pH).
             // This atom should not be present in the residue for ASH/ASP rot opt.
             continue;
           }
           int atomIndex = atomName.ordinal();
           Atom atom = (Atom) residue.getAtomNode(atomName.name());
           if (atom == null) {
             logger.severe(" Atom is null for " + atomName);
             return;
           }
           atom.setAtomType(aspAtomTypes[atomIndex][aspIndex]);
           atom.setMultipoleType(aspMultipoleTypes[atomIndex][aspIndex]);
           atom.setPolarizeType(aspPolarizeTypes[atomIndex][aspIndex]);
           atom.setVDWType(aspVDWTypes[atomIndex][aspIndex]);
           atom.setSoluteType(aspSoluteTypes[atomIndex][aspIndex]);
         }
       }
       case GLU, GLH -> {
         // Assume GLU types
         int gluIndex = GluStates.GLU.ordinal();
         if (rotamer.aminoAcid3 == GLH) {
           // Use GLH2 types
           gluIndex = GluStates.GLH2.ordinal();
         }
         for (GlutamateAtomNames atomName : GlutamateAtomNames.values()) {
           if (atomName.name().equals("HE1")) {
             // Skip the HE1 atom name (used only for GLD during constant pH).
             // This atom should not be present in the residue for GLH/GLU rot opt.
             continue;
           }
           int atomIndex = atomName.ordinal();
           Atom atom = (Atom) residue.getAtomNode(atomName.name());
           if (atom == null) {
             logger.severe(" Atom is null for " + atomName);
             return;
           }
           atom.setAtomType(gluAtomTypes[atomIndex][gluIndex]);
           atom.setMultipoleType(gluMultipoleTypes[atomIndex][gluIndex]);
           atom.setPolarizeType(gluPolarizeTypes[atomIndex][gluIndex]);
           atom.setVDWType(gluVDWTypes[atomIndex][gluIndex]);
           atom.setSoluteType(gluSoluteTypes[atomIndex][gluIndex]);
         }
       }
       case LYS, LYD -> {
         // Assume LYS types
         int lysIndex = LysStates.LYS.ordinal();
         if (rotamer.aminoAcid3 == LYD) {
           // Use LYD types
           lysIndex = LysStates.LYD.ordinal();
         }
         for (LysineAtomNames atomName : LysineAtomNames.values()) {
           int atomIndex = atomName.ordinal();
           Atom atom = (Atom) residue.getAtomNode(atomName.name());
           if (atom == null) {
             logger.severe(" Atom is null for " + atomName);
             return;
           }
           atom.setAtomType(lysAtomTypes[atomIndex][lysIndex]);
           atom.setMultipoleType(lysMultipoleTypes[atomIndex][lysIndex]);
           atom.setPolarizeType(lysPolarizeTypes[atomIndex][lysIndex]);
           atom.setVDWType(lysVDWTypes[atomIndex][lysIndex]);
           atom.setSoluteType(lysSoluteTypes[atomIndex][lysIndex]);
         }
       }
       case CYS, CYD -> {
         // Assume CYS types
         int cysIndex = CysStates.CYS.ordinal();
         if (rotamer.aminoAcid3 == CYD) {
           // Use CYD types
           cysIndex = CysStates.CYD.ordinal();
         }
         for (CysteineAtomNames atomName : CysteineAtomNames.values()) {
           int atomIndex = atomName.ordinal();
           Atom atom = (Atom) residue.getAtomNode(atomName.name());
           if (atom == null) {
             logger.severe(" Atom is null for " + atomName);
             return;
           }
           atom.setAtomType(cysAtomTypes[atomIndex][cysIndex]);
           atom.setMultipoleType(cysMultipoleTypes[atomIndex][cysIndex]);
           atom.setPolarizeType(cysPolarizeTypes[atomIndex][cysIndex]);
           atom.setVDWType(cysVDWTypes[atomIndex][cysIndex]);
           atom.setSoluteType(cysSoluteTypes[atomIndex][cysIndex]);
         }
       }
       case HIS, HIE, HID -> {
         // Assume HIS types.
         int hisIndex = switch (rotamer.aminoAcid3) {
           case HIE -> HisStates.HIE.ordinal();
           case HID -> HisStates.HID.ordinal();
           default -> HisStates.HIS.ordinal();
         };
         for (HistidineAtomNames atomName : HistidineAtomNames.values()) {
           int atomIndex = atomName.ordinal();
           Atom atom = (Atom) residue.getAtomNode(atomName.name());
           if (atom == null) {
             logger.severe(" Atom is null for " + atomName);
             return;
           }
           atom.setAtomType(hisAtomTypes[atomIndex][hisIndex]);
           atom.setMultipoleType(hisMultipoleTypes[atomIndex][hisIndex]);
           atom.setPolarizeType(hisPolarizeTypes[atomIndex][hisIndex]);
           atom.setVDWType(hisVDWTypes[atomIndex][hisIndex]);
           atom.setSoluteType(hisSoluteTypes[atomIndex][hisIndex]);
         }
       }
       default -> logger.severe(
           format(" No support for titrating residue %s with rotamer %s.", residue, rotamer));
     }
 
     // Update local frame defining atoms now that the AtomType and MultipoleType values are set.
     for (Atom atom : residue.getSideChainAtoms()) {
       assignAxisAtoms(atom);
     }
 
     // Should bonded terms be updated.
     if (!updateBondedTerms) {
       return;
     }
 
     // Update Bond force field terms.
     for (Bond bond : residue.getBondList()) {
       AtomType a1 = bond.getAtom(0).getAtomType();
       AtomType a2 = bond.getAtom(1).getAtomType();
       BondType bondType = forceField.getBondType(a1, a2);
       if (bondType == null) {
         bondType = zeroBondType;
       }
       bond.setBondType(bondType);
     }
 
     // Update Angle force field terms.
     for (Angle angle : residue.getAngleList()) {
       AtomType a1 = angle.getAtom(0).getAtomType();
       AtomType a2 = angle.getAtom(1).getAtomType();
       AtomType a3 = angle.getAtom(2).getAtomType();
       AngleType angleType = forceField.getAngleType(a1, a2, a3);
       if (angleType == null) {
         angleType = zeroAngleType;
       }
       angle.setAngleType(angleType);
     }
 
     // Update Stretch-Bend force field terms.
     for (StretchBend stretchBend : residue.getStretchBendList()) {
       AtomType a1 = stretchBend.getAtom(0).getAtomType();
       AtomType a2 = stretchBend.getAtom(1).getAtomType();
       AtomType a3 = stretchBend.getAtom(2).getAtomType();
       StretchBendType stretchBendType = forceField.getStretchBendType(a1, a2, a3);
       if (stretchBendType == null) {
         stretchBendType = zeroStretchBendType;
       }
       stretchBend.setStretchBendType(stretchBendType);
     }
 
     // Update Out-of-Plane Bend force field terms.
     for (OutOfPlaneBend outOfPlaneBend : residue.getOutOfPlaneBendList()) {
       AtomType a4 = outOfPlaneBend.getFourthAtom().getAtomType();
       AtomType a0 = outOfPlaneBend.getFirstAngleAtom().getAtomType();
       AtomType a1 = outOfPlaneBend.getTrigonalAtom().getAtomType();
       AtomType a2 = outOfPlaneBend.getLastAngleAtom().getAtomType();
       OutOfPlaneBendType outOfPlaneBendType = forceField.getOutOfPlaneBendType(a4, a0, a1, a2);
       if (outOfPlaneBendType == null) {
         outOfPlaneBendType = zeroOutOfPlaneBendType;
       }
       outOfPlaneBend.setOutOfPlaneBendType(outOfPlaneBendType);
     }
 
     // Update torsion force field terms.
     for (Torsion torsion : residue.getTorsionList()) {
       AtomType a1 = torsion.getAtom(0).getAtomType();
       AtomType a2 = torsion.getAtom(1).getAtomType();
       AtomType a3 = torsion.getAtom(2).getAtomType();
       AtomType a4 = torsion.getAtom(3).getAtomType();
       TorsionType torsionType = forceField.getTorsionType(a1, a2, a3, a4);
       if (torsionType == null) {
         torsionType = zeroTorsionType;
       }
       torsion.setTorsionType(torsionType);
     }
 
     // Update Pi-Orbital Torsion force field terms.
     for (PiOrbitalTorsion piOrbitalTorsion : residue.getPiOrbitalTorsionList()) {
       Bond middleBond = piOrbitalTorsion.getMiddleBond();
       AtomType a1 = middleBond.getAtom(0).getAtomType();
       AtomType a2 = middleBond.getAtom(1).getAtomType();
       PiOrbitalTorsionType piOrbitalTorsionType = forceField.getPiOrbitalTorsionType(a1, a2);
       if (piOrbitalTorsionType == null) {
         piOrbitalTorsionType = zeroPiOrbitalTorsionType;
       }
       piOrbitalTorsion.setPiOrbitalTorsionType(piOrbitalTorsionType);
     }
 
     // The following terms are not supported yet.
     List<ImproperTorsion> improperTorsions = residue.getImproperTorsionList();
     if (improperTorsions != null && !improperTorsions.isEmpty()) {
       logger.severe(
           " Improper torsions are not supported yet for pH-dependent rotamer optimization.");
     }
 
     List<StretchTorsion> stretchTorsions = residue.getStretchTorsionList();
     if (stretchTorsions != null && !stretchTorsions.isEmpty()) {
       logger.severe(
           " Stretch-torsions are not supported yet for pH-dependent rotamer optimization.");
     }
 
     List<AngleTorsion> angleTorsions = residue.getAngleTorsionList();
     if (angleTorsions != null && !angleTorsions.isEmpty()) {
       logger.severe(" Angle-torsions are not supported yet for pH-dependent rotamer optimization.");
     }
 
     List<TorsionTorsion> torsionTorsions = residue.getTorsionTorsionList();
     if (torsionTorsions != null && !torsionTorsions.isEmpty()) {
       logger.severe(
           " Torsion-torsions are not supported yet for pH-dependent rotamer optimization.");
     }
 
     List<UreyBradley> ureyBradleys = residue.getUreyBradleyList();
     if (ureyBradleys != null && !ureyBradleys.isEmpty()) {
       logger.severe(" Urey-Bradleys are not supported yet for pH-dependent rotamer optimization.");
     }
 
   }
 
   public double[] getMultipole(Atom atom, double titrationLambda, double tautomerLambda,
       double[] multipole) {
     /*
     Step 1: retrieve the atomName from atom instance.
     Step 2: retrieve the oridnal from the atom instance + residueType
      */
 
     AminoAcid3 aminoAcid3;
     try {
       aminoAcid3 = atom.getMSNode(Residue.class).getAminoAcid3();
     } catch (Exception exception) {
       return multipole;
     }
     String atomName = atom.getName();
 
     switch (aminoAcid3) {
       case LYS:
         int atomIndex = LysineAtomNames.valueOf(atomName).ordinal();
         MultipoleType lysM = lysMultipoleTypes[atomIndex][LysStates.LYS.ordinal()];
         MultipoleType lydM = lysMultipoleTypes[atomIndex][LysStates.LYD.ordinal()];
         double[] lys = lysM.getMultipole();
         double[] lyd = lydM.getMultipole();
         for (int i = 0; i < multipole.length; i++) {
           multipole[i] = titrationLambda * lys[i] + (1.0 - titrationLambda) * lyd[i];
         }
         break;
       case CYS:
         atomIndex = CysteineAtomNames.valueOf(atomName).ordinal();
         MultipoleType cysM = cysMultipoleTypes[atomIndex][CysStates.CYS.ordinal()];
         MultipoleType cydM = cysMultipoleTypes[atomIndex][CysStates.CYD.ordinal()];
         double[] cys = cysM.getMultipole();
         double[] cyd = cydM.getMultipole();
         for (int i = 0; i < multipole.length; i++) {
           multipole[i] = titrationLambda * cys[i] + (1.0 - titrationLambda) * cyd[i];
         }
         break;
       case HIS:
         atomIndex = HistidineAtomNames.valueOf(atomName).ordinal();
         MultipoleType hisM = hisMultipoleTypes[atomIndex][HisStates.HIS.ordinal()];
         MultipoleType hidM = hisMultipoleTypes[atomIndex][HisStates.HID.ordinal()];
         MultipoleType hieM = hisMultipoleTypes[atomIndex][HisStates.HIE.ordinal()];
         double[] his = hisM.getMultipole();
         double[] hid = hidM.getMultipole();
         double[] hie = hieM.getMultipole();
         for (int i = 0; i < multipole.length; i++) {
           multipole[i] =
               titrationLambda * his[i] + (1.0 - titrationLambda) * (tautomerLambda * hie[i]
                   + (1 - tautomerLambda) * hid[i]);
         }
         break;
       case ASD:
         atomIndex = AspartateAtomNames.valueOf(atomName).ordinal();
         MultipoleType aspM = aspMultipoleTypes[atomIndex][AspStates.ASP.ordinal()];
         MultipoleType ash1M = aspMultipoleTypes[atomIndex][AspStates.ASH1.ordinal()];
         MultipoleType ash2M = aspMultipoleTypes[atomIndex][AspStates.ASH2.ordinal()];
         double[] asp = aspM.getMultipole();
         double[] ash1 = ash1M.getMultipole();
         double[] ash2 = ash2M.getMultipole();
         for (int i = 0; i < multipole.length; i++) {
           multipole[i] =
               titrationLambda * (tautomerLambda * ash1[i] + (1 - tautomerLambda) * ash2[i])
                   + (1.0 - titrationLambda) * asp[i];
         }
         break;
       case GLD:
         atomIndex = GlutamateAtomNames.valueOf(atomName).ordinal();
         MultipoleType gluM = gluMultipoleTypes[atomIndex][GluStates.GLU.ordinal()];
         MultipoleType glh1M = gluMultipoleTypes[atomIndex][GluStates.GLH1.ordinal()];
         MultipoleType glh2M = gluMultipoleTypes[atomIndex][GluStates.GLH2.ordinal()];
         double[] glu = gluM.getMultipole();
         double[] glh1 = glh1M.getMultipole();
         double[] glh2 = glh2M.getMultipole();
         for (int i = 0; i < multipole.length; i++) {
           multipole[i] =
               titrationLambda * (tautomerLambda * glh1[i] + (1 - tautomerLambda) * glh2[i])
                   + (1.0 - titrationLambda) * glu[i];
         }
         break;
       default:
         return multipole;
     }
     return multipole;
   }
 
   public double[] getMultipoleTitrationDeriv(Atom atom, double titrationLambda,
       double tautomerLambda, double[] multipole) {
     AminoAcid3 aminoAcid3;
     try {
       aminoAcid3 = atom.getMSNode(Residue.class).getAminoAcid3();
     } catch (Exception exception) {
       return multipole;
     }
     String atomName = atom.getName();
     switch (aminoAcid3) {
       case LYS:
         int atomIndex = LysineAtomNames.valueOf(atomName).ordinal();
         double[] lys = lysMultipoleTypes[atomIndex][LysStates.LYS.ordinal()].getMultipole();
         double[] lyd = lysMultipoleTypes[atomIndex][LysStates.LYD.ordinal()].getMultipole();
         for (int i = 0; i < multipole.length; i++) {
           multipole[i] = lys[i] - lyd[i];
         }
         break;
       case CYS:
         atomIndex = CysteineAtomNames.valueOf(atomName).ordinal();
         double[] cys = cysMultipoleTypes[atomIndex][CysStates.CYS.ordinal()].getMultipole();
         double[] cyd = cysMultipoleTypes[atomIndex][CysStates.CYD.ordinal()].getMultipole();
         for (int i = 0; i < multipole.length; i++) {
           multipole[i] = cys[i] - cyd[i];
         }
         break;
       case HIS:
         atomIndex = HistidineAtomNames.valueOf(atomName).ordinal();
         double[] his = hisMultipoleTypes[atomIndex][HisStates.HIS.ordinal()].getMultipole();
         double[] hid = hisMultipoleTypes[atomIndex][HisStates.HID.ordinal()].getMultipole();
         double[] hie = hisMultipoleTypes[atomIndex][HisStates.HIE.ordinal()].getMultipole();
         for (int i = 0; i < multipole.length; i++) {
           multipole[i] = his[i] - (tautomerLambda * hie[i] + (1 - tautomerLambda) * hid[i]);
         }
         break;
       case ASD:
         atomIndex = AspartateAtomNames.valueOf(atomName).ordinal();
         double[] asp = aspMultipoleTypes[atomIndex][AspStates.ASP.ordinal()].getMultipole();
         double[] ash1 = aspMultipoleTypes[atomIndex][AspStates.ASH1.ordinal()].getMultipole();
         double[] ash2 = aspMultipoleTypes[atomIndex][AspStates.ASH2.ordinal()].getMultipole();
         for (int i = 0; i < multipole.length; i++) {
           multipole[i] = (tautomerLambda * ash1[i] + (1 - tautomerLambda) * ash2[i]) - asp[i];
         }
         break;
       case GLD:
         atomIndex = GlutamateAtomNames.valueOf(atomName).ordinal();
         double[] glu = gluMultipoleTypes[atomIndex][GluStates.GLU.ordinal()].getMultipole();
         double[] glh1 = gluMultipoleTypes[atomIndex][GluStates.GLH1.ordinal()].getMultipole();
         double[] glh2 = gluMultipoleTypes[atomIndex][GluStates.GLH2.ordinal()].getMultipole();
         for (int i = 0; i < multipole.length; i++) {
           multipole[i] = (tautomerLambda * glh1[i] + (1 - tautomerLambda) * glh2[i]) - glu[i];
         }
         break;
       default:
         return multipole;
     }
     return multipole;
   }
 
   public double[] getMultipoleTautomerDeriv(Atom atom, double titrationLambda, double tautomerLambda,
       double[] multipole) {
     AminoAcid3 aminoAcid3;
     try {
       aminoAcid3 = atom.getMSNode(Residue.class).getAminoAcid3();
     } catch (Exception exception) {
       return multipole;
     }
     String atomName = atom.getName();
     switch (aminoAcid3) {
       case HIS:
         int atomIndex = HistidineAtomNames.valueOf(atomName).ordinal();
         double[] his = hisMultipoleTypes[atomIndex][HisStates.HIS.ordinal()].getMultipole();
         double[] hid = hisMultipoleTypes[atomIndex][HisStates.HID.ordinal()].getMultipole();
         double[] hie = hisMultipoleTypes[atomIndex][HisStates.HIE.ordinal()].getMultipole();
         for (int i = 0; i < multipole.length; i++) {
           multipole[i] = (1.0 - titrationLambda) * (hie[i] - hid[i]);
         }
         break;
       case ASD:
         atomIndex = AspartateAtomNames.valueOf(atomName).ordinal();
         double[] asp = aspMultipoleTypes[atomIndex][AspStates.ASP.ordinal()].getMultipole();
         double[] ash1 = aspMultipoleTypes[atomIndex][AspStates.ASH1.ordinal()].getMultipole();
         double[] ash2 = aspMultipoleTypes[atomIndex][AspStates.ASH2.ordinal()].getMultipole();
         for (int i = 0; i < multipole.length; i++) {
           multipole[i] = titrationLambda * (ash1[i] - ash2[i]);
         }
         break;
       case GLD:
         atomIndex = GlutamateAtomNames.valueOf(atomName).ordinal();
         double[] glu = gluMultipoleTypes[atomIndex][GluStates.GLU.ordinal()].getMultipole();
         double[] glh1 = gluMultipoleTypes[atomIndex][GluStates.GLH1.ordinal()].getMultipole();
         double[] glh2 = gluMultipoleTypes[atomIndex][GluStates.GLH2.ordinal()].getMultipole();
         for (int i = 0; i < multipole.length; i++) {
           multipole[i] = titrationLambda * (glh1[i] - glh2[i]);
         }
         break;
       case LYS: // No tautomers for LYS.
       case CYS: // No tautomers for CYS.
       default:
         return multipole;
     }
     return multipole;
   }
 
   public double getPolarizability(Atom atom, double titrationLambda, double tautomerLambda,
       double defaultPolarizability) {
     AminoAcid3 aminoAcid3;
     try {
       aminoAcid3 = atom.getMSNode(Residue.class).getAminoAcid3();
     } catch (Exception exception) {
       return defaultPolarizability;
     }
     String atomName = atom.getName();
     switch (aminoAcid3) {
       case LYS:
         int atomIndex = LysineAtomNames.valueOf(atomName).ordinal();
         double lys = lysPolarizeTypes[atomIndex][LysStates.LYS.ordinal()].polarizability;
         double lyd = lysPolarizeTypes[atomIndex][LysStates.LYD.ordinal()].polarizability;
         return titrationLambda * lys + (1.0 - titrationLambda) * lyd;
       case CYS:
         atomIndex = CysteineAtomNames.valueOf(atomName).ordinal();
         double cys = cysPolarizeTypes[atomIndex][CysStates.CYS.ordinal()].polarizability;
         double cyd = cysPolarizeTypes[atomIndex][CysStates.CYD.ordinal()].polarizability;
         return titrationLambda * cys + (1.0 - titrationLambda) * cyd;
       case HIS:
         atomIndex = HistidineAtomNames.valueOf(atomName).ordinal();
         double his = hisPolarizeTypes[atomIndex][HisStates.HIS.ordinal()].polarizability;
         double hid = hisPolarizeTypes[atomIndex][HisStates.HID.ordinal()].polarizability;
         double hie = hisPolarizeTypes[atomIndex][HisStates.HIE.ordinal()].polarizability;
         return titrationLambda * his + (1.0 - titrationLambda) * (tautomerLambda * hie
             + (1.0 - tautomerLambda) * hid);
       case ASD:
         atomIndex = AspartateAtomNames.valueOf(atomName).ordinal();
         double asp = aspPolarizeTypes[atomIndex][AspStates.ASP.ordinal()].polarizability;
         double ash1 = aspPolarizeTypes[atomIndex][AspStates.ASH1.ordinal()].polarizability;
         double ash2 = aspPolarizeTypes[atomIndex][AspStates.ASH2.ordinal()].polarizability;
         return titrationLambda * (tautomerLambda * ash1 + (1.0 - tautomerLambda) * ash2)
             + (1.0 - titrationLambda) * asp;
       case GLD:
         atomIndex = GlutamateAtomNames.valueOf(atomName).ordinal();
         double glu = gluPolarizeTypes[atomIndex][GluStates.GLU.ordinal()].polarizability;
         double glh1 = gluPolarizeTypes[atomIndex][GluStates.GLH1.ordinal()].polarizability;
         double glh2 = gluPolarizeTypes[atomIndex][GluStates.GLH2.ordinal()].polarizability;
         return titrationLambda * (tautomerLambda * glh1 + (1.0 - tautomerLambda) * glh2)
             + (1.0 - titrationLambda) * glu;
       default:
         return defaultPolarizability;
     }
   }
 
   public double getPolarizabilityTitrationDeriv(Atom atom, double titrationLambda,
       double tautomerLambda) {
     AminoAcid3 aminoAcid3;
     try {
       aminoAcid3 = atom.getMSNode(Residue.class).getAminoAcid3();
     } catch (Exception exception) {
       return 0.0;
     }
     String atomName = atom.getName();
     switch (aminoAcid3) {
       case LYS:
         int atomIndex = LysineAtomNames.valueOf(atomName).ordinal();
         double lys = lysPolarizeTypes[atomIndex][LysStates.LYS.ordinal()].polarizability;
         double lyd = lysPolarizeTypes[atomIndex][LysStates.LYD.ordinal()].polarizability;
         return lys - lyd;
       case CYS:
         atomIndex = CysteineAtomNames.valueOf(atomName).ordinal();
         double cys = cysPolarizeTypes[atomIndex][CysStates.CYS.ordinal()].polarizability;
         double cyd = cysPolarizeTypes[atomIndex][CysStates.CYD.ordinal()].polarizability;
         return cys - cyd;
       case HIS:
         atomIndex = HistidineAtomNames.valueOf(atomName).ordinal();
         double his = hisPolarizeTypes[atomIndex][HisStates.HIS.ordinal()].polarizability;
         double hid = hisPolarizeTypes[atomIndex][HisStates.HID.ordinal()].polarizability;
         double hie = hisPolarizeTypes[atomIndex][HisStates.HIE.ordinal()].polarizability;
         return his - (tautomerLambda * hie + (1.0 - tautomerLambda) * hid);
       case ASD:
         atomIndex = AspartateAtomNames.valueOf(atomName).ordinal();
         double asp = aspPolarizeTypes[atomIndex][AspStates.ASP.ordinal()].polarizability;
         double ash1 = aspPolarizeTypes[atomIndex][AspStates.ASH1.ordinal()].polarizability;
         double ash2 = aspPolarizeTypes[atomIndex][AspStates.ASH2.ordinal()].polarizability;
         return (tautomerLambda * ash1 + (1.0 - tautomerLambda) * ash2) - asp;
       case GLD:
         atomIndex = GlutamateAtomNames.valueOf(atomName).ordinal();
         double glu = gluPolarizeTypes[atomIndex][GluStates.GLU.ordinal()].polarizability;
         double glh1 = gluPolarizeTypes[atomIndex][GluStates.GLH1.ordinal()].polarizability;
         double glh2 = gluPolarizeTypes[atomIndex][GluStates.GLH2.ordinal()].polarizability;
         return (tautomerLambda * glh1 + (1.0 - tautomerLambda) * glh2) - glu;
       default:
         return 0.0;
     }
   }
 
   public double getPolarizabilityTautomerDeriv(Atom atom, double titrationLambda,
       double tautomerLambda) {
     AminoAcid3 aminoAcid3;
     try {
       aminoAcid3 = atom.getMSNode(Residue.class).getAminoAcid3();
     } catch (Exception exception) {
       return 0.0;
     }
     String atomName = atom.getName();
     switch (aminoAcid3) {
       case HIS:
         int atomIndex = HistidineAtomNames.valueOf(atomName).ordinal();
         double his = hisPolarizeTypes[atomIndex][HisStates.HIS.ordinal()].polarizability;
         double hid = hisPolarizeTypes[atomIndex][HisStates.HID.ordinal()].polarizability;
         double hie = hisPolarizeTypes[atomIndex][HisStates.HIE.ordinal()].polarizability;
         return (1.0 - titrationLambda) * (hie - hid);
       case ASD:
         atomIndex = AspartateAtomNames.valueOf(atomName).ordinal();
         double asp = aspPolarizeTypes[atomIndex][AspStates.ASP.ordinal()].polarizability;
         double ash1 = aspPolarizeTypes[atomIndex][AspStates.ASH1.ordinal()].polarizability;
         double ash2 = aspPolarizeTypes[atomIndex][AspStates.ASH2.ordinal()].polarizability;
         return titrationLambda * (ash1 - ash2);
       case GLD:
         atomIndex = GlutamateAtomNames.valueOf(atomName).ordinal();
         double glu = gluPolarizeTypes[atomIndex][GluStates.GLU.ordinal()].polarizability;
         double glh1 = gluPolarizeTypes[atomIndex][GluStates.GLH1.ordinal()].polarizability;
         double glh2 = gluPolarizeTypes[atomIndex][GluStates.GLH2.ordinal()].polarizability;
         return titrationLambda * (glh1 - glh2);
       case LYS: // No tautomers for LYS.
       case CYS: // No tautomers for LYS.
       default:
         return 0.0;
     }
   }
 
   public static boolean isTitratingHydrogen(AminoAcid3 aminoAcid3, Atom atom) {
     boolean isTitratingHydrogen = false;
     String atomName = atom.getName();
     switch (aminoAcid3) {
       case ASD -> {
         if (atomName.equals(AspartateAtomNames.HD1.name()) || atomName.equals(
             AspartateAtomNames.HD2.name())) {
           isTitratingHydrogen = true;
         }
       }
       case GLD -> {
         if (atomName.equals(GlutamateAtomNames.HE1.name()) || atomName.equals(
             GlutamateAtomNames.HE2.name())) {
           isTitratingHydrogen = true;
         }
       }
       case HIS -> {
         if (atomName.equals(HistidineAtomNames.HD1.name()) || atomName.equals(
             HistidineAtomNames.HE2.name())) {
           isTitratingHydrogen = true;
         }
       }
       case LYS -> {
         if (atomName.equals(LysineAtomNames.HZ3.name())) {
           isTitratingHydrogen = true;
         }
       }
       case CYS -> {
         if (atomName.equals(CysteineAtomNames.HG.name())) {
           isTitratingHydrogen = true;
         }
       }
     }
     return isTitratingHydrogen;
   }
 
   /**
    * Used to keep track of heavy atoms with changing polarizability. Only affects carboxylic oxygen
    * and sulfur.
    *
    * @param aminoAcid3 The amino acid type.
    * @param atom The atom to check.
    * @return True if the atom is a heavy atom with changing polarizability.
    */
 
   public static boolean isTitratingHeavy(AminoAcid3 aminoAcid3, Atom atom) {
     boolean isTitratingHeavy = false;
     String atomName = atom.getName();
     switch (aminoAcid3) {
       case ASD -> {
         if (atomName.equals(AspartateAtomNames.OD1.name()) || atomName.equals(
             AspartateAtomNames.OD2.name())) {
           isTitratingHeavy = true;
         }
       }
       case GLD -> {
         if (atomName.equals(GlutamateAtomNames.OE1.name()) || atomName.equals(
             GlutamateAtomNames.OE2.name())) {
           isTitratingHeavy = true;
         }
       }
       case CYS -> {
         if (atomName.equals(CysteineAtomNames.SG.name())) {
           isTitratingHeavy = true;
         }
       }
     }
     return isTitratingHeavy;
   }
 
   public static int getTitratingHydrogenDirection(AminoAcid3 aminoAcid3, Atom atom) {
     int tautomerDirection = 0;
     String atomName = atom.getName();
     switch (aminoAcid3) {
       case ASD -> {
         if (atomName.equals(AspartateAtomNames.HD1.name())) {
           tautomerDirection = AspartateAtomNames.HD1.tautomerDirection;
         } else if (atomName.equals(AspartateAtomNames.HD2.name())) {
           tautomerDirection = AspartateAtomNames.HD2.tautomerDirection;
         }
       }
       case GLD -> {
         if (atomName.equals(GlutamateAtomNames.HE1.name())) {
           tautomerDirection = GlutamateAtomNames.HE1.tautomerDirection;
         } else if (atomName.equals(GlutamateAtomNames.HE2.name())) {
           tautomerDirection = GlutamateAtomNames.HE2.tautomerDirection;
         }
       }
       case HIS -> {
         if (atomName.equals(HistidineAtomNames.HD1.name())) {
           tautomerDirection = HistidineAtomNames.HD1.tautomerDirection;
         } else if (atomName.equals(HistidineAtomNames.HE2.name())) {
           tautomerDirection = HistidineAtomNames.HE2.tautomerDirection;
         }
       }
     }
     return tautomerDirection;
   }
 
   private void constructHISState(int biotypeCB, HisStates hisState) {
     int state = hisState.ordinal();
     for (HistidineAtomNames atomName : HistidineAtomNames.values()) {
       int index = atomName.ordinal();
       int offset = atomName.getOffsetHIS(hisState);
       if (offset < 0) {
         hisAtomTypes[index][state] = dummyHydrogenAtomType;
         // Zero out the MultipoleType and PolarizeType.
         if (hisState == HisStates.HID) {
           hisMultipoleTypes[index][state] = hidZeroMultipoleType;
         } else if (hisState == HisStates.HIE) {
           hisMultipoleTypes[index][state] = hieZeroMultipoleType;
         } else {
           logger.severe(" Error constructing HIS states.");
         }
         hisPolarizeTypes[index][state] = zeroPolarizeType;
         hisVDWTypes[index][state] = forceField.getVDWType(Integer.toString(0));
         hisSoluteTypes[index][state] = zeroSoluteType;
       } else {
         int biotype = biotypeCB + offset;
         hisAtomTypes[index][state] = findAtomType(biotype, forceField);
         String key = hisAtomTypes[index][state].getKey();
         hisMultipoleTypes[index][state] = forceField.getMultipoleTypeBeginsWith(key);
         hisPolarizeTypes[index][state] = forceField.getPolarizeType(key);
         int atomClass = hisAtomTypes[index][state].atomClass;
         hisVDWTypes[index][state] = forceField.getVDWType("" + atomClass);
         hisSoluteTypes[index][state] = getSoluteType(forceField, hisAtomTypes[index][state],
             hisVDWTypes[index][state]);
         if (hisMultipoleTypes[index][state] == null || hisPolarizeTypes[index][state] == null
             || hisSoluteTypes[index][state] == null) {
           logger.severe(format(" Titration parameters could not be assigned for His atom %s.\n %s\n",
               atomName, hisAtomTypes[index][state]));
         }
       }
     }
   }
 
   private void constructLYSState(int biotypeCB, LysStates lysState) {
     int state = lysState.ordinal();
     for (LysineAtomNames atomName : LysineAtomNames.values()) {
       int index = atomName.ordinal();
       int offset = atomName.getOffsetLYS(lysState);
       if (offset < 0) {
         // Set the AtomType to null.
         lysAtomTypes[index][state] = dummyHydrogenAtomType;
         // Zero out the MultipoleType and PolarizeType.
         lysMultipoleTypes[index][state] = lydZeroMultipoleType;
         lysPolarizeTypes[index][state] = zeroPolarizeType;
         lysVDWTypes[index][state] = forceField.getVDWType(Integer.toString(0));
         lysSoluteTypes[index][state] = zeroSoluteType;
       } else {
         int biotype = biotypeCB + offset;
         lysAtomTypes[index][state] = findAtomType(biotype, forceField);
         String key = lysAtomTypes[index][state].getKey();
         lysMultipoleTypes[index][state] = forceField.getMultipoleTypeBeginsWith(key);
         lysPolarizeTypes[index][state] = forceField.getPolarizeType(key);
         int atomClass = lysAtomTypes[index][state].atomClass;
         lysVDWTypes[index][state] = forceField.getVDWType("" + atomClass);
         lysSoluteTypes[index][state] = getSoluteType(forceField, lysAtomTypes[index][state],
             lysVDWTypes[index][state]);
         if (lysMultipoleTypes[index][state] == null || lysPolarizeTypes[index][state] == null
             || lysSoluteTypes[index][state] == null) {
           logger.severe(
               format(" Titration parameters could not be assigned for Lys atom %s.\n %s\n", atomName,
                   lysAtomTypes[index][state]));
         }
       }
     }
   }
 
   private void constructASPState(int biotypeCB, AspStates aspState) {
     int state = aspState.ordinal();
     for (AspartateAtomNames atomName : AspartateAtomNames.values()) {
       int index = atomName.ordinal();
       int offset = atomName.getOffset(aspState);
       if (offset < 0) {
         // Set the AtomType to null.
         aspAtomTypes[index][state] = dummyHydrogenAtomType;
         // Zero out the MultipoleType and PolarizeType.
         if (aspState == AspStates.ASP) {
           aspMultipoleTypes[index][state] = aspZeroMultipoleType;
         } else {
           aspMultipoleTypes[index][state] = ashZeroMultipoleType;
         }
         aspPolarizeTypes[index][state] = zeroPolarizeType;
         aspVDWTypes[index][state] = forceField.getVDWType(Integer.toString(0));
         aspSoluteTypes[index][state] = zeroSoluteType;
       } else {
         int biotype = biotypeCB + offset;
         aspAtomTypes[index][state] = findAtomType(biotype, forceField);
         String key = aspAtomTypes[index][state].getKey();
         aspMultipoleTypes[index][state] = forceField.getMultipoleTypeBeginsWith(key);
         aspPolarizeTypes[index][state] = forceField.getPolarizeType(key);
         int atomClass = aspAtomTypes[index][state].atomClass;
         aspVDWTypes[index][state] = forceField.getVDWType("" + atomClass);
         aspSoluteTypes[index][state] = getSoluteType(forceField, aspAtomTypes[index][state],
             aspVDWTypes[index][state]);
         if (aspMultipoleTypes[index][state] == null || aspPolarizeTypes[index][state] == null
             || aspSoluteTypes[index][state] == null) {
           logger.severe(
               format(" Titration parameters could not be assigned for Asp atom %s.\n %s\n", atomName,
                   aspAtomTypes[index][state]));
         }
       }
     }
   }
 
   private void constructGLUState(int biotypeCB, GluStates gluState) {
     int state = gluState.ordinal();
     for (GlutamateAtomNames atomName : GlutamateAtomNames.values()) {
       int index = atomName.ordinal();
       int offset = atomName.getOffset(gluState);
       if (offset < 0) {
         // Set the AtomType to null.
         gluAtomTypes[index][state] = dummyHydrogenAtomType;
         // Zero out the MultipoleType and PolarizeType.
         if (gluState == GluStates.GLU) {
           gluMultipoleTypes[index][state] = gluZeroMultipoleType;
         } else {
           gluMultipoleTypes[index][state] = glhZeroMultipoleType;
         }
         gluPolarizeTypes[index][state] = zeroPolarizeType;
         gluVDWTypes[index][state] = forceField.getVDWType(Integer.toString(0));
         gluSoluteTypes[index][state] = zeroSoluteType;
       } else {
         int biotype = biotypeCB + offset;
         gluAtomTypes[index][state] = findAtomType(biotype, forceField);
         String key = gluAtomTypes[index][state].getKey();
         gluMultipoleTypes[index][state] = forceField.getMultipoleTypeBeginsWith(key);
         gluPolarizeTypes[index][state] = forceField.getPolarizeType(key);
         int atomClass = gluAtomTypes[index][state].atomClass;
         gluVDWTypes[index][state] = forceField.getVDWType("" + atomClass);
         gluSoluteTypes[index][state] = getSoluteType(forceField, gluAtomTypes[index][state],
             gluVDWTypes[index][state]);
         if (gluMultipoleTypes[index][state] == null || gluPolarizeTypes[index][state] == null
             || gluSoluteTypes[index][state] == null) {
           logger.severe(
               format(" Titration parameters could not be assigned for Glu atom %s.\n %s\n", atomName,
                   gluAtomTypes[index][state]));
         }
       }
     }
   }
 
   private void constructCYSState(int biotypeCB, CysStates cysState) {
     int state = cysState.ordinal();
     for (CysteineAtomNames atomName : CysteineAtomNames.values()) {
       int index = atomName.ordinal();
       int offset = atomName.getOffsetCYS(cysState);
       if (offset < 0) {
         // Set the AtomType to null.
         cysAtomTypes[index][state] = dummyHydrogenAtomType;
         // Zero out the MultipoleType and PolarizeType.
         cysMultipoleTypes[index][state] = cydZeroMultipoleType;
         cysPolarizeTypes[index][state] = zeroPolarizeType;
         cysVDWTypes[index][state] = forceField.getVDWType(Integer.toString(0));
         cysSoluteTypes[index][state] = zeroSoluteType;
       } else {
         int biotype = biotypeCB + offset;
         cysAtomTypes[index][state] = findAtomType(biotype, forceField);
         String key = cysAtomTypes[index][state].getKey();
         cysMultipoleTypes[index][state] = forceField.getMultipoleTypeBeginsWith(key);
         // This is an edge case since the CB/HB atom types have more than 1 matching multipole
         if (cysMultipoleTypes[index][state] == null) {
           if (cysState == CysStates.CYS) {
             if (atomName == CysteineAtomNames.CB) {
               cysMultipoleTypes[index][state] = forceField.getMultipoleType(key + " 8 45");
             } else {
               // HB2 & HB3
               cysMultipoleTypes[index][state] = forceField.getMultipoleType(key + " 43 8");
             }
           } else {
             if (atomName == CysteineAtomNames.CB) {
               cysMultipoleTypes[index][state] = forceField.getMultipoleType(key + " 8 49");
             } else {
               // HB2 & HB3
               cysMultipoleTypes[index][state] = forceField.getMultipoleType(key + " 43 8");
             }
           }
         }
         cysPolarizeTypes[index][state] = forceField.getPolarizeType(key);
         int atomClass = cysAtomTypes[index][state].atomClass;
         cysVDWTypes[index][state] = forceField.getVDWType("" + atomClass);
         cysSoluteTypes[index][state] = getSoluteType(forceField, cysAtomTypes[index][state],
             cysVDWTypes[index][state]);
         if (cysMultipoleTypes[index][state] == null || cysPolarizeTypes[index][state] == null
             || cysSoluteTypes[index][state] == null) {
           logger.severe(
               format(" Titration parameters could not be assigned for Cys atom %s.\n %s\n", atomName,
                   cysAtomTypes[index][state]));
         }
       }
     }
   }
 
   private void checkParameterTypes(String label, AtomType[][] atomTypes,
       PolarizeType[][] polarizeTypes, MultipoleType[][] multipoleTypes, VDWType[][] vdwTypes) {
     int states = multipoleTypes.length;
     int types = multipoleTypes[0].length;
     StringBuilder sb = new StringBuilder();
     for (int t = 0; t < types; t++) {
       MultipoleFrameDefinition frame0 = multipoleTypes[0][t].frameDefinition;
       double eps0 = vdwTypes[0][t].wellDepth;
       double rad0 = vdwTypes[0][t].radius;
       sb.append(format("\n %s Type %d\n", label, t));
       sb.append(format(" %s\n  %s\n  %s\n  %s\n", atomTypes[0][t], polarizeTypes[0][t],
           multipoleTypes[0][t], vdwTypes[0][t]));
       for (int s = 1; s < states; s++) {
         sb.append(format(" %s\n  %s\n  %s\n  %s\n", atomTypes[s][t], polarizeTypes[s][t],
             multipoleTypes[s][t], vdwTypes[s][t]));
         MultipoleFrameDefinition frame = multipoleTypes[s][t].frameDefinition;
 
         if (!frame0.equals(frame)) {
           sb.append("\n Incompatible multipole frames:\n");
           sb.append(format(" %s\n  %s\n  %s\n", atomTypes[0][t], polarizeTypes[0][t],
               multipoleTypes[0][t]));
           sb.append(format(" %s\n  %s\n  %s\n", atomTypes[s][t], polarizeTypes[s][t],
               multipoleTypes[s][t]));
         }
 
         if (atomTypes[0][t].atomicNumber != 1) {
           double epsS = vdwTypes[s][t].wellDepth;
           double radS = vdwTypes[s][t].radius;
           if (epsS != eps0 || radS != rad0) {
             sb.append("\n Incompatible vdW types:\n");
             sb.append(format(" %s\n  %s\n", atomTypes[0][t], vdwTypes[0][t]));
             sb.append(format(" %s\n  %s\n", atomTypes[s][t], vdwTypes[s][t]));
           }
         }
       }
     }
 
     if (logger.isLoggable(Level.FINE)) {
       logger.fine(sb.toString());
     }
   }
 
   private SoluteType getSoluteType(ForceField forceField, AtomType atomType, VDWType vdwType) {
     SoluteType soluteType = SoluteType.getCensusSoluteType(atomType.atomicNumber);
     switch (soluteRadiiType) {
       case SOLUTE:
         SoluteType type = SoluteType.getFitSoluteType(forceField, atomType.type);
         if (type != null) {
           soluteType = type;
         }
         break;
       case VDW:
         type = SoluteType.getVDWSoluteType(vdwType);
         if (type != null) {
           soluteType = type;
         }
         break;
     }
     if (soluteType == null) {
       logger.severe(
           format(" No solute type (%s) for %d:\n  \"%s\"\n  %s", soluteRadiiType, atomType.type,
               atomType, vdwType));
     }
     return soluteType;
   }
 
   public void setRotamerPhBias(double temperature, double pH) {
     /*
      * Set ASH pH bias as sum of Fmod and acidostat energy
      */
     rotamerPhBiasMap.put(ASH, 0.0);
 
     /*
      * Set ASP pH bias as sum of Fmod and acidostat energy
      */
     double acidostat = LOG10 * Constants.R * temperature * (Titration.ASHtoASP.pKa - pH);
     double fMod = Titration.ASHtoASP.freeEnergyDiff;
     if(tanhCorrection){
       fMod = Titration.ASHtoASP.freeEnergyDiffGK;
       if(proteinDielectric == 2.0){
         fMod = Titration.ASHtoASP.freeEnergyDiffGK2;
       }
     } else if(proteinDielectric == 2.0){
       fMod = Titration.ASHtoASP.freeEnergyDiff2;
     }
     rotamerPhBiasMap.put(ASP, acidostat - fMod);
 
 
     /*
      * Set ASH pH bias as sum of Fmod and acidostat energy
      */
     rotamerPhBiasMap.put(GLH, 0.0);
 
     /*
      * Set GLU pH bias as sum of Fmod and acidostat energy
      */
     acidostat = LOG10 * Constants.R * temperature * (Titration.GLHtoGLU.pKa - pH);
     fMod = Titration.GLHtoGLU.freeEnergyDiff;
     if(tanhCorrection){
       fMod = Titration.GLHtoGLU.freeEnergyDiffGK;
       if(proteinDielectric == 2.0){
         fMod = Titration.GLHtoGLU.freeEnergyDiffGK2;
       }
     } else if(proteinDielectric == 2.0){
       fMod = Titration.GLHtoGLU.freeEnergyDiff2;
     }
     rotamerPhBiasMap.put(GLU, acidostat - fMod);
 
 
     /*
      * Set LYS pH bias as sum of Fmod and acidostat energy
      */
     rotamerPhBiasMap.put(LYS, 0.0);
 
     /*
      * Set LYD pH bias as sum of Fmod and acidostat energy
      */
     acidostat = LOG10 * Constants.R * temperature * (Titration.LYStoLYD.pKa - pH);
     fMod = Titration.LYStoLYD.freeEnergyDiff;
     if(tanhCorrection){
       fMod = Titration.LYStoLYD.freeEnergyDiffGK;
       if(proteinDielectric == 2.0){
         fMod = Titration.LYStoLYD.freeEnergyDiffGK2;
       }
     } else if(proteinDielectric == 2.0){
       fMod = Titration.LYStoLYD.freeEnergyDiff2;
     }
     rotamerPhBiasMap.put(LYD, acidostat - fMod);
 
     /*
      * Set LYS pH bias as sum of Fmod and acidostat energy
      */
     rotamerPhBiasMap.put(CYS, 0.0);
 
     /*
      * Set LYD pH bias as sum of Fmod and acidostat energy
      */
     acidostat = LOG10 * Constants.R * temperature * (Titration.CYStoCYD.pKa - pH);
     fMod = Titration.CYStoCYD.freeEnergyDiff;
     if(tanhCorrection){
       fMod = Titration.CYStoCYD.freeEnergyDiffGK;
       if(proteinDielectric == 2.0){
         fMod = Titration.CYStoCYD.freeEnergyDiffGK2;
       }
     } else if(proteinDielectric == 2.0){
       fMod = Titration.CYStoCYD.freeEnergyDiff2;
     }
     rotamerPhBiasMap.put(CYD, acidostat - fMod);
 
     /*
      * Set HIS pH bias as sum of Fmod and acidostat energy
      */
     rotamerPhBiasMap.put(HIS, 0.0);
 
     /*
      * Set HID pH bias as sum of Fmod and acidostat energy
      */
     acidostat = LOG10 * Constants.R * temperature * (Titration.HIStoHID.pKa - pH);
     fMod = Titration.HIStoHID.freeEnergyDiff;
     if(tanhCorrection){
       fMod = Titration.HIStoHID.freeEnergyDiffGK;
       if(proteinDielectric == 2.0){
         fMod = Titration.HIStoHID.freeEnergyDiffGK2;
       }
     } else if(proteinDielectric == 2.0){
       fMod = Titration.HIStoHID.freeEnergyDiff2;
     }
     rotamerPhBiasMap.put(HID, acidostat - fMod);
 
     /*
      * Set HIE pH bias as sum of Fmod and acidostat energy
      */
     acidostat = LOG10 * Constants.R * temperature * (Titration.HIStoHIE.pKa - pH);
     fMod = Titration.HIStoHIE.freeEnergyDiff;
     if(tanhCorrection){
       fMod = Titration.HIStoHIE.freeEnergyDiffGK;
       if(proteinDielectric == 2.0){
         fMod = Titration.HIStoHIE.freeEnergyDiffGK2;
       }
     } else if(proteinDielectric == 2.0){
       fMod = Titration.HIStoHIE.freeEnergyDiff2;
     }
     rotamerPhBiasMap.put(HIE, acidostat - fMod);
   }
 
   public double getRotamerPhBias(AminoAcid3 AA3) {
     return rotamerPhBiasMap.getOrDefault(AA3, 0.0);
   }
 
   public double getTotalRotamerPhBias(Rotamer[] rotamers) {
     double total = 0.0;
     for (Rotamer r : rotamers) {
       if (r.isTitrating) {
         total += getRotamerPhBias(r.aminoAcid3);
       }
     }
     return total;
   }
 
   /**
    * Predict pKa from a set of residue fractions (deprotonated / (deprotonated + protonated)). This method minimizes
    * the L2 loss between the the measured residue fractions and various pKa/Hill-coefficient values to get pKa/Hill-
    * coefficient predictions.
    *
    * @param pHScale pH values at which the residue fractions were measured
    * @param residueFractions a sorted array of residue fractions (deprotonated / (deprotonated + protonated))
    * @return {n, pKa}
    */
   public static double[] predictHillCoeffandPka(double[] pHScale, double[] residueFractions) {
 
     // Potentials for n and pKa, since LGBFS optimizer gradient is only for 1D array of gradients
     Potential hendersonHasselbach = new Potential() {
       static final double logb10 = Math.log(10);
 
       @Override
       public double energy(double[] x) {
         return leastSquaresLoss(residueFractions, getValues(x));
       }
 
       public double leastSquaresLoss(double[] residueFractions, double[] guessedFractions) {
         double loss = 0.0;
         for (int i = 0; i < residueFractions.length; i++) {
           loss += Math.pow(residueFractions[i] - guessedFractions[i], 2);
         }
         return loss;
       }
 
       public double[] getValues(double[] x) {
         double[] values = new double[pHScale.length];
         for (int i = 0; i < pHScale.length; i++) {
           values[i] = 1 / (1 + Math.pow(10, x[0] * (x[1] - pHScale[i])));
         }
         return values;
       }
 
       public void gradient(double[] x, double[] gradient) {
         // reset gradient
         Arrays.fill(gradient, 0.0);
         double[] values = getValues(x);
         for (int i = 0; i < pHScale.length; i++) {
           // term = 10^(n(pKa - pH))
           double term = Math.pow(10, x[0] * (x[1] - pHScale[i]));
 
           // d = (1 + term)^2
           double d = (1 + term) * (1 + term);
 
           // -sum(d(cost)/dn) across pH values
           gradient[0] += 2*(residueFractions[i] - values[i]) * logb10 * (x[1] - pHScale[i]) * term / d;
 
           // -sum(d(cost)/dpKa) across pH values
           gradient[1] += 2*(residueFractions[i] - values[i]) * x[0] * logb10 * term / d;
         }
       }
 
       @Override
       public double energyAndGradient(double[] x, double[] g) {
         gradient(x, g);
         return energy(x);
       }
 
       @Override
       public double[] getAcceleration(double[] acceleration) {
         return new double[0];
       }
 
       @Override
       public double[] getCoordinates(double[] parameters) {
         return new double[0];
       }
 
       @Override
       public STATE getEnergyTermState() {
         return null;
       }
 
       @Override
       public void setEnergyTermState(STATE state) {}
       @Override
       public double[] getMass() {
         return new double[0];
       }
 
       @Override
       public int getNumberOfVariables() {
         return 0;
       }
 
       @Override
       public double[] getPreviousAcceleration(double[] previousAcceleration) {
         return new double[0];
       }
 
       @Override
       public double[] getScaling() {
         return null;
       }
 
       @Override
       public void setScaling(double[] scaling) {}
       @Override
       public double getTotalEnergy() {
         return 0;
       }
 
       @Override
       public VARIABLE_TYPE[] getVariableTypes() {
         return new VARIABLE_TYPE[0];
       }
 
       @Override
       public double[] getVelocity(double[] velocity) {
         return new double[0];
       }
 
       @Override
       public void setAcceleration(double[] acceleration) {}
       @Override
       public void setPreviousAcceleration(double[] previousAcceleration) { }
       @Override
       public void setVelocity(double[] velocity) {}
     };
 
     // Call L-BFGS optimizer on hendersonHasselbach least squares potential
     int n = 2;
     double[] x = new double[]{1.0, 7.0}; // initial guess pKa
     int m = 3;
     double energy = hendersonHasselbach.energy(x);
     double[] grad = new double[n];
     hendersonHasselbach.energyAndGradient(x, grad);
     hendersonHasselbach.setScaling(new double[]{1.0, 1.0});
     double eps = 1e-5;
     int maxIterations = 100;
     OptimizationListener listener = new OptimizationListener() {
       @Override
       public boolean optimizationUpdate(int iter, int nBFGS, int nFunctionEvals, double gradientRMS,
                                         double coordinateRMS, double f, double df, double angle,
                                         LineSearch.LineSearchResult info) {
         return true;
       }
     };
 
     int statuspKa = LBFGS.minimize(n, m, x, energy, grad, eps, maxIterations,
             hendersonHasselbach, listener);
 
     return new double[]{x[0], x[1]};
   }
 
   /**
    * Amino acid protonation reactions. Constructors below specify intrinsic pKa and reference free
    * energy of protonation, obtained via BAR on capped monomers. pKa values from Thurlkill, Richard
    * L., et al. "pK values of the ionizable groups of proteins." Protein science 15.5 (2006):
    * 1214-1218.
    * <p>
    * HIS to HID/HIE pKa values from Bashford, Donald, et al. "Electrostatic calculations of
    * side-chain pKa values in myoglobin and comparison with NMR data for histidines." Biochemistry
    * 32.31 (1993): 8045-8056.
    * <p>
    * ASP value from Grimsley, Gerald R., J. Martin Scholtz, and C. Nick Pace.
    * "A summary of the measured pK values of the ionizable groups in folded proteins."
    * Protein Science 18.1 (2009): 247-251.
    * <p>
    * 2023 Fmod values
    * ASP: -71.10
    * GLU: -83.40
    * LYS: 41.77
    * CYS: -66.2
    * HID: 40.20
    * HIE: 37.44
    * <p>
    * March 2024 Fmod values from R. Gogal
    * ASP: -70.35
    * GLU: -81.90
    * LYS: 41.45
    * CYS: -59.5
    * HID: 40.20
    * HIE: 37.44
    */
   public enum Titration {
 
     ASHtoASP(3.94, -70.35, -35.35,-45.39, -23.15, 12.730, -107.430, 166.369, 0.0, AminoAcid3.ASH, AminoAcid3.ASP),
     ASH1toASH2(Double.NaN, 0.00,0,0,0, 0.0, -35.305, 35.305, 0.0, AminoAcid3.ASH, AminoAcid3.ASH),
     GLHtoGLU(4.25, -81.90, -39.71, -55.74, -26.3,28.024, -131.270, 189.980, 0.0,  AminoAcid3.GLH, AminoAcid3.GLU),
     GLH1toGLH2(Double.NaN, 0,0,0,0.00, 0.0, -29.395, 29.395, 0.0, AminoAcid3.GLH, AminoAcid3.GLH),
     LYStoLYD(10.40, 41.35, 20.0, 41.31, 19.7,6.752, -78.804, 26.894, 0.0, AminoAcid3.LYS, AminoAcid3.LYD),
     //TYRtoTYD(10.07, 34.961, 0.0, AminoAcidUtils.AminoAcid3.TYR, AminoAcidUtils.AminoAcid3.TYD),
     CYStoCYD(8.55, -53.1, 0.0, 0.0, 0.0,44.247, -183.990, 226.710, 0.0, AminoAcid3.CYS, AminoAcid3.CYD), //HE2 is the proton that is lost
     HIStoHID(7.00, 40.20, 20.92, 36.65, 18.83, 0.0, -64.317, 30.350, 0.0,  AminoAcid3.HIS, AminoAcid3.HID), //HD1 is the proton that is lost
     HIStoHIE(6.60, 37.44, 18.14, 34.65, 17.95,0.0, -62.931, 32.000, 0.0,AminoAcid3.HIS, AminoAcid3.HIE),
     HIDtoHIE(Double.NaN, 0.00, 0.0, 0.0, 0.0,0.0, -36.830, 34.325, 0.0,AminoAcid3.HID, AminoAcid3.HIE);
     //TerminalNH3toNH2(8.23, 0.0, 00.00, AminoAcidUtils.AminoAcid3.UNK, AminoAcidUtils.AminoAcid3.UNK),
     //TerminalCOOHtoCOO(3.55, 0.0, 00.00, AminoAcidUtils.AminoAcid3.UNK, AminoAcidUtils.AminoAcid3.UNK);
 
 
     public final double pKa;
     // Free energy differences used in rotamer optimization
     public final double freeEnergyDiff;
     public final double freeEnergyDiff2;
     public final double freeEnergyDiffGK;
     public final double freeEnergyDiffGK2;
     public final double cubic;
     public final double quadratic;
     public final double linear;
     public final double offset;
     public final AminoAcid3 protForm;
     public final AminoAcid3 deprotForm;
 
     /** Invoked by Enum; use the factory method to obtain instances. */
 
     Titration(double pKa, double freeEnergyDiff,double freeEnergyDiff2, double freeEnergyDiffGK,
               double freeEnergyDiffGK2, double cubic, double quadratic, double linear, double offset,
         AminoAcid3 protForm, AminoAcid3 deprotForm) {
       this.pKa = pKa;
       this.freeEnergyDiff = freeEnergyDiff;
       this.freeEnergyDiff2 = freeEnergyDiff2;
       this.freeEnergyDiffGK = freeEnergyDiffGK;
       this.freeEnergyDiffGK2 = freeEnergyDiffGK2;
       this.cubic = cubic;
       this.quadratic = quadratic;
       this.linear = linear;
       this.offset = offset;
       this.protForm = protForm;
       this.deprotForm = deprotForm;
     }
   }
 }