GPU Accelerated Side-Chain Optimization
Amino acid side-chain optimization algorithms that utilize discrete rotamer libraries of optimal side-chain conformations are used to find the global minimum energy conformation of a protein. Under a many-body energy expansion, Force Field X can optimize side-chain conformations up to four-body side-chain interactions. Using this aggressive many-body expansion is computationally expensive; through the use of Graphical Processing Units (GPUs) and the OpenMM software package, Force Field X is capable of computing the energy of side-chain conformations 25x faster than the first implementation of side-chain optimization.
Best Practices Overview
The following example demonstrates global optimization of Chignolin side-chains (PDB 1UAO). The best practices protocol is as follows:
- Minimize the model to eliminate obvious steric clashes.
- Optimize the model using all-with-rotamer-elimination global optimization. If the protein is large, use the sliding box method approximate global optimization.
- Minimize the model to allow rigid rotamer conformations to establish ideal intermolecular contacts.
Minimization of a Short Peptide
To perform a minimization on the peptide, use the command below:
ffxc Minimize 1uao.pdb
Output from the minimization will show each iteration of the algorithm and the resulting energy of the protein model. Pictured below are iterations 76-80 and the energy output. This simulation should take less than one minute of computing time on a standard laptop.
76 -242.8328 1.1926 0.3876 0.0032 75.14 77 0.025
77 -243.3192 1.3723 0.4864 0.0041 67.24 78 0.027
78 -243.7189 1.1017 0.3997 0.0068 75.87 79 0.034
79 -243.8713 1.4691 0.1524 0.0028 66.85 80 0.035
80 -244.1078 0.8571 0.2365 0.0010 60.08 81 0.031
Optimization achieved convergence criteria: 0.85712
Computed Potential Energy
Bond Stretching 9.04900448 141 0.000 ( 0.01322)
Angle Bending 50.63504369 249 0.000 ( 3.54833)
Stretch-Bend -0.39314453 229 0.000
Out-of-Plane Bend 4.38249086 108 0.000
Torsional Angle 8.76885188 369 0.000
Pi-Orbital Torsion 2.77304417 25 0.000
Torsion-Torsion -4.58642973 7 0.000
Van der Waals 63.64719498 9063 0.003
Atomic Multipoles -316.37910863 9453
Polarization -62.00472529 9453 0.037
Total Potential -244.10777813 (Kcal/mole) 0.042 (sec)
Saving 1uao.pdb_2
The resulting PDB file is automatically saved as 1uao.pdb_2.
Side-Chain Optimization of a Short Peptide Without a GPU
To perform an all-with-rotamer-elimination side-chain optimization on the minimized peptide without use of a GPU, use the command below:
ffxc ManyBody -a 2 -l 2 -x 1 1uao.pdb_2
Output from the ManyBody algorithm will show energy evaluations of self and pair side-chain energies along with a printout overall system energy. The final rotamers and overall energy are shown below. This simulation should take less than one minute of computing time on a standard laptop.
Final rotamers:
--------------------------------------------------------------------------------------------
Residue | Chi 1 | Chi 2 | Chi 3 | Chi 4 | Energy |
--------------------------------------------------------------------------------------------
1 A ( 2-TYR, 0) | -172.5 0.0 | 90.2 0.0 | 114.2 0.0 | 0.0 0.0 | -19.4350 |
2 A ( 3-ASP, 0) | 176.3 0.0 | 0.0 0.0 | 0.0 0.0 | 0.0 0.0 | -28.3183 |
3 A ( 5-GLU, 0) | -165.5 0.0 | -84.1 0.0 | 22.3 0.0 | 0.0 0.0 | 9.5233 |
4 A ( 6-THR, 5) | 62.0 0.0 | -60.0 0.0 | 0.0 0.0 | 0.0 0.0 | -8.2411 |
5 A ( 8-THR,12) | -175.0 0.0 | -120.0 0.0 | 0.0 0.0 | 0.0 0.0 | -3.3993 |
6 A ( 9-TRP, 0) | -41.5 0.0 | 87.5 0.0 | 0.0 0.0 | 0.0 0.0 | 5.9391 |
--------------------------------------------------------------------------------------------
Final Minimum Energy
Computed Potential Energy
Bond Stretching 8.77023477 141 0.000 ( 0.01299)
Angle Bending 50.20607206 249 0.000 ( 3.53036)
Stretch-Bend -0.50772738 229 0.000
Out-of-Plane Bend 4.40102720 108 0.000
Torsional Angle 8.77155306 369 0.000
Pi-Orbital Torsion 2.76777372 25 0.000
Torsion-Torsion -4.58901318 7 0.000
Van der Waals 71.10186683 9063 0.000
Atomic Multipoles -331.31181960 9453
Polarization -63.51240025 9453 0.012
Total Potential -253.90243277 (Kcal/mole) 0.014 (sec)
Saving 1uao.pdb_3
The resulting PDB file is automatically saved as 1uao.pdb_3.
Alternatively, the previous command can be excuted using OpenMM. Please be sure OpenMM is configured by following the instructions here: OpenMM Installation.
ffxc ManyBody -a 2 -l 2 -x 1 1uao.pdb_2 -Dplatform=omm
Optimization of a Deafness Related Protein With a GPU
This next example is based on the deafness related COCH protein. Start by installing OpenMM by following the instructions here: OpenMM Installation. If OpenMM is not installed, the program will run without a GPU. Next, download the coordinate file and rename it to COCH.pdb (PDB COCH). Perform a minimization and a GPU accelerated side-chain optimization by using the commands below:
ffxc Minimize COCH.pdb
ffxc ManyBody -Dplatform=OMM -a 2 -l 2 -tC 1000 -x 1 -p 1 COCH.pdb_2
When using a GPU with the OpenMM platform, energy evaluations on side-chains will occur approximately 25x faster than without a GPU. This simulation should finish within one hour on a GPU. The resulting PDB file is automatically saved as COCH.pdb_3.
A description of all of the flags used in the ManyBody command is below:
| Command | Description |
|---|---|
| -a 2 | Algorithm using Goldstein Elimination. |
| -l 2 | Richardson rotamer library. |
| -tC 1000 | Cutoff distance for two-body side-chain interactions (1000 Angstroms). |
| -x 1 | Start simulation at first amino acid in protein. |
| -p 1 | Prune side-chain conformations that clash with protein backbone. |
| -Dplatform=OMM | Use OpenMM to run the algorithm on a GPU. |