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Automated conformational energy fitting for force-field development.

ABSTRACT: We present a general conformational-energy fitting procedure based on Monte Carlo simulated annealing (MCSA) for application in the development of molecular mechanics force fields. Starting with a target potential energy surface and an unparametrized molecular mechanics potential energy surface, an optimized set of either dihedral or grid-based correction map (CMAP) parameters is produced that minimizes the root mean squared error RMSE between the parametrized and targeted energies. The fitting is done using an MCSA search in parameter space and consistently converges to the same RMSE irrespective of the randomized parameters used to seed the search. Any number of dihedral parameters can be simultaneously parametrized, allowing for fitting to multi-dimensional potential energy scans. Fitting options for dihedral parameters include non-uniform weighting of the target data, constraining multiple optimized parameters to the same value, constraining parameters to be no greater than a user-specified maximum value, including all or only a subset of multiplicities defining the dihedral Fourier series, and optimization of phase angles in addition to force constants. The dihedral parameter fitting algorithm's performance is characterized through multi-dimensional fitting of cyclohexane, tetrahydropyran, and hexopyranose monosaccharide energetics, with the latter case having a 30-dimensional parameter space. The CMAP fitting is applied in the context of polypeptides, and is used to develop a parametrization that simultaneously captures the phi,psi energetics of the alanine dipeptide and the alanine tetrapeptide. Because the dihedral energy term is common to many force fields, we have implemented the dihedral-fitting algorithm in the portable Python scripting language and have made it freely available as "fit_dihedral.py" for download at http://mackerell.umaryland.edu.

SUBMITTER: Guvench O

PROVIDER: S-EPMC2864003 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Automated conformational energy fitting for force-field development.

Guvench Olgun O MacKerell Alexander D AD

Journal of molecular modeling 20080506 8

We present a general conformational-energy fitting procedure based on Monte Carlo simulated annealing (MCSA) for application in the development of molecular mechanics force fields. Starting with a target potential energy surface and an unparametrized molecular mechanics potential energy surface, an optimized set of either dihedral or grid-based correction map (CMAP) parameters is produced that minimizes the root mean squared error RMSE between the parametrized and targeted energies. The fitting ...[more]

PMID: 18458967

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Project description:By applying REMD simulations we have performed comparative analysis of the conformational ensembles of amino-truncated A?10-40 peptide produced with five force fields, which combine four protein parameterizations (CHARMM36, CHARMM22*, CHARMM22/cmap, and OPLS-AA) and two water models (standard and modified TIP3P). A?10-40 conformations were analyzed by computing secondary structure, backbone fluctuations, tertiary interactions, and radius of gyration. We have also calculated A?10-40 3JHNH?-coupling and RDC constants and compared them with their experimental counterparts obtained for the full-length A?1-40 peptide. Our study led us to several conclusions. First, all force fields predict that A? adopts unfolded structure dominated by turn and random coil conformations. Second, specific TIP3P water model does not dramatically affect secondary or tertiary A?10-40 structure, albeit standard TIP3P model favors slightly more compact states. Third, although the secondary structures observed in CHARMM36 and CHARMM22/cmap simulations are qualitatively similar, their tertiary interactions show little consistency. Fourth, two force fields, OPLS-AA and CHARMM22* have unique features setting them apart from CHARMM36 or CHARMM22/cmap. OPLS-AA reveals moderate ?-structure propensity coupled with extensive, but weak long-range tertiary interactions leading to A? collapsed conformations. CHARMM22* exhibits moderate helix propensity and generates multiple exceptionally stable long- and short-range interactions. Our investigation suggests that among all force fields CHARMM22* differs the most from CHARMM36. Fifth, the analysis of 3JHNH?-coupling and RDC constants based on CHARMM36 force field with standard TIP3P model led us to an unexpected finding that in silico A?10-40 and experimental A?1-40 constants are generally in better agreement than these quantities computed and measured for identical peptides, such as A?1-40 or A?1-42. This observation suggests that the differences in the conformational ensembles of A?10-40 and A?1-40 are small and the former can be used as proxy of the full-length peptide. Based on this argument, we concluded that CHARMM36 force field with standard TIP3P model produces the most accurate representation of A?10-40 conformational ensemble.

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Automated conformational energy fitting for force-field development.

Publications

Automated conformational energy fitting for force-field development.

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