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Free-energy calculations of residue mutations in a tripeptide using various methods to overcome inefficient sampling.

ABSTRACT: Previous free-energy calculations have shown that the seemingly simple transformation of the tripeptide KXK to KGK in water holds some unobvious challenges concerning the convergence of the forward and backward thermodynamic integration processes (i.e., hysteresis). In the current study, the central residue X was either alanine, serine, glutamic acid, lysine, phenylalanine, or tyrosine. Interestingly, the transformation from alanine to glycine yielded the highest hysteresis in relation to the extent of the chemical change of the side chain. The reason for that could be attributed to poor sampling of ?2 /?2 dihedral angles along the transformation. Altering the nature of alanine's C? atom drastically improved the sampling and at the same time led to the identification of high energy barriers as cause for it. Consequently, simple strategies to overcome these barriers are to increase simulation time (computationally expensive) or to use enhanced sampling techniques such as Hamiltonian replica exchange molecular dynamics and one-step perturbation. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.

SUBMITTER: Graf MM

PROVIDER: S-EPMC5082540 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Free-energy calculations of residue mutations in a tripeptide using various methods to overcome inefficient sampling.

Graf Michael M H MM Maurer Manuela M Oostenbrink Chris C

Journal of computational chemistry 20160916 29

Previous free-energy calculations have shown that the seemingly simple transformation of the tripeptide KXK to KGK in water holds some unobvious challenges concerning the convergence of the forward and backward thermodynamic integration processes (i.e., hysteresis). In the current study, the central residue X was either alanine, serine, glutamic acid, lysine, phenylalanine, or tyrosine. Interestingly, the transformation from alanine to glycine yielded the highest hysteresis in relation to the ex ...[more]

PMID: 27634475

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Project description:Approaches for computing small molecule binding free energies based on molecular simulations are now regularly being employed by academic and industry practitioners to study receptor-ligand systems and prioritize the synthesis of small molecules for ligand design. Given the variety of methods and implementations available, it is natural to ask how the convergence rates and final predictions of these methods compare. In this study, we describe the concept and results for the SAMPL6 SAMPLing challenge, the first challenge from the SAMPL series focusing on the assessment of convergence properties and reproducibility of binding free energy methodologies. We provided parameter files, partial charges, and multiple initial geometries for two octa-acid (OA) and one cucurbit[8]uril (CB8) host-guest systems. Participants submitted binding free energy predictions as a function of the number of force and energy evaluations for seven different alchemical and physical-pathway (i.e., potential of mean force and weighted ensemble of trajectories) methodologies implemented with the GROMACS, AMBER, NAMD, or OpenMM simulation engines. To rank the methods, we developed an efficiency statistic based on bias and variance of the free energy estimates. For the two small OA binders, the free energy estimates computed with alchemical and potential of mean force approaches show relatively similar variance and bias as a function of the number of energy/force evaluations, with the attach-pull-release (APR), GROMACS expanded ensemble, and NAMD double decoupling submissions obtaining the greatest efficiency. The differences between the methods increase when analyzing the CB8-quinine system, where both the guest size and correlation times for system dynamics are greater. For this system, nonequilibrium switching (GROMACS/NS-DS/SB) obtained the overall highest efficiency. Surprisingly, the results suggest that specifying force field parameters and partial charges is insufficient to generally ensure reproducibility, and we observe differences between seemingly converged predictions ranging approximately from 0.3 to 1.0 kcal/mol, even with almost identical simulations parameters and system setup (e.g., Lennard-Jones cutoff, ionic composition). Further work will be required to completely identify the exact source of these discrepancies. Among the conclusions emerging from the data, we found that Hamiltonian replica exchange-while displaying very small variance-can be affected by a slowly-decaying bias that depends on the initial population of the replicas, that bidirectional estimators are significantly more efficient than unidirectional estimators for nonequilibrium free energy calculations for systems considered, and that the Berendsen barostat introduces non-negligible artifacts in expanded ensemble simulations.

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Free-energy calculations of residue mutations in a tripeptide using various methods to overcome inefficient sampling.

Publications

Free-energy calculations of residue mutations in a tripeptide using various methods to overcome inefficient sampling.

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