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Biasing Potential Replica Exchange Multisite ?-Dynamics for Efficient Free Energy Calculations.

ABSTRACT: Traditional free energy calculation methods are well-known for their drawbacks in scalability and speed in converging results particularly for calculations with large perturbations. In the present work, we report on the development of biasing potential replica exchange multisite ?-dynamics (BP-REX MS?D), which is a free energy method that is capable of performing simultaneous alchemical free energy transformations, including perturbations between flexible moieties. BP-REX MS?D and the original MS?D are applied to a series of symmetrical 2,5-benzoquinone derivatives covering a diverse chemical space and range of conformational flexibility. Improved ?-space sampling is observed for the BP-REX MS?D simulations, yielding a 2-5-fold increase in the number of transitions between substituents compared to traditional MS?D. We also demonstrate the efficacy of varying the value of c, the parameter that controls the ruggedness of the landscape mediating the sampling of ?-states, based on the flexibility of the fragment. Finally, we developed a protocol for maximizing the transition frequency between fragments. This protocol reduces the "kinetic barrier" for alchemically transforming fragments by grouping and ordering based on volume. These findings are applied to a challenging test set involving a series of geldanamycin-based inhibitors of heat shock protein 90 (Hsp90). Even though the perturbations span volume changes by as large as 60 Å(3), the values for the free energy change achieve an average unsigned error (AUE) of 1.5 kcal/mol relative to experimental Kd measurements with a reasonable correlation (R = 0.56). Our results suggest that the BP-REX MS?D algorithm is a highly efficient and scalable free energy method, which when utilized will enable routine calculations on the order of hundreds of compounds using only a few simulations.

SUBMITTER: Armacost KA

PROVIDER: S-EPMC4731093 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Biasing Potential Replica Exchange Multisite λ-Dynamics for Efficient Free Energy Calculations.

Armacost Kira A KA Goh Garrett B GB Brooks Charles L CL

Journal of chemical theory and computation 20150301 3

Traditional free energy calculation methods are well-known for their drawbacks in scalability and speed in converging results particularly for calculations with large perturbations. In the present work, we report on the development of biasing potential replica exchange multisite λ-dynamics (BP-REX MSλD), which is a free energy method that is capable of performing simultaneous alchemical free energy transformations, including perturbations between flexible moieties. BP-REX MSλD and the original M ...[more]

PMID: 26579773

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Project description:Accurate predictions of changes to protein-ligand binding affinity in response to chemical modifications are of utility in small-molecule lead optimization. Relative free-energy perturbation (FEP) approaches are one of the most widely utilized for this goal but involve significant computational cost, thus limiting their application to small sets of compounds. Lambda dynamics, also rigorously based on the principles of statistical mechanics, provides a more efficient alternative. In this paper, we describe the development of a workflow to set up, execute, and analyze multisite lambda dynamics (MSLD) calculations run on GPUs with CHARMM implemented in BIOVIA Discovery Studio and Pipeline Pilot. The workflow establishes a framework for setting up simulation systems for exploratory screening of modifications to a lead compound, enabling the calculation of relative binding affinities of combinatorial libraries. To validate the workflow, a diverse data set of congeneric ligands for seven proteins with experimental binding affinity data is examined. A protocol to automatically tailor fit biasing potentials iteratively to flatten the free-energy landscape of any MSLD system is developed, which enhances sampling and allows for efficient estimation of free-energy differences. The protocol is first validated on a large number of ligand subsets that model diverse substituents, which shows accurate and reliable performance. The scalability of the workflow is also tested to screen more than 100 ligands modeled in a single system, which also resulted in accurate predictions. With a cumulative sampling time of 150 ns or less, the method results in average unsigned errors of under 1 kcal/mol in most cases for both small and large combinatorial libraries. For the multisite systems examined, the method is estimated to be more than an order of magnitude more efficient than contemporary FEP applications. The results thus demonstrate the utility of the presented MSLD workflow to efficiently screen combinatorial libraries and explore the chemical space around a lead compound and thus are of utility in lead optimization.

Dataset Information

Biasing Potential Replica Exchange Multisite ?-Dynamics for Efficient Free Energy Calculations.

Publications

Biasing Potential Replica Exchange Multisite λ-Dynamics for Efficient Free Energy Calculations.

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