Dataset Information

Adaptive Landscape Flattening Accelerates Sampling of Alchemical Space in Multisite ? Dynamics.

ABSTRACT: Multisite ? dynamics (MS?D) is a powerful emerging method in free energy calculation that allows prediction of relative free energies for a large set of compounds from very few simulations. Calculating free energy differences between substituents that constitute large volume or flexibility jumps in chemical space is difficult for free energy methods in general, and for MS?D in particular, due to large free energy barriers in alchemical space. This study demonstrates that a simple biasing potential can flatten these barriers and introduces an algorithm that determines system specific biasing potential coefficients. Two sources of error, deep traps at the end points and solvent disruption by hard-core potentials, are identified. Both scale with the size of the perturbed substituent and are removed by sharp biasing potentials and a new soft-core implementation, respectively. MS?D with landscape flattening is demonstrated on two sets of molecules: derivatives of the heat shock protein 90 inhibitor geldanamycin and derivatives of benzoquinone. In the benzoquinone system, landscape flattening leads to 2 orders of magnitude improvement in transition rates between substituents and robust solvation free energies. Landscape flattening opens up new applications for MS?D by enabling larger chemical perturbations to be sampled with improved precision and accuracy.

SUBMITTER: Hayes RL

PROVIDER: S-EPMC5824625 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Adaptive Landscape Flattening Accelerates Sampling of Alchemical Space in Multisite λ Dynamics.

Hayes Ryan L RL Armacost Kira A KA Vilseck Jonah Z JZ Brooks Charles L CL

The journal of physical chemistry. B 20170210 15

Multisite λ dynamics (MSλD) is a powerful emerging method in free energy calculation that allows prediction of relative free energies for a large set of compounds from very few simulations. Calculating free energy differences between substituents that constitute large volume or flexibility jumps in chemical space is difficult for free energy methods in general, and for MSλD in particular, due to large free energy barriers in alchemical space. This study demonstrates that a simple biasing potenti ...[more]

PMID: 28112940

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Project description:Molecular dynamics (MD) simulation is widely used to study protein conformations and dynamics. However, conventional simulation suffers from being trapped in some local energy minima that are hard to escape. Thus, most of the computational time is spent sampling in the already visited regions. This leads to an inefficient sampling process and further hinders the exploration of protein movements in affordable simulation time. The advancement of deep learning provides new opportunities for protein sampling. Variational autoencoders are a class of deep learning models to learn a low-dimensional representation (referred to as the latent space) that can capture the key features of the input data. Based on this characteristic, we proposed a new adaptive sampling method, latent space-assisted adaptive sampling for protein trajectories (LAST), to accelerate the exploration of protein conformational space. This method comprises cycles of (i) variational autoencoder training, (ii) seed structure selection on the latent space, and (iii) conformational sampling through additional MD simulations. The proposed approach is validated through the sampling of four structures of two protein systems: two metastable states of Escherichia coli adenosine kinase (ADK) and two native states of Vivid (VVD). In all four conformations, seed structures were shown to lie on the boundary of conformation distributions. Moreover, large conformational changes were observed in a shorter simulation time when compared with structural dissimilarity sampling (SDS) and conventional MD (cMD) simulations in both systems. In metastable ADK simulations, LAST explored two transition paths toward two stable states, while SDS explored only one and cMD neither. In VVD light state simulations, LAST was three times faster than cMD simulation with a similar conformational space. Overall, LAST is comparable to SDS and is a promising tool in adaptive sampling. The LAST method is publicly available at https://github.com/smu-tao-group/LAST to facilitate related research.

Dataset Information

Adaptive Landscape Flattening Accelerates Sampling of Alchemical Space in Multisite ? Dynamics.

Publications

Adaptive Landscape Flattening Accelerates Sampling of Alchemical Space in Multisite λ Dynamics.

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