Biological and Medicinal Chemistry

Virtual reality sampled pathways guide free energy calculation of protein-ligand binding

Authors

Abstract

We describe a novel two-step approach for combining cloud-mounted interactive molecular dynamics in virtual reality (iMD-VR) with free energy sampling (FES) approaches to quantitatively explore the dynamics of biological processes at the molecular level. The combined approach we refer to as the iMD-VR-FES protocol. Stage one involves using a state-of-the-art iMD-VR framework to quickly sample a diverse range of protein-ligand unbinding pathways, benefitting from the sophistication of human spatial and chemical intuition. Stage two involves using the iMD-VR-sampled pathways as initial guesses for defining a path-based reaction coordinate from which we can obtain a corresponding free energy profile using FES methods. To investigate the performance of the method, we apply iMR-VR-FES to investigate the unbinding of a benzamidine ligand from a trypsin protein. Unbinding free energies calculated using iMD-VR-FES show good internal consistency, and broadly agree with previous literature values. Moreover, the resulting free energy profiles can distinguish energetic differences corresponding to various protein-ligand conformations (e.g., helping to identifying favorable vs. unfavorable pathways) and also enable identification of metastable states along the unbinding pathways. The two-step iMD-VR-FES approach offers an intuitive way for researchers to test various hypotheses of dynamical and conformational change, in order to quickly obtain both qualitative and quantitative insight.

Content

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Supplementary material

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Virtual reality sampled pathways guide free energy calculation of protein-ligand binding (supplementary text)
The SI text contains instructions for connecting to a cloud-hosted instance of a trypsin-benzamidine simulation. Furthermore, the SI contains additional details on the MD protocols used in this work, a description of the 6-dimesional CV space, explicit expressions for the pathCVs and the protocols used for Umbrella Sampling and Adaptive String Method calculations.
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Virtual reality sampled pathways guide free energy calculation of protein-ligand binding (supplementary files)
The files necessary for running a standalone simulation of trypsin and benzamidine in Narupa (https://gitlab.com/intangiblerealities/narupa-protocol), simulation parameters, the seven iMD-VR guided trajectories, reference pathways and the free energy profiles for all the runs have been uploaded as part of the supplementary materials.