Perturbation Free-Energy Toolkit: An Automated Alchemical Topology Builder.

Drazen Petrov

doi:10.1021/acs.jcim.1c00428

Abstract

Free-energy calculations play an important role in the application of computational chemistry to a range of fields, including protein biochemistry, rational drug design, or materials science. Importantly, the free-energy difference is directly related to experimentally measurable quantities such as partition and adsorption coefficients, water activity, and binding affinities. Among several techniques aimed at predicting free-energy differences, perturbation approaches, involving the alchemical transformation of one molecule into another through intermediate states, stand out as rigorous methods based on statistical mechanics. However, despite the importance of free-energy calculations, the applicability of the perturbation approaches is still largely impeded by a number of challenges, including the definition of the perturbation path, i.e., alchemical changes leading to the transformation of one molecule to the other. To address this, an automatic perturbation topology builder based on a graph-matching algorithm is developed, which can identify the maximum common substructure (MCS) of two or multiple molecules and provide the perturbation topologies suitable for free-energy calculations using the GROMOS and the GROMACS simulation packages. Various MCS search options are presented leading to alternative definitions of the perturbation pathway. Moreover, perturbation topologies generated using the default multistate MCS search are used to calculate the changes in free energy between lysine and its two post-translational modifications, 3-methyllysine and acetyllysine. The pairwise free-energy calculations performed on this test system led to a cycle closure of 0.5 ± 0.3 and 0.2 ± 0.2 kJ mol–1, with GROMOS and GROMACS simulation packages, respectively. The same relative free energies between the three states are obtained by employing the enveloping distribution sampling (EDS) approach when compared to the pairwise perturbations. Importantly, this toolkit is made available online as an open-source Python package (https://github.com/drazen-petrov/SMArt).

Highlights

Calculation of free-energy differences is one of the main objectives in computational chemistry as such differences characterize chemical processes, directly determining properties such as ligand binding affinities or partition coefficients
While enumerating the substructures, the algorithm evaluates the perturbations based on molecular topologies, making it possible to guide the search toward different outcomes, via a user-defined score function
This study presents an automated tool for generating perturbation topologies (GROMOS and GROMACS file formats) based on the single topology approach by employing a maximum common substructure search algorithm

Summary

Introduction

Calculation of free-energy differences is one of the main objectives in computational chemistry as such differences characterize chemical processes, directly determining properties such as ligand binding affinities or partition coefficients. Perturbation free-energy calculations, involving the alchemical transformation of one chemical into another via a pathway of unphysical intermediate states, present a rigorous approach derived from statistical mechanics.[1−12] Several such methods have been developed over the years, including, for instance, thermodynamic integration,[13] its extended version,[14] or Bennett’s acceptance ratio.[15] More recently, nonequilibrium techniques like the Crooks Gaussian intersection method[16,17] and the Jarzynski equality[18,19] have been applied. The dual topology approach either replaces (by perturbing into and from noninteracting dummy atoms) all atoms of one compound with the atoms of the other[29,30] or replaces only a subset of nonmatching atoms while keeping atoms with matching atom types unperturbed.[31,32] Alternatively, only a subset of nonmatching atoms can be perturbed into each other while minimizing the number of such perturbations, i.e., the single topology approach,[29,31,32] which is especially beneficial when

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