Issue 4, 2020

Large scale relative protein ligand binding affinities using non-equilibrium alchemy

Abstract

Ligand binding affinity calculations based on molecular dynamics (MD) simulations and non-physical (alchemical) thermodynamic cycles have shown great promise for structure-based drug design. However, their broad uptake and impact is held back by the notoriously complex setup of the calculations. Only a few tools other than the free energy perturbation approach by Schrödinger Inc. (referred to as FEP+) currently enable end-to-end application. Here, we present for the first time an approach based on the open-source software pmx that allows to easily set up and run alchemical calculations for diverse sets of small molecules using the GROMACS MD engine. The method relies on theoretically rigorous non-equilibrium thermodynamic integration (TI) foundations, and its flexibility allows calculations with multiple force fields. In this study, results from the Amber and Charmm force fields were combined to yield a consensus outcome performing on par with the commercial FEP+ approach. A large dataset of 482 perturbations from 13 different protein–ligand datasets led to an average unsigned error (AUE) of 3.64 ± 0.14 kJ mol−1, equivalent to Schrödinger's FEP+ AUE of 3.66 ± 0.14 kJ mol−1. For the first time, a setup is presented for overall high precision and high accuracy relative protein–ligand alchemical free energy calculations based on open-source software.

Graphical abstract: Large scale relative protein ligand binding affinities using non-equilibrium alchemy

Supplementary files

Article information

Article type
Edge Article
Submitted
25 juil. 2019
Accepted
01 déc. 2019
First published
02 déc. 2019
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2020,11, 1140-1152

Large scale relative protein ligand binding affinities using non-equilibrium alchemy

V. Gapsys, L. Pérez-Benito, M. Aldeghi, D. Seeliger, H. van Vlijmen, G. Tresadern and B. L. de Groot, Chem. Sci., 2020, 11, 1140 DOI: 10.1039/C9SC03754C

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements