Relative binding free energy calculations with transformato: A molecular dynamics engine-independent tool

Johannes Karwounopoulos, Marcus Wieder, Stefan Boresch (Korresp. Autor*in)

Veröffentlichungen: Beitrag in FachzeitschriftArtikelPeer Reviewed

Abstract

We present the software package transformato for the setup of large-scale relative binding free energy calculations. Transformato is written in Python as an open source project (https://github.com/wiederm/transformato); in contrast to comparable tools, it is not closely tied to a particular molecular dynamics engine to carry out the underlying simulations. Instead of alchemically transforming a ligand L1 directly into another L2, the two ligands are mutated to a common core. Thus, while dummy atoms are required at intermediate states, in particular at the common core state, none are present at the physical endstates. To validate the method, we calculated 76 relative binding free energy differences ΔΔGbindL1→L2 for five protein–ligand systems. The overall root mean squared error to experimental binding free energies is 1.17 kcal/mol with a Pearson correlation coefficient of 0.73. For selected cases, we checked that the relative binding free energy differences between pairs of ligands do not depend on the choice of the intermediate common core structure. Additionally, we report results with and without hydrogen mass reweighting. The code currently supports OpenMM, CHARMM, and CHARMM/OpenMM directly. Since the program logic to choose and construct alchemical transformation paths is separated from the generation of input and topology/parameter files, extending transformato to support additional molecular dynamics engines is straightforward.
OriginalspracheEnglisch
Aufsatznummer954638
Seitenumfang16
FachzeitschriftFrontiers in Molecular Biosciences
Jahrgang9
DOIs
PublikationsstatusVeröffentlicht - 6 Sep. 2022

ÖFOS 2012

  • 106005 Bioinformatik
  • 104017 Physikalische Chemie
  • 102009 Computersimulation

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