AUTHOR=Karwounopoulos Johannes , Wieder Marcus , Boresch Stefan 

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

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2022.954638

DOI=10.3389/fmolb.2022.954638

ISSN=2296-889X

ABSTRACT=<p>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 (<ext-link ext-link-type="uri" xlink:href="https://github.com/wiederm/transformato" xmlns:xlink="http://www.w3.org/1999/xlink">https://github.com/wiederm/transformato</ext-link>); 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 <italic>L</italic><sub>1</sub> directly into another <italic>L</italic><sub>2</sub>, 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 <inline-formula id="inf1"><mml:math id="m1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi mathvariant="normal">Δ</mml:mi><mml:mi mathvariant="normal">Δ</mml:mi><mml:msubsup><mml:mrow><mml:mi>G</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mrow><mml:mi>L</mml:mi></mml:mrow><mml:mrow><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>→</mml:mo><mml:msub><mml:mrow><mml:mi>L</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msub></mml:mrow><mml:mrow><mml:mi>b</mml:mi><mml:mi>i</mml:mi><mml:mi>n</mml:mi><mml:mi>d</mml:mi></mml:mrow></mml:msubsup></mml:math></inline-formula> 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.</p>