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

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 ΔΔGL1→L2bind 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.

Calculations of Absolute Solvation Free Energies with Transformato─Application to the FreeSolv Database Using the CGenFF Force Field

“…The present results, as well as those of refs and , demonstrate the utility of in setting up and carrying out large-scale free energy calculations. By relying on SAI, the underlying MD program does not need support for special purpose code, such as soft-core potentials.…”

“…Finally, the multistate Bennett’s acceptance ratio method (MBAR) as implemented in ( 51 ) is used to obtain free energy differences from these data. 40 For the full details, we refer the reader to refs ( 41 ) and ( 42 ).…”

“…39,40 Large-scale free energy simulations require automated setups. We recently developed and presented a tool, called transformato, 41,42 for calculating relative solvation and relative binding free energies using the common-core/serialatom-insertion approach 43 in a semi-automated manner. Given their importance, we extended the functionality of transformato to the computation of ASFEs.…”

Updates to Protex for Simulating Proton Transfers in an Ionic Liquid

“…These changes directly facilitate or hinder proton transfers. The seamless interoperation with free energy calculating programs, like transformato, , is also a strong benefit of Protex. In transformato, the atoms are distinguished into common core and dummy regions.…”

Broadening the Scope of Binding Free Energy Calculations Using a Separated Topologies Approach

“… 11 The single and the hybrid topology approaches are based on having a common core, distinct from the Separated Topologies approach, as described below. The common core is often defined as the maximum common substructure between the two ligands 12 , 13 (or between multiple ligands 14 , 15 ); however, additional mapping ideas are possible. 16 The RBFE approach is less computationally demanding and has lower statistical uncertainties than absolute binding free energy (ABFE) calculations.…”