Exhaustive Search of Ligand Binding Pathways via Volume-based Metadynamics

TL;DR

This paper introduces a volume-based metadynamics method to comprehensively identify ligand binding and unbinding pathways, accurately estimate affinities, and discover new pathways efficiently, aiding drug discovery efforts.

Contribution

The authors developed a novel metadynamics technique that uncovers all ligand pathways, including previously unknown ones, with low computational cost, enhancing drug discovery and mutation analysis.

Findings

Successfully identified all known ligand pathways.

Discovered 3 new ligand binding pathways.

Achieved binding free energy estimates consistent with experiments.

Abstract

Determining the complete set of ligands' binding/unbinding pathways is important for drug discovery and to rationally interpret mutation data. Here we have developed a metadynamics-based technique that addressed this issue and allows estimating affinities in the presence of multiple escape pathways. Our approach is shown on a Lysozyme T4 variant in complex with the benzene molecule. The calculated binding free energy is in agreement with experimental data. Remarkably, not only we were able to find all the previously identified ligand binding pathways, but also we uncovered 3 new ones. This results were obtained at a small computational cost, making this approach valuable for practical applications, such as screening of small compounds libraries.