jz9b01183_si_001.pdf (1.82 MB)
Exhaustive Search of Ligand Binding Pathways via Volume-Based Metadynamics
journal contribution
posted on 2019-06-03, 00:00 authored by Riccardo Capelli, Paolo Carloni, Michele ParrinelloDetermining the complete
set of ligands’ binding–unbinding
pathways is important for drug discovery and for rational interpretation
of mutation data. Here we have developed a metadynamics-based technique
that addresses 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 a benzene molecule. The calculated binding
free energy is in agreement with experimental data. Remarkably, not
only were we able to find all the previously identified ligand binding
pathways, but also we identified three pathways previously not identified
as such. These results were obtained at a small computational cost,
making this approach valuable for practical applications, such as
screening of small compound libraries.