ct9b00753_si_001.pdf (15.73 MB)
PELE-MSM: A Monte Carlo Based Protocol for the Estimation of Absolute Binding Free Energies
journal contribution
posted on 2019-10-17, 18:37 authored by Joan F. Gilabert, Christoph Grebner, Daniel Soler, Daniel Lecina, Martí Municoy, Oriol Gracia Carmona, Robert Soliva, Martin J. Packer, Samantha J. Hughes, Christian Tyrchan, Anders Hogner, Victor GuallarIn
this study, we present a fully automatic platform based on our
Monte Carlo algorithm, the Protein Energy Landscape Exploration method
(PELE), for the estimation of absolute protein–ligand binding
free energies, one of the most significant challenges in computer
aided drug design. Based on a ligand pathway approach, an initial
short enhanced sampling simulation is performed to identify reasonable
starting positions for more extended sampling. This stepwise approach
allows for a significant faster convergence of the free energy estimation
using the Markov State Model (MSM) technique. PELE-MSM was applied
on four diverse protein and ligand systems, successfully ranking compounds
for two systems. Based on the results, current limitations and challenges
with physics-based methods in computational structural biology are
discussed. Overall, PELE-MSM constitutes a promising step toward computing
absolute binding free energies and in their application into drug
discovery projects.