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PELE-MSM: A Monte Carlo Based Protocol for the Estimation of Absolute Binding Free Energies.

Joan F GilabertChristoph GrebnerDaniel SolerDaniel LecinaMartí MunicoyOriol Gracia CarmonaRobert SolivaMartin J PackerSamantha J HughesChristian TyrchanAnders HognerVictor Guallar
Published in: Journal of chemical theory and computation (2019)
In 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.
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