Advances in all atom sampling methods for modeling protein–ligand binding affinities

Conformational dynamics plays a fundamental role in the regulation of molecular recognition processes. Conformational heterogeneity and entropy variations upon binding, although not always evident from the analysis of structural data, can substantially affect affinity and specificity. Computer modeling is able to provide some of the most direct insights into these aspects of molecular recognition. We review recent physics-based computational studies that employ advanced conformational sampling algorithms and effective potentials to model the three main classes of degrees of freedom relevant to the binding process: ligand positioning relative to the receptor, ligand and receptor internal reorganization, and hydration. Collectively these studies show that all of these elements are important for proper modeling of protein-ligand interactions.

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► Conformational sampling methods in binding free energy calculations are reviewed.
► Methods to sample intermolecular degrees of freedom (ligand positioning).
► Methods to sample intramolecular degrees of freedom (reorganization).
► Methods to study hydration and the effects of solvent displacement.
► All of the main aspects discussed are important to achieve high predictive ability.