Conformational Sampling of Proteins: Methods for Simulate Protein Plasticity and Ensemble Docking

The understanding of protein function by emphasizing the critical role of structural dynamics, or protein plasticity, in biological processes is a field of knowledge in constant evolution. It highlights that proteins are not static entities but exhibit intrinsic, nonrandom movements crucial for their interactions with other molecules. Advances in cryoelectron microscopy (cryo-EM) and crystallography have provided snapshots of proteins in various conformations, revealing the dynamic nature of macromolecules. Different mechanisms of molecular recognition, such as conformational selection and induced fit, could be simulated by using hybrid methods that integrate molecular dynamics and normal mode analysis to study protein conformational spaces. These approaches have significant implications for drug discovery, as they allow for more accurate modeling of protein–ligand interactions by considering the inherent flexibility of protein structures. Methods such as MDeNM, which integrates normal modes into molecular dynamics simulations, is highlighted for its ability to promote significant conformational changes, facilitating the flexible fitting of atomic structures into cryo-EM maps and revealing complex protein motions. Collective molecular dynamics (coMD) and ClustENM are also discussed, emphasizing their roles in conformational sampling and protein–ligand interactions. Ensemble docking strategies, including the recent essential dynamic ensemble docking (EDED) protocol, are reviewed for their potential in drug design, particularly in improving the accuracy of molecular docking by considering the flexibility of both ligands and target proteins. These methodologies, combined with advancements in force fields and postdocking techniques, contribute to a more comprehensive understanding and prediction of biomolecular interactions.