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Pre‐existing soft modes of motion uniquely defined by native contact topology facilitate ligand binding to proteins
Author(s) -
Meireles Lidio,
Gur Mert,
Bakan Ahmet,
Bahar Ivet
Publication year - 2011
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.711
Subject(s) - docking (animal) , searching the conformational space for docking , ligand (biochemistry) , molecular dynamics , protein–ligand docking , protein structure , protein ligand , binding site , biological system , biophysics , chemistry , computational biology , crystallography , computational chemistry , biology , biochemistry , receptor , virtual screening , medicine , nursing
Modeling protein flexibility constitutes a major challenge in accurate prediction of protein–ligand and protein–protein interactions in docking simulations. The lack of a reliable method for predicting the conformational changes relevant to substrate binding prevents the productive application of computational docking to proteins that undergo large structural rearrangements. Here, we examine how coarse‐grained normal mode analysis has been advantageously applied to modeling protein flexibility associated with ligand binding. First, we highlight recent studies that have shown that there is a close agreement between the large‐scale collective motions of proteins predicted by elastic network models and the structural changes experimentally observed upon ligand binding. Then, we discuss studies that have exploited the predicted soft modes in docking simulations. Two general strategies are noted: pregeneration of conformational ensembles that are then utilized as input for standard fixed‐backbone docking and protein structure deformation along normal modes concurrent to docking. These studies show that the structural changes apparently “induced” upon ligand binding occur selectively along the soft modes accessible to the protein prior to ligand binding. They further suggest that proteins offer suitable means of accommodating/facilitating the recognition and binding of their ligand, presumably acquired by evolutionary selection of the suitable three‐dimensional structure.