Abstract
Motivation: Protein movements form a continuum from large domain rearrangements (including folding and restructuring) to side-chain rotamer changes and small rearrangements. Understanding side-chain flexibility upon binding is important to understand molecular recognition events and predict ligand binding.Methods: In the present work, we developed a well-curated non-redundant dataset of 188 proteins in pairs of structures in the Apo (unbound) and Holo (bound) forms to study the extent and the factors that guide side-chain rotamer changes upon binding.Results: Our analysis shows that side-chain rotamer changes are widespread with only 10% of binding sites displaying no conformational changes. Overall, at most five rotamer changes account for the observed movements in 90% of the cases. Furthermore, rotamer changes are essential in 32% of flexible binding sites. The different amino acids have a 11-fold difference in their probability to undergo changes. Side-chain flexibility represents an intrinsic property of amino acids as it correlates well with configurational entropy differences. Furthermore, on average b-factors and solvent accessible surface areas can discriminate flexible side-chains in the Apo form. Finally, there is a rearrangement of the hydrogen-bonding network upon binding primarily with a loss of H-bonds with water molecules and a gain of H-bonds with protein residues for flexible residues. Interestingly, only 25% of side chains capable of forming H-bonds do so with the ligand upon binding. In terms of drug design, this last result shows that there is a large number of potential interactions that may be exploited to modulate the specificity and sensitivity of inhibitors.Contact: rafael.najmanovich@usherbrooke.ca
Highlights
Proteins bind small molecules as substrates, cofactors and allosteric regulators in order to perform essential cellular functions
We showed that up to three flexible residues account for the conformational changes observed in 85% of all bindingsites studied and that different amino acid types have different probabilities to be observed in conformationally different states upon binding
We generated a database that consists of pairs of identical proteins in Holo and Apo forms to analyze side-chain flexibility upon ligand binding
Summary
Proteins bind small molecules as substrates, cofactors and allosteric regulators in order to perform essential cellular functions. As a consequence of induced fit (Koshland, 1958), conformational selection (Rubin and Changeux, 1966) or more likely a combination of both (Csermely et al, 2010), the ligand-bound protein may display a wide gamut of structural changes These changes can range from large movements of entire domains to small side-chain rearrangements in the binding site. One can compare two structures of the same protein crystalized in different conditions, say in the bound (Holo) and unbound (Apo) forms This type of comparison is neutral with respect to the mechanism of binding (induced-fit or conformational selection), it makes possible, given the amount of available data, to perform statistically significant large-scale studies of conformational changes associated to ligand binding
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