title: Side-chain rotamer changes upon ligand binding: common, crucial, correlate with entropy and rearrange hydrogen bonding.
abstract: BACKGROUND
  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.
  
  
  BACKGROUND
  rafael.najmanovich@usherbrooke.ca.
authors.affiliation: Department of Biochemistry, Université de Sherbrooke, 3001, Québec, Canada J1H 5N4.
authors.forename: Francis
authors.initials: F
authors.lastname: Gaudreault
authors.forename: Matthieu
authors.initials: M
authors.lastname: Chartier
authors.forename: Rafael
authors.initials: R
authors.lastname: Najmanovich
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D001665:Binding Sites; D030562:Databases, Protein; D019277:Entropy; D006860:Hydrogen Bonding; D008024:Ligands; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D008024:Ligands; D011506:Proteins