title: Steric interactions determine side-chain conformations in protein cores.
abstract: We investigate the role of steric interactions in defining side-chain conformations in protein cores. Previously, we explored the strengths and limitations of hard-sphere dipeptide models in defining sterically allowed side-chain conformations and recapitulating key features of the side-chain dihedral angle distributions observed in high-resolution protein structures. Here, we show that modeling residues in the context of a particular protein environment, with both intra- and inter-residue steric interactions, is sufficient to specify which of the allowed side-chain conformations is adopted. This model predicts 97% of the side-chain conformations of Leu, Ile, Val, Phe, Tyr, Trp and Thr core residues to within 20°. Although the hard-sphere dipeptide model predicts the observed side-chain dihedral angle distributions for both Thr and Ser, the model including the protein environment predicts side-chain conformations to within 20° for only 60% of core Ser residues. Thus, this approach can identify the amino acids for which hard-sphere interactions alone are sufficient and those for which additional interactions are necessary to accurately predict side-chain conformations in protein cores. We also show that our approach can predict alternate side-chain conformations of core residues, which are supported by the observed electron density.
authors.affiliation: Department of Physics, Yale University, New Haven, CT 06520, USA.|Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, CT 06520, USA.
authors.forename: D
authors.initials: D
authors.lastname: Caballero
authors.affiliation: Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, CT 06520, USA.|Department of Mechanical Engineering and Materials Science, Yale University, New Haven, CT 06520, USA.
authors.forename: A
authors.initials: A
authors.lastname: Virrueta
authors.affiliation: Department of Physics, Yale University, New Haven, CT 06520, USA.|Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, CT 06520, USA.|Department of Mechanical Engineering and Materials Science, Yale University, New Haven, CT 06520, USA.|Graduate Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: O'Hern
authors.affiliation: Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, CT 06520, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.|Department of Chemistry, Yale University, New Haven, CT 06520, USA.|Raymond and Beverly Sackler Institute for Biological, Physical, and Engineering Sciences, Yale University, New Haven, CT 06520, USA.
authors.forename: L
authors.initials: L
authors.lastname: Regan
mesh_terms: D004583:Electrons; D008958:Models, Molecular; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*
chemical_list: D011506:Proteins
keywords: electron density; protein crystal structures; protein design; side-chain conformations; steric interactions