title: Collective repacking reveals that the structures of protein cores are uniquely specified by steric repulsive interactions.
abstract: Protein core repacking is a standard test of protein modeling software. A recent study of six different modeling software packages showed that they are more successful at predicting side chain conformations of core compared to surface residues. All the modeling software tested have multicomponent energy functions, typically including contributions from solvation, electrostatics, hydrogen bonding and Lennard-Jones interactions in addition to statistical terms based on observed protein structures. We investigated to what extent a simplified energy function that includes only stereochemical constraints and repulsive hard-sphere interactions can correctly repack protein cores. For single residue and collective repacking, the hard-sphere model accurately recapitulates the observed side chain conformations for Ile, Leu, Phe, Thr, Trp, Tyr and Val. This result shows that there are no alternative, sterically allowed side chain conformations of core residues. Analysis of the same set of protein cores using the Rosetta software suite revealed that the hard-sphere model and Rosetta perform equally well on Ile, Leu, Phe, Thr and Val; the hard-sphere model performs better on Trp and Tyr and Rosetta performs better on Ser. We conclude that the high prediction accuracy in protein cores obtained by protein modeling software and our simplified hard-sphere approach reflects the high density of protein cores and dominance of steric repulsion.
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.|Integrated Graduate Program in Physical and Engineering Biology (IGPPEB), Yale University, New Haven, CT 06520, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Gaines
authors.affiliation: Integrated Graduate Program in Physical and Engineering Biology (IGPPEB), 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: C. Eugene Bennett Department of Chemistry, 217 Clark Hall, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Buch
authors.affiliation: Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: S J
authors.initials: SJ
authors.lastname: Fleishman
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.|Integrated Graduate Program in Physical and Engineering Biology (IGPPEB), Yale University, New Haven, CT 06520, USA.|Department of Mechanical Engineering and Materials Science, Yale University, New Haven, CT 06520, USA.|Department of Physics, Yale University, New Haven, CT 06520, USA.|Department of Applied Physics, Yale University, New Haven, CT 06520, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: O'Hern
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.|Integrated Graduate Program in Physical and Engineering Biology (IGPPEB), 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.
authors.forename: L
authors.initials: L
authors.lastname: Regan
mesh_terms: D030562:Databases, Protein; D008958:Models, Molecular; D000072417:Protein Domains; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D012984:Software
chemical_list: D011506:Proteins
keywords: Rosetta; protein core repacking; protein crystal structures; protein design; side chain conformations