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Proteins. 2018 May;86(5):581-591. doi: 10.1002/prot.25479. Epub 2018 Feb 26.

Comparing side chain packing in soluble proteins, protein-protein interfaces, and transmembrane proteins.

Author information

1
Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, 06520.
2
Integrated Graduate Program in Physical and Engineering Biology (IGPPEB), Yale University, New Haven, Connecticut, 06520.
3
Department of Mechanical Engineering and Materials Science, Yale University, New Haven, Connecticut, 06520.
4
Department of Physics and Astronomy, University of Southern California, Los Angeles, California, 90007.
5
Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, Connecticut, 06520.
6
Department of Chemistry, Yale University, New Haven, Connecticut, 06520.
7
Department of Physics, Yale University, New Haven, Connecticut, 06520.
8
Department of Applied Physics, Yale University, New Haven, Connecticut, 06520.

Abstract

We compare side chain prediction and packing of core and non-core regions of soluble proteins, protein-protein interfaces, and transmembrane proteins. We first identified or created comparable databases of high-resolution crystal structures of these 3 protein classes. We show that the solvent-inaccessible cores of the 3 classes of proteins are equally densely packed. As a result, the side chains of core residues at protein-protein interfaces and in the membrane-exposed regions of transmembrane proteins can be predicted by the hard-sphere plus stereochemical constraint model with the same high prediction accuracies (>90%) as core residues in soluble proteins. We also find that for all 3 classes of proteins, as one moves away from the solvent-inaccessible core, the packing fraction decreases as the solvent accessibility increases. However, the side chain predictability remains high (80% within 30°) up to a relative solvent accessibility, rSASA≲0.3, for all 3 protein classes. Our results show that ≈40% of the interface regions in protein complexes are "core", that is, densely packed with side chain conformations that can be accurately predicted using the hard-sphere model. We propose packing fraction as a metric that can be used to distinguish real protein-protein interactions from designed, non-binding, decoys. Our results also show that cores of membrane proteins are the same as cores of soluble proteins. Thus, the computational methods we are developing for the analysis of the effect of hydrophobic core mutations in soluble proteins will be equally applicable to analyses of mutations in membrane proteins.

KEYWORDS:

hydrophobic amino acids; protein design; protein interfaces; protein structure prediction; protein-peptide interactions; protein-protein interactions; rotamer prediction; side chain dihedral angles; side chain repacking; transmembrane proteins

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