Explaining Unexpected Interactions in the Structurally Characterized Proteome With Large-scale Electronic Structure Modeling

Helena Qi, Massachusetts Institute of Technology

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Since the advent of X-ray crystallography, knowledge of a protein's crystal structure has provided critical new insights into protein function, either inferred from interatomic distances or as a starting point for atomistic simulation of dynamics and reactivity. Unusually short, non-bonded distances in protein structures, i.e. close contacts, arise in even the highest-resolution (i.e., sub-2.0 Å) crystal structures available. These close contacts are expected to correspond to unusually energetically strong interactions, such as strong hydrogen bonds exhibiting charge transfer, or other interactions that are otherwise not fully understood and cannot be well characterized by commonly employed molecular mechanics force fields. First-principles simulation can provide valuable insights into the nature of these interactions, particularly when bolstered by recent advances enabling large-scale electronic structure modeling of thousands of atoms. Here, we take a bird's-eye view of the structurally characterized proteome to identify the overall nature of all unusually short intra-protein residue-residue interactions in high-resolution crystal structures. We: (1) resolve the residue and secondary-structure dependent nature of these unusually short interactions; (2) quantify the extent to which components from energy decomposition (i.e., electrostatic versus van der Waals) in a classical and first-principles picture differ; and (3) validate and explain representative newly discovered interaction motifs through large-scale simulation of the effect of the greater protein environment. These newly discovered interactions will provide key insights into established protein structure-function relationships.

Abstract Author(s): Helena W. Qi, Heather J. Kulik