Protein crystal structures have provided new insight into protein function, either inferred from interatomic distances or as a starting point for atomistic simulation of dynamics and reactivity. Over 110,000 solved protein structures have been made publically accessible, of which around half are considered high-resolution (sub 2.0 Å) and less than 3% are at atomic-level resolution (sub 1.2 Å). Even in this high-resolution dataset of protein structures, unusually short, non-bonded distances,<i> i.e. </i>close contacts, are pervasive. 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 are not well characterized by commonly employed molecular mechanics force fields. Recent advances in algorithms and hardware have made first-principles modeling of thousands of atoms increasingly routine. Such developments are necessary to fully describe electronic (<i>i.e</i>., large-scale charge transfer and polarization) and geometric properties of proteins. After screening the structurally characterized proteome to identify and examine all unusually short intra-protein residue-residue interactions in high-resolution crystal structures, we identify cases of close contacts amenable to large-scale electronic structure simulation. In these case studies, we validate and explain the quantum-mechanical sources of close contacts observed in protein structures using a combination of energetic decomposition, charge density, and geometric analyses.

Understanding unusual noncovalent interactions in proteins through large-scale electronic structure

256th National Meeting (2018)

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