Mining unexpected interactions in proteins

We have investigated unexpectedly short non-covalent distances (< 85% of the sum of van der Waals radii) in X-ray crystal structures of proteins. We curated over 11,000 high quality protein crystal structures and an ultra-high resolution (1.2 Å or better) subset containing > 900 structures. Although our non-covalent distance criterion excludes standard hydrogen bonds known to be essential in protein stability, we observed over 75,000 close contacts in the curated protein structures. Analysis of the frequency of amino acids participating in these interactions demonstrates some expected trends (i.e., enrichment of charged Lys, Arg, Asp, and Glu) but also reveals unexpected enhancement of Tyr in such interactions. Nearly all amino acids are observed to form at least one close contact with all other amino acids, and most interactions are preserved in the much smaller ultra high-resolution subset. We quantum-mechanically characterize the interaction energetics of a subset of > 5,000 close contacts with symmetry adapted perturbation theory to enable decomposition of interactions. We observed the majority of close contacts to be favorable. The shortest favorable non-covalent distances are under 2.2 Å and are very repulsive when characterized with classical force fields. This analysis reveals stabilization by a combination of electrostatic and charge transfer effects between hydrophobic (i.e., Val, Ile, Leu) amino acids and charged Asp or Glu. We also observe a unique hydrogen bonding configuration between Tyr and Asn/Gln involving both residues acting simultaneously as hydrogen bond donors and acceptors. Our work confirms the importance of first-principles simulation in explaining unexpected geometries in protein crystal structures.


Check out the recent publication in Journal of Chemical Information and Modeling as part of the "Women in Computational Chemistry" special issue here!

About Us

The Kulik group focuses on the development and application of new electronic structure methods and atomistic simulations tools in the broad area of catalysis.

Our Interests

We are interested in transition metal chemistry, with applications from biological systems (i.e. enzymes) to nonbiological applications in surface science and molecular catalysis.

Our Focus

A key focus of our group is to understand mechanistic features of complex catalysts and to facilitate and develop tools for computationally driven design.

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