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Issue 3, 2021
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When are two hydrogen bonds better than one? Accurate first-principles models explain the balance of hydrogen bond donors and acceptors found in proteins

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Abstract

Hydrogen bonds (HBs) play an essential role in the structure and catalytic action of enzymes, but a complete understanding of HBs in proteins challenges the resolution of modern structural (i.e., X-ray diffraction) techniques and mandates computationally demanding electronic structure methods from correlated wavefunction theory for predictive accuracy. Numerous amino acid sidechains contain functional groups (e.g., hydroxyls in Ser/Thr or Tyr and amides in Asn/Gln) that can act as either HB acceptors or donors (HBA/HBD) and even form simultaneous, ambifunctional HB interactions. To understand the relative energetic benefit of each interaction, we characterize the potential energy surfaces of representative model systems with accurate coupled cluster theory calculations. To reveal the relationship of these energetics to the balance of these interactions in proteins, we curate a set of 4000 HBs, of which >500 are ambifunctional HBs, in high-resolution protein structures. We show that our model systems accurately predict the favored HB structural properties. Differences are apparent in HBA/HBD preference for aromatic Tyr versus aliphatic Ser/Thr hydroxyls because Tyr forms significantly stronger O–H⋯O HBs than N–H⋯O HBs in contrast to comparable strengths of the two for Ser/Thr. Despite this residue-specific distinction, all models of residue pairs indicate an energetic benefit for simultaneous HBA and HBD interactions in an ambifunctional HB. Although the stabilization is less than the additive maximum due both to geometric constraints and many-body electronic effects, a wide range of ambifunctional HB geometries are more favorable than any single HB interaction.

Graphical abstract: When are two hydrogen bonds better than one? Accurate first-principles models explain the balance of hydrogen bond donors and acceptors found in proteins

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Supplementary files

Article information


Submitted
14 Sep 2020
Accepted
18 Nov 2020
First published
19 Nov 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2021,12, 1147-1162
Article type
Edge Article

When are two hydrogen bonds better than one? Accurate first-principles models explain the balance of hydrogen bond donors and acceptors found in proteins

V. Vennelakanti, H. W. Qi, R. Mehmood and H. J. Kulik, Chem. Sci., 2021, 12, 1147
DOI: 10.1039/D0SC05084A

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