A Structural Role for Tryptophan in Proteins, And the Ubiquitous Trp C^δ1—H···O=C (Backbone) Hydrogen Bond

Authors

Michal Szczygiel, University of Virginia
Urszula Derewenda, University of Virginia
Steve Scheiner, Utah State UniversityFollow
Wladek Minor, University of Virginia
Zygmunt S. Derewenda, University of VirginiaFollow

Document Type

Article

Author ORCID Identifier

Wladek Minor https://orcid.org/0000-0001-7075-7090

Journal/Book Title

Acta Crystallographica. Section D: Structural Biology

Publication Date

6-28-2024

Publisher

Wiley-Blackwell Publishing, Inc.

Journal Article Version

Version of Record

Volume

80

Issue

7

First Page

551

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Last Page

562

Abstract

Tryptophan is the most prominent amino acid found in proteins, with multiple functional roles. Its side chain is made up of the hydrophobic indole moiety, with two groups that act as donors in hydrogen bonds: the N^ε—H group, which is a potent donor in canonical hydrogen bonds, and a polarized C^δ1—H group, which is capable of forming weaker, noncanonical bonds. Due to adjacent electron-withdrawing moieties, C—H···O hydrogen bonds are ubiquitous in macromolecules, albeit contingent on the polarization of the donor C—H group. Consequently, C^α groups (adjacent to the carbonyl and amino groups of flanking peptide bonds), as well as the C^ε1—H and C^δ2—H groups of histidines (adjacent to imidazole N atoms), are known to serve as donors in hydrogen bonds, for example stabilizing parallel and antiparallel Β-sheets. However, the nature and the functional role of interactions involving the C^δ1—H group of the indole ring of tryptophan are not well characterized. Here, data mining of high-resolution (r ≤ 1.5 Å) crystal structures from the Protein Data Bank was performed and ubiquitous close contacts between the C^δ1—H groups of tryptophan and a range of electronegative acceptors were identified, specifically main-chain carbonyl O atoms immediately upstream and downstream in the polypeptide chain. The stereochemical analysis shows that most of the interactions bear all of the hallmarks of proper hydrogen bonds. At the same time, their cohesive nature is confirmed by quantum-chemical calculations, which reveal interaction energies of 1.5–3.0 kcal mol^-1, depending on the specific stereochemistry.

Recommended Citation

Szcygiel, Michal, Derewenda, Urszula, Scheiner, Steve, Minor, Wladek, and Derewenda, Zygmunt S., "A structural role for tryptophan in proteins, and the ubiquitous Trp C^δ1—H···O=C (backbone) hydrogen bond," Acta Cryst. D: Structural Biology vol. 80, no. 7, 2024, pp. 551-562. https://doi.org/10.1107/S2059798324005515