Work

Quantifying the Cooperativity of Backbone Hydrogen Bonding

Year: 2025

Type: article

Abstract: ABSTRACT The hydrogen bonds (H‐bonds) between backbone amide and carbonyl groups are fundamental to the stability, structure, and dynamics of proteins. A key feature of such hydrogen bonding interactions is that multiple H‐bonds can enhance each other when aligned, as such in the ‐helix or ‐sheet secondary structures. To better understand this cooperative effect, we propose a new physical quantity to evaluate the cooperativity of intermolecular interactions. Using H‐bond aligned N‐methylacetamide molecules as the model system, we assess the cooperativity of protein backbone hydrogen bonds using quantum chemistry (QM) calculations at the MP2/aug‐cc‐pVTZ level, revealing cooperative energies ranging from 2 to 4.3 kcal/mol. A set of protein force fields was benchmarked against QM results. While the additive force field failed to reproduce cooperativity, polarizable force fields, including the Drude and AMOEBA protein force fields, have been found to reproduce the trend of QM results, albeit with smaller magnitude. This work demonstrates the theoretical utility of the proposed formula for quantifying cooperativity and its relevance in force field parameterization. Incorporating cooperative energy into polarizable models presents a pathway to achieving more accurate simulations of biomolecular systems.

Source: Journal of Computational Chemistry

DOI: 10.1002/jcc.70133

Authors: You Xu, Jing Huang

Institution: Westlake University

Language: English

Topic: Protein Structure and Dynamics

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funder: National Natural Science Foundation of China

Awards: G4394419333, G5446815508