Hydrogen bond donors and acceptors are generally depolarized in α-helices as revealed by a molecular tailoring approach.

Hiroko X Kondo,Yu Takano,Shusuke Yamanaka,Jinta Onari,Colin K Kitakawa,Haruki Nakamura,Ayumi Kusaka

doi:10.1002/jcc.25859

Hiroko X Kondo, Yu Takano + Show 5 more

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https://doi.org/10.1002/jcc.25859

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Abstract

Hydrogen‐bond (H‐bond) interaction energies in α‐helices of short alanine peptides were systematically examined by precise density functional theory calculations, followed by a molecular tailoring approach. The contribution of each H‐bond interaction in α‐helices was estimated in detail from the entire conformation energies, and the results were compared with those in the minimal H‐bond models, in which only H‐bond donors and acceptors exist with the capping methyl groups. The former interaction energies were always significantly weaker than the latter energies, when the same geometries of the H‐bond donors and acceptors were applied. The chemical origin of this phenomenon was investigated by analyzing the differences among the electronic structures of the local peptide backbones of the α‐helices and those of the minimal H‐bond models. Consequently, we found that the reduced H‐bond energy originated from the depolarizations of both the H‐bond donor and acceptor groups, due to the repulsive interactions with the neighboring polar peptide groups in the α‐helix backbone. The classical force fields provide similar H‐bond energies to those in the minimal H‐bond models, which ignore the current depolarization effect, and thus they overestimate the actual H‐bond energies in α‐helices. © 2019 The Authors. Journal of Computational Chemistry published by Wiley Periodicals, Inc.

Highlights

The hydrogen bond (H-bond) is one of the major factors that build the macromolecular structures of proteins, nucleic acids and their complexes
We designed a single-turn model (ST model), which is composed of three successive alanine residues, (Ala)3, in the a-helix capped by acetyl and N-methyl groups at the N- and Ctermini, respectively (Figure 1C)
Electron density changes were computed using the cube files in the Gaussian09 program packages17), and the figures of the molecules with the electron density changes were produced by Results H-bond energies in a-helices The total energies of acetyl group (Ace)-(Ala)n-N-methyl amide group (Nme) estimated by molecular tailoring approach (MTA) (EMTA), computed by eq [1], coincided well with the ordinary total energies E(F0) of the complete a-helical structure (AH) models

Summary

Introduction

The hydrogen bond (H-bond) is one of the major factors that build the macromolecular structures of proteins, nucleic acids and their complexes. Pair-wise H-bonds in protein backbones are essential to form their characteristic three-dimensional (3D) structures based on their ordered secondary structures, a-helices and b-sheets. Their structural energies should be correctly computed for analyses and predictions of protein 3D structures. The individual force-fields used in classical molecular dynamics (MD) simulations show particular preferences and produce a-helical and b-structures1-3) This phenomenon is usually not a problem for simulations of rigid globular protein structures, but it becomes a critical issue for folding simulations of flexible disordered regions4,5) and long loops between secondary structures6,7), to understand the functionally important conformational changes that occur as allosteric effects or induced folding upon ligand binding). These preferences have remained unclear, since their actual origins are unknown

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