Site Specificity on OH α-H Abstraction Reaction for a Zwitterionic β-Hairpin Peptide in Aqueous Solution: A Theoretical Investigation

Abstract

Protein backbone oxidation was investigated by studying the α-H abstraction reaction in a ß-hairpin peptide, called Chignolin (PDB ID 1UAO), with density functional theory calculation at B3LYP/6-31G(d,p) without any constraint. In order to stabilize the zwitterionic form of Chignolin with the salt bridges, the effects of aqueous solution were implemented by using microsolvation combined with a conductor-like polarizable continuum model (CPCM). Comparison between three glycine residues located at three different sites in Chignolin was used to examine the possible site specificity of this backbone oxidation. To construct the reaction profile of these α-H abstraction reactions, the pre- and postreactive complexes along with their associated transition states were located and verified with the intrinsic reaction coordinate (IRC) method. The bond dissociation energy and reaction rates of these OH α-H abstraction reactions were calculated with transition state theory. The differences in this abstraction reaction between the neutral and zwitterionic forms of Chignolin were also compared. A molecular dynamics simulation was implemented to study the explicit solvation effect on the abstracted Chignolin structure. The range of the simulation time scale covers from femtoseconds to microseconds, i.e., from onset of the abstraction to the abstracted products reaching thermal equilibrium. Our results show that there are three kinds of site-specificity in this abstraction reaction. The reactivity and stability of the abstraction products and their abstraction modes are all dependent on the location where OH attacks. Furthermore, the free energy landscapes of these abstraction products are distinctively different. This may imply that the pathological disorders or diseases caused by this type of radicals are also dependent on the abstraction location.

An ONIOM investigation of the effect of conformation on bond dissociation energies in peptides

“…For example, Rauk and coworkers used density‐functional‐theory calculations to show that conformational differences can have a substantial effect on the α‐CH bond dissociation energies . In addition, Li and coworkers have examined the conformational effects for α‐radical formation in a small naturally occurring peptide . Investigations of a similar nature have helped to unravel the effects on kinetics in other cases .…”

“…Ultimately, direct calculations on the full peptide radicals and their parent peptides would provide the most accurate computational approach to this problem. This is indeed the methodology used by Li and coworkers, who used density‐functional‐theory (DFT) methods [e.g., B3‐LYP/6‐31G(d) to study the radical chemistry of a 10‐residue small peptide. While advances in quantum chemistry methodologies and computing technologies have made it possible to carry out explicit DFT computations for even larger molecules, a significantly more efficient strategy would be to use a multilayer approach such as the ONIOM method of Morokuma and coworkers …”

A computational study of radical initiated protein backbone homolytic dissociation on all natural amino acids

“…Several computational studies investigated the H abstraction reaction, 22,[24][25][26][27][28][29][30]31,33,42,43,[48][49][50][51][52][53][54][55][56][57] focusing mainly on glycine and alanine. Galano et al employed different levels of theory to characterize the reaction in the gas-phase.…”

“…Similarly, Rauk et al observed that the b-sheet conformation favors the radical attack due to a larger captodative effect. 54 The effect that the protein conformation has on the reaction has also been investigated in two different 10 residue-long proteins, chignolin 56 and b-hairpin. 57 The attack of the OH radical on other amino acids has also been investigated, including asparagine, 31 serine, 22 methionine, 48 leucine, 50 isoleucine 30 or proline.…”

Thermodynamics and Kinetics for the Free Radical Oxygen Protein Oxidation Pathway in a Model for β-Structured Peptides

“…They found that the alpha-carbon is consistently a competitive site of • OH attack. Lin et al investigated hydrogen abstraction in a β-hairpin peptide . Molecular dynamics was used to sample peptide conformations, and ab initio methods are used to determine energies and to examine the potential energy surface along the reaction pathway.…”