Protein Stability and Unfolding Following Glycine Radical Formation.

Michael C Owen,,Birgit Strodel,Imre G Csizmadia,Béla Viskolcz

doi:10.3390/molecules22040655

Abstract

Glycine (Gly) residues are particularly susceptible to hydrogen abstraction; which results in the formation of the capto-dative stabilized Cα-centered Gly radical (GLR) on the protein backbone. We examined the effect of GLR formation on the structure of the Trp cage; tryptophan zipper; and the villin headpiece; three fast-folding and stable miniproteins; using all-atom (OPLS-AA) molecular dynamics simulations. Radicalization changes the conformation of the GLR residue and affects both neighboring residues but did not affect the stability of the Trp zipper. The stability of helices away from the radical center in villin were also affected by radicalization; and GLR in place of Gly15 caused the Trp cage to unfold within 1 µs. These results provide new evidence on the destabilizing effects of protein oxidation by reactive oxygen species.

Highlights

Due to its role in several pathological disorders and aging, radical-mediated protein oxidation attracts ever-increasing attention [1,2]
The dynamics of the first 100 ns of the trajectories of the Trp cage, Trp zipper, villin headpiece and their respective protein radicals are presented as follows
The presence of GLR10 and GLR15 in the Trp cage reduced the cluster size by half, and GLR11 in the villin headpiece led to a reduction by more than two-thirds

Summary

Introduction

Due to its role in several pathological disorders and aging, radical-mediated protein oxidation attracts ever-increasing attention [1,2]. The hydroxy radical (OH), which can be produced in the cell via the transition metal catalyzed Fenton reaction, is capable of abstracting hydrogen atoms in a site-specific manner [5,6,7,8]. The low bond dissociation energy facilitates the preferential Hα abstraction from the Cα by the OH radical and other reactive oxygen species (ROS) compared to other sites, though OH addition can occur [9,10]. The variation in the rate constant (k) of OH reactions with amino acid residues range between 107 and 1010 M−1 ·s−1 [11]. Peptides generally react faster than their respective free amino acids, with k ranging between 108 and

Methods

Results

Discussion

Conclusion