Unfolding of an Alpha-Helical Peptide Exposed to High Temperature: Suggesting a Critical Residue in the Process Publisher



Alizadehrahrovi J^{1, 2} ; Ebrahimhabibi A² Show Affiliations
Source: Structural Chemistry Published:2023

Abstract

Unfolding of proteins is a crucial event that leads to a range of deleterious results, such as inactivation of a therapeutic protein or onset of a misfolding disease. A better insight onto details of unfolding mechanisms may help to design more stable proteins or prevent/delay the unfolding process by suitable ligands. In this study, we have used molecular dynamics (MD) simulations (AMBER14 force field implemented in YASARA) to investigate the unfolding of an albumin binding domain at atomic level. The aim was to find and target a possible initial site of the peptide’s unfolding. The original peptide has a relatively simple structure composed of three alpha helices which were exposed to high temperature. A potential critical point in unfolding (Lys 11) was localized based on secondary structure changes. Eight different mutations with diverse physicochemical properties were then proposed for this site, and the mutated peptides were simulated to check their effect on the unfolding process. We found that replacement of the critical residue with aliphatic ones seems to be better suited for this position in comparison with charged and bulkier aromatic residues. We believe that this approach could be further developed in order to provide a simple and relatively fast tool to rationally stabilize peptides. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.