Protein Stability and Unfolding Following Glycine Radical Formation

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.

Role of Oxidized Gly25, Gly29, and Gly33 Residues on the Interactions of Aβ1–42 with Lipid Membranes

“…Owen and co-workers examined the effect of C α -centered radical formation on the stability of a model helical peptides in different solvent systems . Moreover, MD simulations demonstrated the effect of glycine residue radicalization on protein conformation depends both on the protein and the position of the radical . The effect of radicalization at Gly25 on the Aβ42 dimer in solution was further investigated by Liao et al Although the occurrence of oxidative stress in several neurodegenerative diseases is well-established, there is no computational evidence on the effect of radicalization on peptide-membrane interactions.…”

Pigmentation Chemistry and Radical‐Based Collagen Degradation in Alkaptonuria and Osteoarthritic Cartilage

“…We propose that transient formation of glycyl radicals underlie the disruption of hydrogen bonding in pigmented cartilage observed in the current study. Molecular dynamics indicate that the formation of a glycyl radical is accompanied by large changes in the backbone dihedral angles, [34] since hydrogen abstraction occurs at C a of glycines, [35] and have been observed in EPR of powdered collagen (freeze-dried and rehydrated) subjected to gamma rays. [36] While glycyl radicals are known to be key to many enzymatic processes, they are not usually oxygen-stable.…”

Pigmentierungschemie und radikalbasierter Kollagenabbau bei Alkaptonurie und Arthrose

“…Wir schlagen vor, dass die vorübergehende Bildung von Glycylradikalen der in der aktuellen Studie beobachteten Störung der Wasserstoffbindung im pigmentierten Knorpel zugrunde liegt. Die Molekulardynamik zeigt, dass die Bildung eines Glycylradikals mit großen Änderungen der Rückgrat‐Diederwinkel einhergeht, da die Wasserstoffabstraktion an den C α von Glycinen auftritt und in der EPR an pulverisiertem Kollagen beobachtet wurde (gefriergetrocknet und rehydratisiert), das Gammastrahlen ausgesetzt wurde . Obwohl Glycylradikale als Schlüssel für viele enzymatische Prozesse bekannt sind, sind sie normalerweise nicht sauerstoffstabil .…”