Disulfide Bond Cleavage: A Redox Reaction Without Electron Transfer

Abstract

By using Car-Parrinello molecular dynamics (CPMD) simulations we have simulated a mechanically induced redox reaction. Previous single-molecule atomic force microscopy (AFM) experiments demonstrated that the reduction of disulfide bonds in proteins with the weak reducing agent dithiothreitol depends on a mechanical destabilization of the breaking bond. With reactive molecular dynamics simulations the single steps of the reaction mechanism can be elucidated and the motion of the electrons can be monitored. The simulations show that the redox reaction consists of the heterolytic cleavage of the S--S bond followed by a sequence of proton transfers.

Retraction: Unraveling Solvent-Mediated Reaction Pathways Leading to Regiospecific Mechanochemical Cleavage of Disulfide Bonds in Peptides

“…In particular, solvent exposure versus backbone shielding explains how S 24 -S 55 in B selects its path during the cascade of nucleophilic substitutions, whereas standard pK a arguments fail to explain regiospecificity as found in AFM experiments. Given the recent advances in force probe simulations [10][11][12][13][14][15][16] it looks promising to analyze other mechanochemically activated reactions in (bio)macromolecules in light of the ideas advocated here. Figure 2.…”

CPMD Simulation of a Bimolecular Chemical Reaction: Nucleophilic Attack of a Disulfide Bond under Mechanical Stress

“…[11] Again, in static calculations, this point depends on the geometry optimization algorithm chosen. The force needed to overcome this energy barrier is about 0.3 nN.…”

“…This CÀC length was increased from the starting value of 8.0 with constant velocities (11,22, and 44 m s À1 ) until it reached 9.0 . This CÀC length was increased from the starting value of 8.0 with constant velocities (11,22, and 44 m s À1 ) until it reached 9.0 .…”

“…[10] In particular, we simulated the reaction of a nucleophile with the disulfide bond of DTT. [11] In the absence of a reagent, homolytic bond rupture is usually observed when pulling molecules apart, resulting in the formation of radicals. Bond rupture can occur either at the S À S or the C À S bonds, which is in agreement with previous experiments.…”

Theoretical Approaches for Understanding the Interplay Between Stress and Chemical Reactivity

“…CPMD simulations in which F was applied by increasing the separation of a pair of atoms at a constant velocity in conjunction with detailed analyses of the electronic structure have also been used to study the dissociation of disulfide bonds in the presence of reducing agents [100]. Those simulations showed that this reaction does not necessarily involve electron transfer, as is common for redox processes, but rather can occur through heterolytic dissociation of the S-S bond followed by proton transfer.…”