Forcing the reversibility of a mechanochemical reaction

• Published in: Nature communications 2018-08, Vol.9 (1), p.3155-9, Article 3155
• Main Authors: Beedle, Amy E. M., Mora, Marc, Davis, Colin T., Snijders, Ambrosius P., Stirnemann, Guillaume, Garcia-Manyes, Sergi
• Format: Article
• Language: English
• Subjects: 119/118; 631/57/2265; 639/638/440/56; 639/638/77/603; 82/58; Amino Acid Substitution; Chemical bonds; Chemical kinetics; Chemical Phenomena; Chemical reactions; Chemical Sciences; Cleavage; Covalent bonds; Disulfides - chemistry; Free energy; Humanities and Social Sciences; Kinetics; Mechanical Phenomena; Models, Molecular; multidisciplinary; or physical chemistry; Organic chemistry; Polymers; Polymers - chemistry; Protein Conformation; Protein Engineering; Protein Folding; Proteins; Proteins - chemistry; Reaction kinetics; Science; Science (multidisciplinary); Spectroscopy; Sulfhydryl Compounds - chemistry; Theoretical and; Thermodynamics; Thiols
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05115-6

Mechanical force modifies the free-energy surface of chemical reactions, often enabling thermodynamically unfavoured reaction pathways. Most of our molecular understanding of force-induced reactivity is restricted to the irreversible homolytic scission of covalent bonds and ring-opening in polymer mechanophores. Whether mechanical force can by-pass thermodynamically locked reactivity in heterolytic bimolecular reactions and how this impacts the reaction reversibility remains poorly understood. Using single-molecule force-clamp spectroscopy, here we show that mechanical force promotes the thermodynamically disfavored S N 2 cleavage of an individual protein disulfide bond by poor nucleophilic organic thiols. Upon force removal, the transition from the resulting high-energy unstable mixed disulfide product back to the initial, low-energy disulfide bond reactant becomes suddenly spontaneous, rendering the reaction fully reversible. By rationally varying the nucleophilicity of a series of small thiols, we demonstrate how force-regulated chemical kinetics can be finely coupled with thermodynamics to predict and modulate the reversibility of bimolecular mechanochemical reactions. Mechanical force can facilitate thermodynamically unfavourable reactions. Here, the authors found that a stretching force can promote the SN2 cleavage of a protein disulfide bond by weak nucleophilic thiols, and that removing this force reverses the reaction yielding the original disulfide bond.