Mechanochemistry: pre-stress for tuning biochemical reactions in proteins

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Chemical and enzymatic reactions can be guided by mechanical stress. While single molecule force spectroscopy experiments are an emerging technique to study the chemistry of bond cleavage under external forces, theoretical knowledge to understand or predict the force dependency of reaction rates is limited to simple models. The proposed project aims at examining the effect of force on the electronic and molecular structures and energies during the reaction, including quantum and dynamical effects. We will use combined quantum and molecular mechanical methods, together with enforced transition path sampling, to study and compare two fundamentally different, yet related biologically important reactions, protein disulphide bond reduction by chemical reducing agents and by the protein thioredoxin, and peptide bond hydrolysis in water and by a zinc metalloprotease. Our results will represent the first systematic study of the mechanochemistry of bond cleavage by nucleophilic attack. This will help to explain how nature makes use of mechanical stress to alter enzymatic function, as a new way of mechanotransduction.