title: Base-catalyzed peptide hydrolysis is insensitive to mechanical stress.
abstract: Biochemical reactions can be guided by mechanical stress. An external force has been previously shown both experimentally and theoretically to act as a catalyst for the scission of a disulfide bond in thiol/disulfide exchange reactions. How the dynamics of peptide hydrolysis, one of the most prevalent biochemical reactions, is influenced by a stretching force was investigated here using combined quantum and molecular mechanical (QM/MM) simulations together with transition path sampling. Our simulations predict mechanical force to only marginally enhance the reactivity of the rate-limiting step, the nucleophilic attack of hydroxide to the peptide moiety, and not to alter the reaction mechanism, even though the peptide bond and its π-electron conjugation is weakened by force. We describe a previously unidentified hydrogen bonded intermediate state, which is likely to play a role in general in base-catalyzed and analogous enzymatic reactions. Our predictions can be directly tested by single molecule stretching experiments.
authors.affiliation: CAS-MPG Partner Institute and Key Laboratory for Computational Biology (PICB), Shanghai 200031, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xia
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Bronowska
authors.forename: Shanmei
authors.initials: S
authors.lastname: Cheng
authors.forename: Frauke
authors.initials: F
authors.lastname: Gräter
mesh_terms: D002384:Catalysis; D004220:Disulfides / Q000737:chemistry; D006868:Hydrolysis; D010455:Peptides / Q000737:chemistry*; D013314:Stress, Mechanical; D013438:Sulfhydryl Compounds / Q000737:chemistry
chemical_list: D004220:Disulfides; D010455:Peptides; D013438:Sulfhydryl Compounds