Enzyme catalysis

Modeling enzyme catalysis to understand reaction mechanisms

Enzyme regulation is not only about facilitating target reactions but also about preventing those which are undesired. The idea that enzymes lower the activation energy of a chemical transformation is central to the understanding of how reactions are catalyzed at astounding rates, relative to the uncatalyzed process in solution. However, reactions that involve highly reactive and unstable intermediates, such as a radical species, present an entirely new set of catalytic challenges.

How do enzymes deal with highly reactive intermediates?



  • B12-dependent enzymes employ radical species with exceptional prowess to catalyze some of the most chemically challenging, thermodynamically unfavorable reactions.
  • Dealing with highly reactive intermediates is an extremely demanding task, requiring sophisticated control strategies to prevent unwanted side reactions.
  • Using hybrid QM/MM simulations, we follow the full catalytic cycle of an AdoB12-dependent enzyme
  • We present the details of a mechanism that utilizes a highly effective mechano-chemical switch.
  • Reference publications:
    • Brunk, E; Rothlisberger, U. Mixed Quantum Mechanical/Molecular Mechanical Molecular Dynamics Simulations of Biological Systems in Ground and Electronically Excited States. Chemical Reviews (2015) DOI: 10.1021/cr500628b
    • Brunk, E; Kellett, WF; Richards, NGJ; Rothlisberger, U. A Mechano-Chemical Switch to Control Reactive Intermediates Biochemistry (2014) 53 (23), 3830-3838
    • Kellett, WF; Brunk, E; Desai, BJ; Fedorov, AA; Almo, SC; Gerlt, JA; Rothlisberger, U; Richards, NGJ. Computational, Structural and Kinetic Evidence that Vibrio vulnicus FrsA is not a Cofactor-Independent Pyruvate Decarboxylase Biochemistry (2013) 2 (11), 1842-1844.
    • Brunk, E; Ashari, N; Athri, P; Campomanes, P; de Carvalho, FF; Curchod, BFE; Diamantis, P; Doemer, M; Garrec, J; Laktionov, A; Micciarelli, M; Neri, M; Palermo, G; Penfold, TJ; Vanni, S; Tavernelli, I; Rothlisberger, U. Pushing the Frontiers of First-Principles Based Computer Simulations of Chemical and Biological Systems CHIMIA (2011) 65, 667.