The inside-out approach to enzyme design has been successfully employed to generate active de novo enzymes that catalyzed the Kemp elimination,[1] retro-aldol reaction,[2] and the Diels-Alder reaction.[3] The insights gained from these efforts have encouraged us to undertake a very challenging target that combines multiple elements from previously designed enzymes towards the Baylis-Hillman reaction. Here, we describe our efforts to produce active enzyme catalysts for this complex bimolecular multistep transformation using quantum mechanics and molecular dynamics simulations.[1] Rothlisberger D.; Khersonsky, O.; Wollacott, A. M.; Jiang, L.; DeChancie, J.; Betker, J.; Gallaher, J. L.; Althoff, E. A.; Zanghellini, A.; Dym, O.; Albeck, S.; Houk, K. N.; Tawfik, D. S.; Baker, D. Nature 2008 , 453, 190-195.[2] Jiang L.; Althoff, E. A.; Clemente, F. R.; Doyle, L.; Rothlisberger, D.; Zangehllini, A.; Galleher, J. L.; Betker, J. L.; Tanaka, F.; Barbas, C. F.; Hilvert, D.; Houk, K. N.; Stoddard, B. L.; Baker, D. Science 2008 , 319, 1387-1391.[3] Siegel, J. B.; Zanghellini, A.; Lovik, H. M.; Kiss, G.; Lambert, A. R.; Clair, J. L. S.; Gallaher, J. L.; Hilvert, D.; Gelb, M. H.; Stoddard, B. L.; Houk, K. N.; Michael, F. E.; Baker, D. Science 2010 , 329, 309-313.

Towards the computational design of Baylis-Hillmanases

243rd National Meeting (2012)

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