title: Quantum mechanical design of enzyme active sites.
abstract: The design of active sites has been carried out using quantum mechanical calculations to predict the rate-determining transition state of a desired reaction in presence of the optimal arrangement of catalytic functional groups (theozyme). Eleven versatile reaction targets were chosen, including hydrolysis, dehydration, isomerization, aldol, and Diels-Alder reactions. For each of the targets, the predicted mechanism and the rate-determining transition state (TS) of the uncatalyzed reaction in water is presented. For the rate-determining TS, a catalytic site was designed using naturalistic catalytic units followed by an estimation of the rate acceleration provided by a reoptimization of the catalytic site. Finally, the geometries of the sites were compared to the X-ray structures of related natural enzymes. Recent advances in computational algorithms and power, coupled with successes in computational protein design, have provided a powerful context for undertaking such an endeavor. We propose that theozymes are excellent candidates to serve as the active site models for design processes.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, California 92093, USA.
authors.forename: Xiyun
authors.initials: X
authors.lastname: Zhang
authors.forename: Jason
authors.initials: J
authors.lastname: DeChancie
authors.forename: Hakan
authors.initials: H
authors.lastname: Gunaydin
authors.forename: Arnab B
authors.initials: AB
authors.lastname: Chowdry
authors.forename: Fernando R
authors.initials: FR
authors.lastname: Clemente
authors.forename: Adam J T
authors.initials: AJ
authors.lastname: Smith
authors.forename: T M
authors.initials: TM
authors.lastname: Handel
authors.forename: K N
authors.initials: KN
authors.lastname: Houk
mesh_terms: D000171:Acrolein / Q000737:chemistry; D000447:Aldehydes / Q000737:chemistry; D001665:Binding Sites; D002384:Catalysis; D003042:Cocaine / Q000737:chemistry / Q000378:metabolism; D004789:Enzyme Activation; D004798:Enzymes / Q000737:chemistry* / Q000378:metabolism*; D006868:Hydrolysis; D007536:Isomerism; D008958:Models, Molecular; D015394:Molecular Structure; D009284:Naphthols / Q000737:chemistry; D009596:Nitrophenols / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D011392:Proline / Q000737:chemistry; D011789:Quantum Theory; D012524:Sarin / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D014867:Water / Q000737:chemistry
chemical_list: D000447:Aldehydes; D004798:Enzymes; D009284:Naphthols; D009596:Nitrophenols; D010455:Peptides; D014867:Water; C012547:scytolone; D000171:Acrolein; C008642:4-nitrophenyl acetate; C116609:3-hydroxybutanal; D011392:Proline; D012524:Sarin; D003042:Cocaine