title: Designing a new Diels-Alderase: a combinatorial, semirational approach including dynamic optimization.
abstract: A computationally inexpensive design strategy involving 'semirational' screening for enzymatic catalysis is presented. The protocol is based on well-established computational methods and represents a holistic approach to the catalytic process. The model reaction studied here is the Diels-Alder, for which a successful computational design has recently been published (Siegel, J. B. et al. Science 2010, 329, 309-313). While it is a leap forward in the field of computational design, the focus on designing only a small fraction of the active site gives little control over dynamics. Our approach explicitly incorporates mutagenesis and the analysis of binding events and transition states, and a promising enzyme-substrate candidate is generated with relatively little effort. We estimate catalytic rate accelerations of up to 10⁵.
authors.affiliation: Physical Chemistry, Royal Institute of Technology (KTH), Stockholm, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Linder
authors.forename: Adam Johannes
authors.initials: AJ
authors.lastname: Johansson
authors.forename: Tjelvar S G
authors.initials: TS
authors.lastname: Olsson
authors.forename: John
authors.initials: J
authors.lastname: Liebeschuetz
authors.forename: Tore
authors.initials: T
authors.lastname: Brinck
mesh_terms: D001665:Binding Sites; D055162:Biocatalysis; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D057225:Data Mining; D030562:Databases, Protein; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D016296:Mutagenesis; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000737:chemistry; D011485:Protein Binding; D011506:Proteins / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D011506:Proteins; D054852:Small Molecule Libraries