Designing a New Diels–Alderase: A Combinatorial, Semirational Approach Including Dynamic Optimization

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...

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Bibliographic Details
Published in:Journal of chemical information and modeling 2011-08, Vol.51 (8), p.1906-1917
Main Authors: Linder, Mats, Johansson, Adam Johannes, Olsson, Tjelvar S. G, Liebeschuetz, John, Brinck, Tore
Format: Article
Language:English
Subjects:
Binding Sites
Biocatalysis
Biological and medical sciences
Catalysis
Catalytic Domain
Chemical reactions
Chemistry
Chemistry, Pharmaceutical - methods
Combinatorial Chemistry Techniques
Computational Biochemistry
Computer Science
Computer Simulation
Data Mining
Databases, Protein
Design optimization
Drug Design
Drug Discovery - methods
Enzymes
Exact sciences and technology
General and physical chemistry
General pharmacology
General. Nomenclature, chemical documentation, computer chemistry
Humans
Information Systems
Interdisciplinary Applications
Kinetics
Ligands
Medical sciences
Models, Molecular
Multidisciplinary
Mutagenesis
Pharmaceutical Preparations - analysis
Pharmaceutical Preparations - chemistry
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Protein Binding
Proteins - analysis
Proteins - chemistry
Proteins - metabolism
Small Molecule Libraries
Substrate Specificity
Theory of reactions, general kinetics. Catalysis. Nomenclature, chemical documentation, computer chemistry
Thermodynamics
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Description
Summary: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.
ISSN:1549-9596
1549-960X
DOI:10.1021/ci200177d