Computational enzymology

Techniques for modelling enzyme-catalyzed reaction mechanisms are making increasingly important contributions to biochemistry. They can address fundamental questions in enzyme catalysis and have the potential to contribute to practical applications such as drug development

Mechanistic Insights into the Reaction of Chlorination of Tryptophan Catalyzed by Tryptophan 7-Halogenase

Tryptophan 7-halogenase catalyzes chlorination of free tryptophan to 7-chlorotryptophan, which is the first step in the antibiotic pyrrolnitrin biosynthesis. Many biologically and pharmaceutically active natural products contain chlorine and thus, an understanding of the mechanism of its introduction into organic molecules is important. Whilst enzyme-catalyzed chlorination is accomplished with ease, it remains a difficult task for the chemists. Therefore, utilizing enzymes in the synthesis of chlorinated organic compounds is important, and providing atomistic mechanistic insights about the reaction mechanism of tryptophan 7-halogenase is vital and timely. In this work, we examined a mechanism for the reaction of tryptophan chlorination, performed by tryptophan 7-halogenase, by calculating potential energy and free energy surfaces using two different Combined Quantum Mechanical/Molecular Mechanical (QM/MM) methods both employing Density Functional Theory (DFT) for the QM region. Both computational strategies agree on the nature of the rate-limiting step and provided close results for the reaction barriers of the two reaction steps. The calculations for both the potential energy and the free energy profiles showed very similar geometric features and hydrogen bonding interactions for the characterized stationary point

Combined Quantum Mechanics and Molecular Mechanics Studies of Enzymatic Reaction Mechanisms

The combined quantum mechanics/molecular mechanics (QM/MM) methods have become a valuable tool in computational biochemistry and received versatile applications for studying the reaction mechanisms of enzymes. The approach combines the calculations of the electronic structure of the active site by QM, with modeling of the protein environment using MM force field, which allows the long-range electrostatics and steric effects on the enzyme reactivity to be accounted for. In this review, we review some key theoretical and computational aspects of the method and we also present some applications to particular enzymatic reactions such as tryptophan-7-halogenase, cyclooxygenase-1, and the epidermal growth factor receptor

QM/MM modelling of oleamide hydrolysis in fatty acid amide hydrolase (FAAH) reveals a new mechanism of nucleophile activation

Fatty acid amide hydrolase (FAAH), a promising target for the treatment of several central and peripheral nervous system disorders, such as anxiety, pain and hypertension, has an unusual catalytic site, and its mechanism has been uncertain; hybrid quantum mechanics/molecular mechanics (QM/MM) calculations reveal a new mechanism of nucleophile activation (involving a Lys-Ser-Ser catalytic triad), with potentially crucial insights for the design of potent and selective inhibitors

QM/MM modelling of oleamide hydrolysis in fatty acid amide hydrolase (FAAH) reveals a new mechanism of nucleophile activation

Fatty acid amide hydrolase (FAAH), a promising target for the treatment of several central and peripheral nervous system disorders, such as anxiety, pain and hypertension, has an unusual catalytic site, and its mechanism has been uncertain; hybrid quantum mechanics/molecular mechanics (QM/MM) calculations reveal a new mechanism of nucleophile activation (involving a Lys-Ser-Ser catalytic triad), with potentially crucial insights for the design of potent and selective inhibitors

Insight into the mechanism of carbamate inactivation of FAAH by QM/MM modelling study

XXII Congresso Nazionale della della Società Chimica Italiana, SCI 2006 (Poster FAR-P-078) 19

Chemical Determinants of Fatty Acid Amide Hydrolase Inactivation Explored by QM/MM Mechanistic Modelling

XX National Meeting on Medicinal Chemistry Book of Abstract SC21, 79

Understanding the role of carbamate reactivity in fatty acid amide hydrolase inhibition by QM/MM mechanistic modelling.

QM/MM modelling of FAAH inactivation by O-biphenyl-3-yl carbamates identifies the deprotonation of Ser241 as the key reaction step, explaining why FAAH is insensitive to the electron-donor effect of conjugated substituents; this may aid design of new inhibitors with improved selectivity and in vivo potency