Conformational effects in enzyme catalysis: reaction via a high energy conformation in fatty acid amide hydrolase.

Quantum mechanics/molecular mechanics and molecular dynamics simulations of fatty acid amide hydrolase show that reaction (amide hydrolysis) occurs via a distinct, high energy conformation. This unusual finding has important implications for fatty acid amide hydrolase, a key enzyme in the endocannabinoid system. These results demonstrate the importance of structural fluctuations and the need to include them in the modeling of enzyme reactions. They also show that approaches based simply on studying enzyme-substrate complexes can be misleading for understanding biochemical reactivity.

[1]  D. Piomelli.  The molecular logic of endocannabinoid signalling , 2003, Nature Reviews Neuroscience.

[2]  Lars Ridder,et al.  Mechanisms of antibiotic resistance: QM/MM modeling of the acylation reaction of a class A beta-lactamase with benzylpenicillin. , 2005, Journal of the American Chemical Society.

[3]  Adrian J Mulholland,et al.  Atomic Description of an Enzyme Reaction Dominated by Proton Tunneling , 2006, Science.

[4]  Adrian J Mulholland,et al.  Conformational effects in enzyme catalysis: QM/MM free energy calculation of the 'NAC' contribution in chorismate mutase. , 2004, Chemical communications.

[5]  J. Andrew McCammon,et al.  Influence of Structural Fluctuation on Enzyme Reaction Energy Barriers in Combined Quantum Mechanical/Molecular Mechanical Studies , 2003 .

[6]  M. Karplus,et al.  Molecular dynamics and protein function. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[7]  B. Cravatt,et al.  Evidence for Distinct Roles in Catalysis for Residues of the Serine-Serine-Lysine Catalytic Triad of Fatty Acid Amide Hydrolase* , 2003, Journal of Biological Chemistry.

[8]  Kevin J. Naidoo,et al.  Implementation of an adaptive umbrella sampling method for the calculation of multidimensional potential of mean force of chemical reactions in solution , 2003, J. Comput. Chem..

[9]  Adrian J Mulholland,et al.  Modelling enzyme reaction mechanisms, specificity and catalysis. , 2005, Drug discovery today.

[10]  Johannes C. Hermann,et al.  QM/MM modelling of oleamide hydrolysis in fatty acid amide hydrolase (FAAH) reveals a new mechanism of nucleophile activation. , 2005, Chemical communications.

[11]  A. Mulholland,et al.  The Fe-CO bond energy in myoglobin: a QM/MM study of the effect of tertiary structure. , 2006, Biophysical journal.

[12]  M Karplus,et al.  Solvent effects on protein motion and protein effects on solvent motion. Dynamics of the active site region of lysozyme. , 1989, Journal of molecular biology.

[13]  Alexander D. MacKerell,et al.  All-atom empirical potential for molecular modeling and dynamics studies of proteins. , 1998, The journal of physical chemistry. B.

[14]  M. Karplus,et al.  A combined quantum mechanical and molecular mechanical potential for molecular dynamics simulations , 1990 .