Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Biophysics, MOLECULAR-DYNAMICS, QM/MM, MECHANISMS, Amidohydrolases, Binding Sites, Computer Simulation, Energy Transfer, Enzyme Activation, Models, Chemical, Models, Molecular, Protein Binding, Protein Conformation, Structure-Activity Relationship, 02 Physical Sciences, 03 Chemical Sciences, 06 Biological Sciences, 31 Biological sciences, 34 Chemical sciences, 51 Physical sciences

Abstract:

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.