The role of enzyme conformational dynamics in the chemical step of catalysis and enhancing reaction rates has remained a controversial issue. With atomistic molecular dynamics simulations in an unconstrained manner, we investigate this issue in cyclophilin A (CypA), a widely studied cis-trans isomerase. Without any bond breaking or formation, CypA is an ideal system for molecular mechanics studies. Using enhanced sampling, we characterized free energy landscapes as well as kinetics of isomerization in the free and CypA-bound substrates.  We show that conformational dynamics of CypA, which occurs on a wide range of timescales, is intricately coupled to the isomerization dynamics. The range of enzyme modes that are selected for coupling depends on the energy barrier height of the reaction. We suggest that enzyme dynamical effects can be incorporated in the effective diffusion coefficient of Kramers' theory. Enzyme dynamical effects alter the pre-exponential factor and slow down the potential rate enhancement from barrier effects. Our work conforms to transition state stabilization as the pre-dominant effect in rate enhancement and provides a unifying view of enzyme dynamical effects on catalysis.

Complex role of enzyme conformational dynamics in catalytic function: Molecular dynamics study on a cis-trans isomerase

245th National Meeting (2013)

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