The mechanism of action of enzymes is mainly due to their ability to preferentially stabilize the transition state. This knowledge has lead to the development of transition state mimics as potent enzyme inhibitors. However, the role enzyme conformational dynamics play in the mechanism of action and recognition is not well understood. Here, we show that the human cyclophilin A, a well-studied cis-trans isomerase, adopts ensembles of conformations that can selectively bind the substrate in the different states during catalytic turnover. We have analyzed the principal modes of the active site dynamics of cyclophilin A from molecular dynamics simulations to show that a distinct ensemble of enzyme conformations is responsible for the transitions state stabilization of the substrate and recognition of potent inhibitors. These results provide a detailed atomistic description of cyclophilin A recognition that can be exploited in designing novel inhibitors.

Conformational plasticity of cyclophilin A in catalysis and recognition

243rd National Meeting (2012)

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