LAUSR

The molecular mechanism of enzyme catalysis has been of great interest in protein studies. While the catalytic role of amino acids in enzymes at the transition states has been of great interest, and have been studied by various experimental and theoretical techniques, the dynamic picture of enzyme reactions, e.g. how the protein environment changes during the reaction, has been largely unclear and controversial. Proline isomerization is a typical enzymatic reaction which plays a key role in folding and regulating the function of proteins. The mechanism of such isomerization reactions have been investigated extensively, e.g. multiple residues which play important roles in stabilizing the reactant and transition state has been discussed. In addition, a few residues which may transiently play a role about the transition state has been proposed, yet the mechanism and dynamics remains unclear. Here we study the proline isomerization reaction of Pin1, a prototypical peptidyl-prolyl isomerase protein, from a theoretical perspective to reveal the dynamic picture of an enzyme catalysis. A molecular dynamics simulation and transition path sampling approach is applied to sample and analyze the transition events at molecular detail. The residues which are statically and dynamically important are identified, and the changes in the hydrogen bonding network and protein-ligand interactions about the active site as the reaction proceeds is discussed. The current study provides a dynamic view of protein, in addition to a static role of stabilizing the transition state, in a proline isomerization reaction. It is expected that the dynamics also plays a fundamental role in broader enzymatic reactions in order to achieve high efficiency and selectivity.