The enzyme Pin1 specifically catalyzes the cis-trans isomerization of peptide bonds between phosphorylated threonine or serine residues and proline. Besides its importance in many biological proceses a detailed understanding of the catalysis mechanism is still missing.We employ extensive QM/MM molecular dynamics simulations combined with the mean reaction force (MRF) to discern the influence of the enzyme on the reaction mechanism and compare the results to the isomerization in aqueous solution. The recently introduced MRF method separates the activation free energy barrier into structural and electronic contributions providing a more detailed description of the enzyme's function.In both environments the same free energy barrier for the isomerization from the cis form is obtained (see Figure), but with different decomposition in structural and electronic contributions by the mean reaction force. The enzyme reduces the energy required for structural rearrangements to reach the transition state, pointing to a destabilization of the reactant, but increases the electronic contribution to the barrier through specific enzyme-peptide hydrogen bonds.In the reverse reaction the enzyme changes the reaction coordinate through unfavorable, steric enzyme-peptide interactions in the catalytic cavity, resulting in two minima with small free energy differences to the transition state (see Figure). These small free energy barriers should in principle make the reaction feasible at room temperature once the conformer is bound in the right conformation.The author would like to thanks FONDECYT for financial support through Project No. 11121179.

Towards a better understanding of enzyme catalyis through the mean reaction force: The case study of Pin1

247th National Meeting (2014)

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