Computational perspective and evaluation of plausible catalytic mechanisms of peptidyl-prolyl cis-trans isomerases.

Background: Peptidyl prolyl cis-trans isomerization of the protein backbone is involved in the regulation of many biological processes. Cis-trans isomerization is notoriously slow and is catalyzed by a family of cis-trans peptidyl prolyl isomerases (PPIases) that have been implicated in many diseases. A general consensus on how these enzymes speed up prolyl isomerization has not been reached after decades of both experimental and computational studies.

Scope Of Review: Computational studies carried out to understand the catalytic mechanism of the prototypical FK506 binding protein 12, Cyclophilin A and peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) are reviewed. A summary and an evaluation of the implications of the proposed mechanisms from computational studies are presented.

Major Conclusions: The analysis of computational studies and evaluation of the proposed mechanisms provide a general consensus and a better understanding of PPIase catalysis. The speedup of the rate of peptidyl-prolyl isomerization by PPIases can be best described by a catalytic mechanism in which the substrate in transition state configuration is stabilized. The enzymes preferentially bind the transition state configuration of the substrate relative to the cis conformation, which in most cases is bound better than the trans conformation of the substrate. Stabilization of the transition state configuration of the substrate leads to a lower free energy barrier and a faster rate of isomerization when compared to the uncatalyzed isomerization reaction.

General Significance: Fully understanding the catalytic mechanism of PPIases has broad implications for drug design, elucidation of the molecular basis of many diseases, protein engineering, and enzyme catalysis in general. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets.