title: Mechanistic insights into Pin1 peptidyl-prolyl cis-trans isomerization from umbrella sampling simulations.
abstract: The peptidyl-proyl isomerase Pin1 plays a key role in the regulation of phospho(p)-Ser/Thr-Pro proteins, acting as a molecular timer of the cell cycle. After recognition of these motifs, Pin1 catalyzes the rapid cis-trans isomerization of proline amide bonds of substrates, contributing to maintain the equilibrium between the two conformations. Although a great interest has arisen on this enzyme, its catalytic mechanism has long been debated. Here, the cis-trans isomerization of a model peptide system was investigated by means of umbrella sampling simulations in the Pin1-bound and unbound states. We obtained free energy barriers consistent with experimental data, and identified several enzymatic features directly linked to the acceleration of the prolyl bond isomerization. In particular, an enhanced autocatalysis, the stabilization of perturbed ground state conformations, and the substrate binding in a procatalytic conformation were found as main contributions to explain the lowering of the isomerization free energy barrier.
authors: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-Università di Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
authors: Giovanni Paolo
authors: GP
authors: Di Martino
authors: Matteo
authors: M
authors: Masetti
authors: Andrea
authors: A
authors: Cavalli
authors: Maurizio
authors: M
authors: Recanatini
mesh_terms: D002384:Catalysis; D016000:Cluster Analysis; D007536:Isomerism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D014867:Water
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D014867:Water; D019696:Peptidylprolyl Isomerase
keywords: autocatalysis; enhanced sampling; parvulins; peptidyl-prolyl isomerases; pyramidalization