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• W803607603 abstract "Cyclophilin A (CypA) is the well-studied member of a group of ubiquitous and evolutionarily conserved families of enzymes called peptidyl–prolyl isomerases (PPIases). These enzymes catalyze the cistrans isomerization of peptidyl-prolyl bond in many proteins. The distinctive functional path triggered by each isomeric state of peptidyl-prolyl bond renders PPIase-catalyzed isomerization a molecular switching mechanism to be used on physiological demand. PPIase activity has been implicated in protein folding, signal transduction, and ion channel gating as well as pathological condition such as cancer, Alzheimer’s, and microbial infections. The more than five order of magnitude speed-up in the rate of peptidyl–prolyl cis–trans isomerization by CypA has been the target of intense research. Normal and accelerated molecular dynamic simulations were carried out to understand the catalytic mechanism of CypA in atomistic details. The results reaffirm transition state stabilization as the main factor in the astonishing enhancement in isomerization rate by enzyme. The ensuing intramolecular polarization, as a result of the loss of pseudo double bond character of the peptide bond at the transition state, was shown to contribute only about −1.0 kcal/mol to stabilizing the transition state. This relatively small contribution demonstrates that routinely used fixed charge classical force fields can reasonably describe these types of biological systems. The computational studies also revealed that the undemanding exchange of the free substrate between βand αhelical regions is lost in the active site of the enzyme, where it is mainly in the β-region. The resultant relative change in conformational entropy favorably contributes to the free energy of stabilizing the transition state by CypA. The isomerization kinetics is strongly coupled to the enzyme motions while the chemical step and enzyme–substrate dynamics are in turn buckled to solvent fluctuations. The chemical step in the active site of the enzyme is therefore not separated from the fluctuations in the solvent. Of special interest is the nature of catalysis in a more realistic crowded environment, for example, the cell. Enzyme motions in such complicated medium are subjected to different viscosities and hydrodynamic properties, which could have implications for allosteric regulation and function. INDEX WORDS: Cyclophilin A (CypA), Accelerated molecular dynamics, Cis-trans isomerization, Enzyme dynamics, Solvent effects, Kramers rate theory COMPUTATIONAL PERSPECTIVE ON INTRICACIES OF INTERACTIONS, ENZYME DYNAMICS AND SOLVENT EFFECTS IN THE CATALYTIC ACTION OF CYCLOPHILIN A" @default.
• W803607603 created "2016-06-24" @default.
• W803607603 creator A5059558476 @default.
• W803607603 date "2015-01-01" @default.
• W803607603 modified "2023-09-27" @default.
• W803607603 title "Computational perspective on intricacies of interactions, enzyme dynamics and solvent effects in the catalytic action of cyclophilin A" @default.
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