Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 15, Pages 5699-5704Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1117060109
Keywords
cis-trans isomerization; Cyclophilin A; enzyme catalysis; enzyme dynamics; Kramers' rate theory
Categories
Funding
- National Science Foundation [MCB- 0953061]
- Georgia Cancer Coalition (GCC) scholar award
- Georgia State University
- Georgia State's IBM System p5 supercomputer
- Southeastern Universities Research Association
- IBM
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [0953061] Funding Source: National Science Foundation
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Despite growing evidence suggesting the importance of enzyme conformational dynamics (ECD) in catalysis, a consensus on how precisely ECD influences the chemical step and reaction rates is yet to be reached. Here, we characterize ECD in Cyclophilin A, a well-studied peptidyl-prolyl cis-trans isomerase, using normal and accelerated, atomistic molecular dynamics simulations. Kinetics and free energy landscape of the isomerization reaction in solution and enzyme are explored in unconstrained simulations by allowing significantly lower torsional barriers, but in no way compromising the atomistic description of the system or the explicit solvent. We reveal that the reaction dynamics is intricately coupled to enzymatic motions that span multiple timescales and the enzyme modes are selected based on the energy barrier of the chemical step. We show that Kramers' rate theory can be used to present a clear rationale of how ECD affects the reaction dynamics and catalytic rates. The effects of ECD can be incorporated into the effective diffusion coefficient, which we estimate to be about ten times slower in enzyme than in solution. ECD thereby alters the preexponential factor, effectively impeding the rate enhancement. From our analyses, the trend observed for lower torsional barriers can be extrapolated to actual isomerization barriers, allowing successful prediction of the speedup in rates in the presence of CypA, which is in notable agreement with experimental estimates. Our results further reaffirm transition state stabilization as the main effect in enhancing chemical rates and provide a unified view of ECD's role in catalysis from an atomistic perspective.
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