Conformational Changes and Free Energies in a Proline Isomerase

Journal of Chemical Theory and Computation
Elena PapaleoKresten Lindorff-Larsen


Proteins are dynamic molecules and their ability to adopt alternative conformations is central to their biological function. The structural and biophysical properties of transiently and sparsely populated states are, however, difficult to study and an atomic-level description of those states is challenging. We have used enhanced-sampling all-atom, explicit-solvent molecular simulations, guided by structural information from X-ray crystallography and NMR, to describe quantitatively the transition between the major and a minor state of Cyclophilin A, thus providing new insight into how dynamics can affect enzyme function. We calculate the conformational free energy between the two states, and comparison with experiments demonstrates a surprisingly high accuracy for both the wild type protein and a mutant that traps the protein in its alternative conformation. Our results demonstrate how the combination of state-of-the-art force fields and enhanced sampling methods can provide a detailed and quantitative description of the conformational changes in proteins such as those observed in Cyclophilin A.


Dec 27, 2016·Frontiers in Molecular Biosciences·Mads NygaardElena Papaleo
Apr 5, 2018·Nature Communications·Renee OttenJames S Fraser
Nov 26, 2015·PLoS Computational Biology·Silvia LoveraFrancesco L Gervasio
Mar 27, 2015·PloS One·Fernando Martín-GarcíaKresten Lindorff-Larsen

Related Concepts

Enzyme Activation
Peptidylprolyl Isomerase
Crystallography, X-Ray
Research Study
Spectroscopy, Nuclear Magnetic Resonance

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