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Understanding the molecular mechanism of enzymatic processes by a combination of NMR spectroscopy and molecular dynamics simulations

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Atomic action in enzyme reactions

Enzymes can increase rates of reaction by 15 orders of magnitude, a thousand trillion times faster! EU research has looked at the dynamics of enzyme behaviour in a reaction at atomic level.


Involved in all chemical reactions in the body, enzymes are crucial for optimal health and can be used in many industrial processes mimicking natural systems. The MMEP project has developed a detailed definition of action for two important enzymes, cyclophilin A (CypA) and PagP. CypA in particular is a key player in human disease. It regulates protein folding and trafficking and is secreted in response to inflammatory stimuli. Researchers incorporated experimental measurements in molecular dynamics simulations. The team used a novel approach involving chemical shifts, changes in resonant frequencies of the nuclei of the atoms. These were measured using nuclear magnetic resonance spectroscopy. Input of experimental data resulted in effective corrections of the force field so the simulation is in better agreement with the experimental data. The scientists also integrated advanced sampling methods to alleviate the problem of conformational sampling as the molecules change shape to effect changes in the substrate. MMEP has unveiled the details of how CypA works at the atomic level when the enzyme successfully substitutes an atom in the substrate. Using this model as a base, the team has designed a striking test involving a single atom substitution that is enough to regulate the turnover of the reaction. Project work has successfully outlined the sub-molecular dynamics of the enzyme CypA. Ubiquitous in cell management, CypA has an input into diseases as diverse as cardiovascular diseases, viral infections, neurodegeneration, cancer, rheumatoid arthritis, sepsis, asthma and periodontitis. It is likely that elucidating the role of CyPA will provide a better understanding of the molecular mechanisms underlying these diseases and will help develop novel pharmacological therapies.


Atomic, enzyme, CypA, protein folding, molecular dynamics, simulation, chemical shift, nuclear magnetic resonance spectroscopy, conformation, disease, therapy

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