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Title: A molecular dynamics simulation approach for calculation of gas diffusion rates in proteins with applications to hydrogenases and dehydrogenases
Author: Wang, P. H.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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We describe and apply a microscopic model for the calculation of gas diffusion rates in several proteins, including [NiFe]-hydrogenases, [FeFe]-hydrogenases, and carbon monoxide dehydrogenases. These proteins share a common feature that their substrate gas molecules have to diffuse through the protein matrix before they can reach the active site and be catalysed. For hydrogenases, H₂ serves as a substrate but O₂ and CO are strong inhibitors. For dehydrogenases, CO₂ is the substrate and CO is the product. How they manage to control transport of different gas molecules inside the protein remains a question. In our model, the diffusive hopping of gas molecules in the protein interior is coarse grained using a master equation approach with transition rates estimated from equilibrium and non-equilibrium pulling simulations. Propagating the rate matrix in time, we find that the probability for a gas molecule to reach the enzyme active site follows a mono-exponential increase. Fits to a phenomenological rate law gives an effective diffusion rate constant for gas molecules that is in very good agreement with experimental measurements. This method enables us to characterise gas diffusion in proteins not only qualitatively but also, more importantly, in a quantitative manner. Based on the findings we explore, we can provide insights into how proteins can filter different gas molecules without being affected in their enzymatic activity and further suggest specific amino acid side chains for future mutation experiments in order to protein-engineer a more robust and efficient enzyme.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available