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Eur Biophys J. 2012 Dec;41(12):1065-76. doi: 10.1007/s00249-012-0865-x. Epub 2012 Oct 20.

Rationalization of stereospecific binding of propranolol to cytochrome P450 2D6 by free energy calculations.

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Institute of Molecular Modeling and Simulation, University of Natural Resources and Life Sciences, Muthgasse 18, 1190 Vienna, Austria.


Cytochrome P450 2D6 is a major drug-metabolising enzyme with a wide substrate range. A single-point mutation introduced in this enzyme induces stereoselective binding of R and S-propranolol whereas the wild type has no preference. The system has previously been studied both experimentally and computationally (de Graaf et al. in Eur Biophys J 36:589-599, 2007a). The in silico study reported hysteresis and significant deviations from closure of thermodynamic cycles, probably because of lack of sampling. Here, we focus on the effect of prolonged simulation time and enhanced sampling methods, such as Hamiltonian replica exchange, to reduce these problems and to improve the precision of free energy calculations. Finally we rationalize the results at a molecular level and compare data with experimental findings and previously estimated free energies.

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