Cytochrome P450 monooxygenases can catalyse the stereoselective C-H activation of a very broad range of substrates. Prediction and control of enantioselectivity of this enzyme class is of great interest for the synthesis of high value chiral molecules. Here we use a combination of molecular dynamics simulations and experimental screening to study the enantioselectivity of a library of active site mutants of chimeric P450cam-RhFRed towards the benzylic hydroxylation of structurally related regio-isomers of ethyl,methyl benzene. Small variations in either substrate structure or enzyme active site architecture were shown to lead to dramatic changes in enantioselectivity, which was broadly in agreement with computational predictions. In addition to validating computational approaches, these studies have provided us with a deeper understanding of effects that might control stereoselectivity in these biooxidation reactions.
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