A comparative molecular field analysis (CoMFA) was used to model the efficacy with which the Rhodococcus erythropolis mono-oxygenase, DszC, catalyzes the enantioselective sulfoxidation of a broad range of substrates. Experimentally determined values of both the yield and enantiomeric excess for this reaction were employed to create these CoMFA models. A highly predictive CoMFA model was constructed for the prediction of enantiomeric excess of the sulfoxide product. The predictive ability of the model was demonstrated by both cross-validation of the training set (q 2 = 0.74) and for an external test set of substrates. The enantiomeric excesses of the members of the test set, which also included two amino acid sulfides that were structurally distinct from the membership of the training set, were predicted well by the CoMFA model. Product yield was not modelled well by any CoMFA model. Different models comparing the likely bioactive conformations of the substrates suggest that most compounds assume an 'extended' conformation upon binding. Contour diagrams illustrating significant substrate-enzyme interactions suggest that the model, which predicts the enantiomeric excess, is consistent with previous conclusions regarding the effect of various substrate substitutions on the enantiopurity of the product of the biotransformation.
Bibliographical noteFunding Information:
This paper is dedicated to the memory of Herbert L. Holland. The corresponding authors would like to acknowledge the assistance of F. Brown and helpful suggestions of S.M. Rothstein. This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada (NSERC).
Copyright 2012 Elsevier B.V., All rights reserved.
- Rhodococcus erythropolis