The use of computational chemistry in the study of sex steroid biosynthesis

Many of the steroidogenic enzymes and cofactor proteins are bound to intrac ellular membranes, frustrating standard methods of structure determination. Structural models of steroidogenic P450 enzymes, however, may be predicted from the x-ray crystal structures of prokaryotic P450s. Using P450-BMP as primary structural template, models of hepatic and steroidogenic P450s have been generated using computational chemistry and graphics techniques. We h ave developed an analogous model of human P450c17 using an approach that re lies heavily on energy minimization and molecular dynamics to yield the fin al structure. The final model predicts the known activities of the enzyme a nd explains why all reported mutations disrupt one or more activities. Alth ough the term "computational chemistry" suggests that modeling is an operat or-independent, fully automated process, modeling exercises are fraught wit h pitfalls, choices, and practical dilemmas which make each attempt a uniqu e endeavor. This paper describes the procedure in detail, using P450c17 as an example, and highlights the opportunities that computational chemistry o ffers for the study of sex steroid biosynthesis.