General Transition-State Force Field for Cytochrome P450 Hydroxylation.

We have developed force-field parameters for the hydrogen-abstraction transition state of aliphatic hydroxylation by cytochrome P450 using the Q2MM approach. The parametrization is based on quantum chemical (B3LYP) transition-state structures and Hessian matrices for 24 diverse substrate models (14 in the training set and 10 in the test set). The force field is intended to be applicable to any druglike molecule by the use of the general Amber force field (GAFF) for the substrates. The parameters reproduce the geometries within 0.1 Å and 1.2° for bond lengths and angles, respectively, with no significant differences between the training and test sets. The Hessian matrix is also well reproduced with a correlation coefficient of 0.99. The parametrization is performed by the ideal iterative approach of Norrby and Liljefors, which we have implemented for the Amber software.