William Jorgensen of Yale University is supported by an award from the Theoretical and Computational Chemistry program to carry out research on the development of semi-empirical quantum mechanical (SQM) techniques for the simulation of organic reactions. To enable routine computational study of organic and enzymatic reactions in solution, improved SQM methods are being developed. Inclusion of previously neglected "Pauli" repulsions and the addition of d-orbitals are expected to yield much enhanced results, especially for the description of conformational energy changes and barriers, hydrogen bonding, small ring compounds, and activation energies for reactions. The new SQM methods are being applied in QM/MM calculations to numerous organic reactions in solution, which exhibit significant solvent effects on their rates. This includes nucleophilic substitution, acylation, and Menshutkin reactions, decarboxylations, and [2,3] sigmatropic rearrangements. For general studies of reactions, it is also necessary to incorporate configuration interaction (CI) into the QM framework. This is being pursued using the Pair Excited CI method with initial applications to solvolysis reactions and Bergman cyclization. In all cases, the SQM and CI calculations are performed on-the-fly in MC simulations for the reactions in solution. The recently developed CRA (concerted rotation with variable bond angles) method will be used in MC simulations to perform ab initio folding of polypeptides. Optimization of the simulation protocols and application to small proteins are priority items in this case. Related studies are aimed at the prediction and optimization of the structures of peptides that catalyze asymmetric reactions, e.g., reactions for which the rate is different for mirror-image substrates. The work is expected to have a broad impact on the conceptual understanding of organic reaction mechanisms.
