Combined QM/MM approach based on linear-scaling DFT and CPE methods

Applications involving complex chemical reactions ultimately require the rigor afforded by high level first-principle methods. Fortunately, regions where chemical bond cleavage and formation occur, such as the active site of an enzyme, typically account for only a relatively small portion of the total system. An attractive strategy for attacking very large problems involves combining quantum mechanical (QM) and molecular mechanical (MM) models.

A hybrid QM/MM force field based on the chemical potential equalization and linear-scaling electronic structure methods overcomes many of the difficulties of conventional QM/MM methods, and is particularly well suited for systems where the quantum mechanical and molecular mechanical regions interact strongly and are separated by a chemical bond. This method avoids the necessity of employing artificial "link" atoms to cap dangling bonds, includes many-body effects in the molecular mechanical region, and allows charge transfer to occur across the QM/MM boundary. These methodological developments are ongoing in the lab and applications are just beginning to be realized.

Current Projects

ENZYME CATALYSIS IN HIV-1 RT

Current QM/MM methodological developments will be used to study the reaction profile of phosphate hydrolysis by HIV-1 reverse transcriptase within the entire enzyme system. The active site where phosphate hydrolysis takes place can be treated by quantum mechanics while the bulk protein is handled with molecular mechanics. Our hybrid potential combines the CHARMM22 force field with our new reaction specific PM3/d Hamiltonian. We treat the well known QM/MM "link atom" problem with a "pseudo atom" which mimics the nature of the severed covalent bond at the QM/MM boundary.