Development of simulation methods
We develop classical and quantum simulation methods. This includes tools for nuclear quantum effects that are useful for studying enzyme catalysis. This entails development of new path-integral methods for the simulations of zero-point energy and tunneling effects in condensed phase environments. Several new methods are being developed and are incorporated into simulation platforms for enzymatic reactions (e.g. CHARMM). The simulations tools are typically used in conjunction with hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) methods.
In order to accurately predict reaction rates for proton, hydrogen, and hydride transfer reactions it is necessary to include nuclear quantum effects (NQE) in the simulations. Additionally, in order to predict isotope effects, such as kinetic, equilibrium, or binding isotope effects, inclusion of NQE is essential. The main source of NQE in enzymes is zero-point energy and tunneling. In the path-integral (PI) approach, classical particles are replaced by a necklace of beads that are connected via harmonic springs (i.e. a ring polymer), which gives the particle a delocalized quantum behavior. The theory provides the correct thermodynamic behavior of quantum particles. We have developed a range of PI methods that are suitable for quantum simulations of condensed phase chemical reactions, and these have been applied to many enzymes in our group and many others. The methods are highly scalable with number of cores and are implemented in the CHARMM simulation platform.