› research

In the Hollett group we perform research in both theoretical and computational chemistry. A major part of our research is the development of our own unique approach to cumulant functional theory (ΔNO), an efficient and universal electronic structure method. We also apply current state-of-the-art computational chemistry methods to solve chemical problems of interest to us, and our colleagues. We are particularly interested in using quantum mechanics and molecular mechanics simulations to study the function and inhibition of viral proteins.

› the ΔNO approach

The natural orbitals (NOs) represent the best set of one-particle functions that may be used to describe the N-electron wave function. Unlike, Hartree-Fock (i.e. molecular orbital theory) or density functional theory (DFT) in which orbitals are occupied by zero, one, or two electrons, the occupancies of the natural orbitals can take any value between zero and two. The variational occupancies of the NOs effectively deal with the static correlation problem that currently plagues DFT methods. The occupancies of the NOs of the ΔNO approach are determined by a complementary set of electron transfer variables that transfer electrons between correlated NOs. This electron transfer captures static correlation, while an on-top density functional captures the remaining dynamic correlation. Ongoing efforts include the development of accurate dynamic correlation functionals, a linear-scaling ΔNO algorithm, and the adaptation of the method to excited states and materials. All code is initially implemented within the MUNgauss computational chemistry package, to provide an efficient and universal computational chemistry tool.

DNO energy expression

ΔNO energy expression.

› computational virology

A main focus of our computational studies are centered on understanding the structure and function of viral proteins. In particular, we are focused on the key proteins of the hepatitis C virus (HCV) and human imuunodefficiency virus (HIV).

NS5B in complex with two GTP molecules

Figure 1: RNA-dependent RNA polymerase of HCV (NS5B) in complex with two GTP molecules
(J. Biol. Chem. 2010, 285, 32906-32918).

Our study of HCV currently involves using hybrid quantum mechanics and molecular mechanics (QM/MM) methods to perform molecular dynamics simulations of the RNA-dependent RNA polymerase, NS5B, interacting with naturally occuring substrates as well as small molecule inhibitors. Our investigation will lead to further understanding of the sophisticated viral reproduction and the discovery of potential drug candidates.

VRC01 in complex with gp120

Figure 2: Ribbon representation of crystal structure of broadly neutralizing antibody (NAb) VRC01 in complex with gp120. The gp120 inner domain (gray), outer domain (red), bridging sheet (dark blue) and CD4+ T-cell binding loop (purple) are shown. The light (light blue) and heavy (green) chains of VRC01 participate in the gp120 interaction (Science 2010, 329, 811-817).

The present focus of our HIV study is the antibody-viral envelope complex. Understanding the interactions between these proteins is key to the design of effective vaccines for HIV. Through the use of MM molecular dynamics simulations, for which we employ the latest methods for specifically defining the force fields that describe the atomic interactions, we determine free energies of interactions and also observe the key residues responsible for protein binding.