The central goal of our work is to understand the fundamental mechanism of molecular recognition and binding kinetics using theory and classical mechanical models. Our research involves the development and application of computational methods and theoretical models to address medically and chemically important problems. These methods are of practical importance in studying biomolecular function, and in the design of new molecules that bind strongly to their receptors. Systems of particular interest include existing or potential drug targets, cell signaling complexes and chemical host-guest systems.
Understanding Molecular Recognition: Molecular recognition plays an essential role in most chemical and biological processes, as well as in protein-drug interactions and protein folding. A thorough understanding of molecular recognition will be very helpful in practical application such as ligand and receptor design. We use the tools of multi-scale computer simulation and statistical mechanics to study and explain molecular recognition, with the aim of gaining a deeper understanding of the phenomenon. By working on new methods and applying methods we have developed, issues of free energy, entropy, enthalpy, and protein conformational changes upon binding are studied.
Modeling Molecular Association: The association of ligand and protein is of fundamental importance in biology, playing roles in functions as diverse as immunity, metabolism, signaling, and cognition. Recent advances on Brownian dynamics and continuum simulation methods provide powerful tools to study diffusion in biomolecular systems, but they are mostly restricted to systems that are near the limit of diffusion-control one-step association processes. For more complicated processes, such as two-step association processes that involve short-range interactions and conformational changes of ligands and proteins, existing methods may not be reliable enough to study the association pathways and predict the rate constants. The project is to develop new computer simulation tools and theoretical models to allow the study of the two-step binding processes. We are currently working on chemical host-guest systems (cyclophane and chloroform binding), chemical compounds binding to either HIV protease or p38 MAP kinase.
Computer-aided ligand/receptor design and discovery: In drug design and discovery, finding a small molecule that maximizes binding free energy is very important and is an interesting challenge. A thorough understanding of driving forces, binding penalties, and conformational changes induced by ligand binding, should enable more accurate prediction of binding affinities. Our lab assembles state of the art methods, e.g. docking and scoring, QSAR and applies methods we develop to improve the ligand-design work. We will not only focus on finding tight binding ligands, but also consider drug resistance and early ADME (Absorption, Distribution, Metabolism, Excretion, critical for the optimization of pharmacokinetic properties) in the calculations. We are currently working on cannabinoid receptor and tryptophan synthase alpha-subunit as our drug targets. (more)
Our group collaborates with Joanna Trylska’s group for coarse-grained Brownian dynamics simulations, Dr. Yuhui Cheng in the Northern Pacific National Lab for continuum modeling, Dr. Mathew Mizwicki for experimental kinetics and thermodynamics data of vitamin D receptor, and Dr. Li Fang and Dr. Shih-hsin Kan for protein engineering. Moreover, for the drug design and discovery projects, we collaborate with the Marsella group for organic synthesis and the Dunn group for experimental binding assays.
Understand synergistic and allosteric regulation and chemical catalysis: Conformational changes of enzyme complexes are often related to regulating and creating an optimal environment for efficient chemistry. We investigated the synergistic regulation of the tryptophan synthase (TRPS) complex, studied for decades as a model of allosteric regulation and substrate channeling within protein complexes. The enzyme has α- and β-subunits and the center of the active sites of both α- and β-subunits are connected by a 25 Å long hydrophobic tunnel, which allows for direct substrate channeling of the reaction intermediate without diffusing it into the water. The mechanism of their activation and allosteric regulation in TRPS is associated with an open–closed transition of both subunits. Here we focus on how proteins communicate and regulate their function. We apply classical molecular dynamics simulations, accelerated molecular dynamics simulations, coarse-grained Brownian dynamics simulations, energy and entropy calculations to answer these questions.
We collaborate with the Mueller group in which we apply NMR to study protein dynamics, ligand protonation states and mechanisms of chemical catalysis.