Understanding complex molecular systems using experiments alone is difficult. Computer simulations based on physical and chemical principles can complement experiments and provide novel insights into the behavior of these systems at an atomic level. Our research targets the development and applications of state-of-the-art computational tools that explore the underlying mechanisms of complex molecular systems. Enzymes and other biological macromolecules, along with bio-inorganic ligands, are of primary interest.
Developing computational techniques and theoretical models for complex systems
A substantial amount of research activity in our group is geared toward developing novel computational techniques to make the simulation of complex biomolecular systems possible. One major area involves improving the efficiency and accuracy of combined quantum mechanical and classical mechanical methods, such that bond-breaking and bond-formation (chemistry!) can be studied in detail for realistic biological environments. Another area is related to the development of coarse-grained models for proteins and membranes, such that insights into the driving force of conformational transitions in proteins, protein/peptide aggregation and membrane remodeling processes (e.g., membrane fusion) can be obtained computationally. In these coarse-grained model developments, we explore both particle and continuum mechanics based models, and integration with not only atomistic simulations but also experimental observables such as thermodynamics data for complex solutions.
Simulation of complex molecular machines in bio-energy transduction
Biological systems involve many fascinating "molecular machines" that transform energy from one form to the other. Important examples are F1-ATP synthase and proton pumps, the former utilizes the proton motive force to synthesize ATP, while the latter employs the free energy of chemical reactions (e.g., oxygen reduction) to generate the proton motive force across the membrane. With the recent developments in crystallography, cyro-EM and single molecule spectroscopy, the working mechanisms of these nano-machines are being discovered. In order to understand the energy transduction process at an atomic level, our group is developing and applying state-of-the-art computational techniques to analyze the detailed mechanisms of several large molecular complexes including: myosin, DNA repair enzymes and the cytochrome c oxidase. Questions of major interest include: (i). What are the functionally relevant motions of these complexes? (ii). How are the chemical events (e.g., ATP binding and hydrolysis) coupled to the mechanical (e.g., conformational transition) process? (iii). How are the efficiency and vectorial nature of energy transduction regulated?
Understanding the catalytic mechanism of enzymes
Enzymes overshadow most chemical catalysts because they are extremely efficient and highly reaction-specific. Our group is developing and applying novel computational methods to explore the physical and chemical mechanisms behind the catalytic efficiency and specificity of several fascinating enzymatic systems. These include enzymes that exploit transition metal ions (phosphatases) and radical intermediates (DNA repair enzymes). In addition to their important biological implications, an underlying theme for these systems is catalysis modulated by protein motion. Our studies will not only provide insights into the fundamental working mechanisms of enzymes, but may also lead to the rational design of proteins/enzymes (e.g., metal ion activated transcrption factors) with improved or even altered functions.
Interfacing biology and material science
The last decades have seen the thrilling developments in the science of materials at the nanometer scale. Nano-materials with tailored electrical, optical or mechanical properties have been synthesized. An exciting direction that has been recently recognized is that biomolecules can be used to provide control in organizing technologically important (non-biological) objects into functional nano-materials. The interaction between biomolecules and inorganic materials is fundamental to these applications, and we are using computational techniques to investigate this aspect. These studies are expected to play a guiding role in the design of novel hybrid materials, new sensors for biological molecules, as well as in understanding the fascinating process of biomineralization.