My research is concerned with the dynamics of large biomolecules, in particular with protein dynamics, folding and binding. Through the impressive achievements of structural biology, much has been learnt about the function of proteins by solving the structures of their stable states (e.g. active, inactive conformations). Studying the dynamics and mechanism of transitions between these states is still a major challenge for both experiment and simulation, yet is equally important for understanding function. I develop novel methods for studying macromolecular dynamics and apply them to biologically interesting systems, using a combination of simulation and theory appropriate for addressing each question.
For example, we have devised algorithms for enhanced sampling of the “rare events” in simulations, which constitute the reactive portions of the trajectory; by designing good “reaction coordinates”, we are able to describe the progress of the reaction (mechanism) quantitatively. To study larger systems or longer time scales, we are developing coarse-grained models with reduced complexity. We have also devised improvements to all-atom simulation models, towards the goal of more accurately simulating protein folding and the mechanism of coupled folding and binding. We work closely with experimental collaborators, either by using theory to help in interpreting experiments or experimental data to refine simulation methodology. We have used coarse-grained models to help interpret single molecule protein folding experiments based on fluorescence resonance energy transfer or atomic force microscopy and all-atom models to interpret NMR dynamics experiments.
Tackling force-field bias in protein folding simulations: folding of Villin HP35 and pin WW domains in explicit water, Biophys. J., 99, L26 (2010)
Balance between α and β structures in ab initio protein folding, J. Phys. Chem. B, 114, 8790 (2010)
Coordinate-dependent diffusion in protein folding. Proc. Natl. Acad. Sci. U. S. A. 107, 1088 (2010)
Dependence of protein folding stability and dynamics on the density and composition of macromolecular crowders, Biophys. J., 98, 315 (2010)
Single molecule spectroscopy of the temperature-induced collapse of unfolded proteins. Proc. Natl. Acad. Sci. U. S. A., 106, 20740 (2009)
Evidence for a partially structured state of the amylin monomer. Biophys. J., 97, 2948 (2009)
Optimized molecular dynamics force fields applied to the helix-coil transition of polypeptides. J. Phys. Chem. B, 113, 9004 (2009)
Thermodynamics and kinetics of protein folding under confinement. Proc. Natl. Acad. Sci. U. S. A. 105, 20233 (2008)
Binding-induced folding of a natively unstructured transcription factor. PLoS Comp. Biol., 4, 1000060 (2008)