- Structure-dynamics-function of biomolecules: One of my research interests is to understand structure-dynamics-function relationship of biomolecules, especially the membrane proteins with great physiological and biomedical significance. During my postdoctoral and graduate research, I have studied the molecular mechanism of inactivation in K+ channels and state transition of membrane transporters. My study led to several discoveries that have significantly advanced our understanding of C-type inactivation of K+ channels and alternating-access mechanism of membrane transporters.
Molecular mechanism of inactivation in K+ channels:
Molecular mechanism of water leak through membrane transporter:
- Enhanced sampling of molecular dynamics simulation to characterize state transition of biomolecules. Structural switching between major functional states of biomolecules usually involves large-scale conformational changes, and most of them are still far beyond the timescale of brute-force molecular dynamics simulation. I am interested in developing new enhanced sampling methods to overcome this technical barrier. Team-working with my previous colleagues, we have already developed a special-protocol time-dependent biased simulation combined with free energy calculation to explore the transition pathway. It has shown the feasibility to address this question in transporters and channels. I am also planning to use deep learning algorithm to generate reaction coordinates for free energy calculation based on available structural and simulation data.
- Protein sequence coevolution analysis. The evolutionary amino-acid correlations based on multiple sequence alignment can identify coevolving protein “sectors” working as group (or cluster) for a particular functional role, or extract pairs of directly coupled residues. I would like to use this coevolutionary information to extract residue contacts critical for the function of the whole protein family.
- Biological mechanism of diseases due to missense mutations. To open a virtual and efficient route to illuminate the biological mechanisms of diseases in the era of big data, we will develop a computational tool with multiple modules to collect sequence variants for protein of interest from diverse human disorder-related genomic databases, integrate sequence and structure analysis, and guide/generate MD simulation and free energy calculation to assess the structural role of the disorder-related missense mutations.
mapping missense mutations from human disorder-related genomic databases to 3D protein structures:
