Lei Shi

Computational Structural Biology of Membrane Proteins

Research Summary:

Computational Structural Biology of Membrane Proteins

Cell membrane separates the cellular machinery from external fluids. Membrane proteins (MP) initiate intracellular signaling pathways, control the flow of energy and materials in and out of the cell, and thereby account for more than 30% of proteome and 40% of drug targets. Research interests in the lab are focused on identifying common and specific structural basis of MP functions to advance the mechanistic understanding of key cellular processes, from the disparate yet intertwined perspectives of Structure-Dynamic-Function Relationships and Molecular Recognition.

The dynamics of a protein molecule, which is characterized by traversing multiple conformational states, ultimately defines its functional mechanism. Crystal structures represent conformational states of proteins that are crystallizable and remain scarce for MP. Using a combined approach of computational and experimental analysis, we are interested in elucidating the atomistic details of allosteric conformational transitions and propagations during signal transduction and transport processes. In particular, we investigate the critical structural and dynamic elements that determine individual and combined ligand binding specificities, the interactions among MP and their coupled proteins, and the associations of MP with the lipid bilayer. The findings allow us to rationally optimize existing and develop new compounds that shift the conformational equilibrium of MP, which will facilitate functional studies and lead to novel drug discovery.

The methodology applied by the lab comprises computational molecular biophysics and bioinformatics. The current emphasis is utilizing and improving the biasing techniques of molecular dynamics (MD) simulations, which are efficient in steering the trajectories from initial to final state, to address the biological questions that are beyond the timescale accessible to conventional MD simulations. In addition to close collaborations with wet labs required by the iterative in silico and in vitro studies, we develop informatics tools and databases for collecting, organizing, and mining MP structural information from the literature and high-throughput data.