Understanding structure-function relationships in complex biochemical systems at the single molecule scale.
There are critical links between structure and function across many biochemical systems. Complex assemblies of molecules are transiently bound to and regulated by specific factors. Our laboratory is interested in identifying the rules that govern these interactions, and how they might be influenced by small molecule-based therapies. Our work aims to reveal the molecular basis of function and regulation to help inform improved disease therapies.
To support life, biological molecules must rapidly transact with diverse cellular components and efficiently navigate functionally distinct native state conformations to carry out their physiological functions. Our team therefore seeks to develop methodological approaches to gain direct, quantitative insights into the timing and role of these compositional and conformational changes and how these events govern function and regulation.
We explore structure-function relationships in biomolecules using genetic, biochemical, spectroscopic and structural techniques, where the focus is to develop a quantitative framework to explain function. A central endeavor is to bridge the gap between different static structures of biomolecules obtained through X-ray crystallography and cryo-electron microscopy and the dynamic transactions of individual biomolecules. Research projects in our laboratory delve into the mechanisms of protein synthesis, signaling and transport across cellular membranes, and virus–host cell engagement at both the ensemble and single-molecule scales. Such efforts include collaborative studies on the mechanisms of fidelity during protein synthesis from messenger RNA; how directional transport of small-molecule ligands across membranes is achieved; conformational transitions in HIV-1 Env and SARS-CoV-2 spike and how they relate to engagement with host cells and recognition by antibodies; and physiological regulation of the conformational dynamics and oligomerization of G protein–coupled receptors (GPCRs).
Different conformational states of the bacterial ribosomal complex during translocation. Animation By: Zhaowen Luo
Within each of these areas, our group strives to advance technological developments towards quantitative, physical descriptions of biomolecular function. Key to our progress have been advances in microscope instrumentation and in the development of self-healing organic fluorophores, which have enabled increased spatial and temporal resolution as well as noise reduction in our measurements. Computational and engineering initiatives have also played a pivotal role in leading our studies towards automated experimental pipelines, data analysis options and drug discovery initiatives.