Research Interests:

Understanding molecular mechanisms underlying biological processes is one of the major goals in modern biophysics and molecular biology. As biology gets more quantitative, this goal is becoming more accessible. However, major roadblocks still exist on the way. Among those is the difficulty that one often encounters in characterizing complex dynamics of biological processes: the existence of multiple kinetic paths and transient intermediate states makes these processes difficult to dissect by ensemble methods. To tackle this problem, my research group is developing physical techniques to monitor the behavior of individual biological molecules and particles and thus to elucidate complex dynamics beyond the limit of ensemble methods. Currently we are exploiting these techniques in the following areas.

1. Fundamental understanding of viral infection.
We are developing state-of-the-art instrumentation to image the behavior of individual viral proteins, viral RNAs and viruses in cells and to elucidate molecular mechanisms and cellular pathways of viral infection. Three specific areas are being studied. 1) We are tracking the behavior of individual viruses to elucidate individual steps of the endocytic pathway. 2) We are investigating the conformational dynamics of viral fusion protein at the single-molecule level to illuminate the mechanism by which fusion proteins catalyze viral membrane fusion. 3) We are tracking the behavior of single viral genes to explore the molecular mechanisms underlying the nuclear traffic of viral genes.

These experiments allow us to visualize directly the infection process in real time, dissect individual stages of the viral entry pathway, and obtain a better understanding of the molecular mechanisms governing the influenza infection.

2. Structural dynamics and function RNA and ribonucleoprotein (RNP) enzymes.
We are studying the folding and assembly dynamics of these enzymes at the single-molecule level using fluorescence spectroscopy and exploring the correlation between their structural dynamics and function. Three specific areas are being studied. 1) We are investigating small RNA enzymes to uncover basic molecular mechanisms of RNA structural formation. 2) We are investigating large multi-domain RNA enzymes to explore the capabilities and limitations of RNA as functional enzymes. 3) We are investigating RNP enzymes to elucidate the effect of proteins on the structural dynamics and functional capabilities of RNA.

These single-molecule experiments can detect non-accumulative intermediate states that are extremely difficult if not impossible to detect by ensemble methods and thus can greatly improve our ability to characterize complex RNA structural dynamics. These experiments will provide new and critical knowledge about RNA-RNA and RNA-protein interactions, and thus uncover the physical and chemical principles that determine the structure and behavior of RNA and RNP.

3. Nano-electronic devices for sensing bio-molecules and bio-pathogens at the single-unit level.
Despite the tremendous potential that single-molecule approaches have in exploring complex biological systems, current single-molecule techniques all have limitations and new single-molecule detection technology is in great demand. We are developing nano-electronic FRET devices for sensing biological molecules and biological pathogens at the single-unit level in collaboration with Prof. Lieber’s group. These ultra-sensitive semiconductor nanowires based sensors will strongly enhance our ability to detect and characterize a large variety of microscopic biological entities at the single-unit level, opening a new realm of single-molecule biophysics and biological sensing technology.

Selected Publications:

M. Lakadamyali, M. J. Rust, H P. Babcock, X. Zhuang, “Visualizing infection of individual influenza viruses,” Proc. Natl. Acad. Sci. USA 100, 9280-9285 (2003).

G. Bokinsky, D. Rueda, V. K. Misra, A. Gordus, M. M. Rhodes, H. P. Babcock, N. G. Walter, X. Zhuang. “Single-molecule transition-state of RNA folding,” Proc. Natl. Acad. Sci. USA 100, 9302-9307 (2003).

X. Zhuang and M. Rief, “Single-molecule folding,” Curr. Opin. Struct. Biol. 13, 88 (2003).

X. Zhuang, H. Kim, M. Pereira, H. Babcock, N. Walter, S. Chu, "Correlating Structural Dynamics and Function in Single Ribozyme Molecules," Science 296, 1473 (2002).

R. Russell, X. Zhuang, H. Babcock, I. S. Millett, S. Doniach, S. Chu, D. Herschlag, “Exploring the Folding Landscape of a Structured RNA,” Proc. Natl. Acad. Sci. USA, 99, 155 (2002).

X. Zhuang, L. Bartley, H. Babcock, R. Russell, T. Ha, D. Herschlag, S. Chu, "A Single-Molecule Study of RNA Catalysis and Folding," Science 288, 2048 (2000).