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Yawen Bai, Ph.D.

Laboratory of Biochemistry and Molecular Biology Head, Protein Folding Section Senior Investigator Building 37, Room 6114E National Cancer Institute 37 Convent Drive, MSC 4255 Bethesda, MD 20892-4255 Phone:   301-594-2375 Fax:   301-402-3095 E-Mail:   yawen@helix.nih.gov

Biography

Dr. Yawen Bai received his Ph.D. in biophysics (advisor: S. Walter Englander) from the medical school, University of Pennsylvania in 1994 and completed postdoctoral training (advisor: Peter E. Wright) at the Scripps Research Institute. He was offered a tenure-track fellowship in the Laboratory of Biochemistry of NCI in September 1997.

Research

Our research has focused on the studies of kinetic principle of protein folding using multiple experimental tools (multi-dimesional NMR, mass spectrometry, hydrogen exchange, stopped-flow fluorescence and circular dichroism, site-directed mutagenesis, and phage-display). Recently, we have initiated the studies on the dynamic behavior of nucleosomes. We have also collaborated with other investigators at NCI to develop small molecule drugs for cancer.

I. The Kinetic Principle of Protein Folding
Protein folding is the final step in the transfer of genetic information from DNA to proteins. In the 1960s, Anfinsen and coworkers at NIH demonstrated that protein molecules could fold spontaneously from the unfolded state to the native state. They hypothesized that the native structure is the most stable state, which has become the basis for predicting protein structures from their amino acid sequences (Anfinsen was awarded the Nobel Prize in 1972 for the discovry of this thermodynamic principle of protein folding). But the physical principle for the kinetic folding process of proteins remains unsolved. In recent years, it has been found that more than twenty human diseases, termed amyloid diseases, are related to protein misfolding and precipitation in cells, including Alzheimer's, type II diabetes, and Creutzfeldt-Jakob diseases (CJD). In several cases, it was shown that partially unfolded intermediates are the major precursors for the formation of amyloid and could be the direct cause for the death of cells. For example, the partially unfolded form of human alpha-lactalbumin can kill cancer cells and has been used in the treatment of skin papillomas in a clinical trial. In addition, about half of human cancer is associated with mutations in a tumor suppressor protein: p53. Many of the mutations cause cancer because they unfold the native structure. Therefore, it is important to understand the kinetic folding/misfolding mechanism of proteins.

In the last several years, our group has studied the folding behavior of small single domain proteins, including cyt c, Rd-apocyt b562, barnase, PDZ domain, and FAT domain. We found that these proteins fold through partially unfolded intermediates that exist after the rate-limiting step. We called them 'hidden intermediates' since they can not be detected in conventional kinetic experiments. Further, we have developed a native-state hydrogen exchange-directed protein engineering method for populating the intermediates and determined the first high-resolution structures of the intermediates by multi-dimensional NMR methods. Recently, we have extended our studies to include multi-domain proteins such as T4 lysozyme and a redesigned protein by coupling protein A B-domain with Rd-apocyt b562. The results obtained from these studies provide strong support for the hypothesis that the kinetic principle of protein folding is the step-wise folding of cooperative structure units (foldons) (see pictures in the Gallery). We also provided theoretical arguments on why proteins should fold in a step-wise manner and why the current funnel-like energy landscape view is inadequate to describe the folding behavior of proteins, i.e., desolvation during folding leads to energy barrier on the energy landscape, random search, and coopertive formation of partially unfolded intermediates.

II. Nucleosome Dynamics
Nucleosome is the structural unit of DNA organization in eukaryotic cells. A canonical nucleosome consists of four small histones (H2A, H2B, H3, and H4) wrapping around a 146 base pair DNA. The X-ray structure of nucleosome has been determined (Luger et al., Nature, 1997). But its dynamic behavior, which is intimately involved in gene expression and regulation, has not been fully characterized. In addition, there are many variants of H2A and H3 whose biological functions are not understood. Moreover, histone chaperons are involved in the nucleosome assembly/disassembly. Their functions need to be elucidated.

We are interested in applying the biophysical tools, in particular NMR, to investigate the above issues. Currently, we are developing a method that would allow us to measure the hydrogen exchange rates of amide protons in the nucleosome, which would provide us with the thermodynamic and kinetic information on the disassembly/assembly of nucleosomes. At the same time, we are studying the physical properties and solving the structure of a recently discovered histone-chaperone complex in collaboration with Dr. Carl Wu's group by multi-dimensional NMR.

This page was last updated on 6/11/2008.