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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 from the Medical School, University of Pennsylvania in 1994. He did his Ph.D. work in Walter Englander's lab, where he developed the native-state hydrogen exchange method to detect partially unfolded states of proteins under native conditions. He completed his postdoctoral training in Peter Wright's lab at the Scripps Research Institute, where he studied protein folding using multi-dimensional NMR methods. In 1997, he joined the Laboratory of Biochemistry of NCI as a tenure-track investigator.

Research

I am interested in understanding the principle that governs the dynamic process of protein folding. We use several experimental tools to characterize the pathways of protein folding, including multi-dimensional NMR, mass spectrometry, hydrogen exchange, stop-flow fluorescence and circular dichroism, site-directed mutagenesis, and phage-display. More recently, we have expanded our study to include chromatin folding.

(1) 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 established the thermodynamic principle of protein folding, which states that the native state of a protein has the lowest free energy under physiological conditions. But the principle that governs the dynamic process of protein folding remains unclear.

Our approach for determining the dynamic process of protein folding involves three steps: (1) identify partially unfolded intermediates by the native-state hydrogen exchange method; (2) populate the partially unfolded intermediates by a native-state hydrogen exchange-guided protein engineering method; (3) determine the high-resolution structures of the populated folding intermediates by multi-dimensional NMR methods. We have investigated the folding behavior of a number of small proteins, including cytochrome c, Rd-apocytochrome b562, barnase, PDZ domain, FAT domain, T4 lysozyme, and ribonuclease H. For Rd-apocytochrome b562, T4 lysozyme, and ribonuclease H, we have determined the structures of the folding intermediates. Our experimental results strongly suggest that the principle that governs the dynamic process of protein folding is the stepwise folding of cooperative structure units (foldons).

We have also provided the theoretical argument on why proteins should fold in a stepwise manner and why the popular funnel-like energy landscape view is inadequate to describe the dynamic process of protein folding. In brief, desolvation process during folding leads to no energy bias in local steps that would favor the formation of native interactions and proteins have to do random move to search the conformational space. Therefore, they can only fold by accidentally finding a series of partially unfolded intermediates and the native state.

(2) Chromatin Folding
DNAs in eukaryotic cells are super long molecules. They need to fold to more compact forms in order to fit in the cell nucleus. The folding/packing of DNA is helped by histone proteins. Histones and DNA first form nucleosomes, the structural unit of chromatin. Each nucleosome contains eight histones (H2A-H2B-H3-H4)2 and 146 base pair DNA. The formation of nucleosomes and higher-order structures of chromatin follows a hierarchical process and is highly regulated in cells. The dynamic process of the folding and unfolding of nucleosomes and chromatins is essential for the function of cells and forms the physical basis of epigenetics. A number of proteins have been known to regulate such processes, including histone chaperones, linker histones (H1, H5), high mobility groups (HMGNs), and nucleosome remodelers, in addition to the well-known posttranslational modifications of histone tails.

We are interested in using biophysical tools, in particular, modern NMR methods to investigate: (1) interactions between histones and their chaperones; (2) interactions between nucleosomes and nucleosome-binding proteins; (3) the conformations of histone tails in different states of chromatins. Current projects include (a) the interactions between histones H2A.Z-H2B and its chaperone Chz1, (b) the interactions between histones Cse4-H4 and Scm3, (c) Methyl-TROSY NMR studies of the nucleosme and its interactions with H1 and HMGN2, and (d) conformations of histone tails at different sates of nucleosome arrays by NMR and hydrogen exchange.

In addition to the folding studies, we also collaborate with other investigators at NCI with the goal to develop cancer drugs.

Our current collaborators include: Carl Wu, Michael Bustin, and Ettore Appella at NCI. Lewis Kay at University of Toronto and Nico Tjandra at NHLBI.

This page was last updated on 11/11/2009.