Jiang lab focuses on computational structural biology and drug design for Alzheimer's, Parkinson's, Lou Gehrig's disease and other degenerative disorders. Current research is driven by two key questions: How do unfolded or misfolded proteins self-associate into abnormal aggregates? How do these aggregates propagate and lead to disease? Ongoing research is to develop new therapeutic approach for neurodegenerative and other brain diseases, which includes: 1) design allosteric BACE inhibitor that specifically blocks the APP cleavage and Abeta production; 2) design protein inhibitor that blocks the prion-like transmission of protein aggregates in neurodegenerative diseases; 3) design and test new protein that crosses the blood-brain barrier via carrier-mediated transport. The findings of the research will identify new drug targets, develop new therapeutics and design new therapeutic compounds or peptides for the treatment of neurodegenerative disorders. All of these will strengthen our ability of designing biological systems with desired properties, provide an alternative perspective for us to ultimately understand our living world, and promise solutions to some of the most pressing problems in human health.
Protein aggregates (both amyloid oligomers and fibers) have been associated with a diverse group of more than 40 diseases, ranging from Alzheimer's disease, Parkinson’s disease, type II diabetes to prion diseases. The search for amyloid inhibitors is of fundamental importance for both academic and industrial research. I took a structure-based approach on 1) designing novel Amyloid inhibitors that effectively block HIV transmission, by targeting protein aggregates in human semen. 2) discovering new fibril-binding molecule to inhibit Amyloid beta toxicity.
According to Centers for Disease Control and Prevention, at the end of 2006, an estimated 1.1 million persons in the United States were living with diagnosed or undiagnosed HIV/AIDS. While the expensive treatment could control the symptoms and viral load, a preventive method of the virus spread would be a feasible and potentially cheaper way. Recently, research has shown that sexual transmission of HIV is dramatically enhanced with abundant protein aggregates of human semen (termed SEVI; Semen-derived Enhancer of Viral Infection). I have designed from scratch five new peptides that effectively inhibit the SEVI formation. These inhibitors have also been shown to inhibit SEVI’s enhancement of HIV infection in human cells in collaboration with Jan Munch's group at Ulm University Hospital, Germany. UCLA Newsroom reported my research published on Nature and Plos Biology. This work has been expanded into several exciting and ongoing collaborative projects, in which computation design methods were applied in different disease models. The collaborations include: 1) D-peptide inhibitor design for prion fibrillation and conversion with Christina Sigurdson’s lab at UCSD; 2) D-peptide inhibitor design for p53 aggregation; 3) macrocyclic peptide inhibitor design for Amyloid beta aggregation with James Norwick’s lab at UC Irvine.
Alzheimer’s disease is a progressive and fatal brain disorder and is the seventh-leading cause of death in the United States. Right now there is no cure for this disease or treatments to slow down the disease progression. In 2009, the estimated economic value of the health care of Alzheimer’s and other dementias was $144 billion, and total health care payments for 2010 are expected to be $172 billion. Amyloid beta (Aβ), a peptide of 39-42 amino acids processed from the Amyloid precursor protein (APP), is the major protein component of amyloid deposits in Alzheimer's disease patients. I applied computational docking tools to high-throughput screening of small molecules from large compound databases. By docking ~18 thousand small molecules from Cambridge Structure Database (CSD) and ZINC database, 29 compounds were selected for experimental characterization and validation. Six candidate molecules not only specifically bind to the Aβ aggregates but also reduce the Aβ toxicity in Mammalian cells. The derivatives/homologs of active compounds were included to expand the set and refine amyloid pharmacophore. The inhibitors from the second round achieved further improvement in inhibition. The success of our inhibitors not only validated the accuracy of our amyloid pharmacophore but also demonstrated our powerful approach for structure-based inhibitor discovery, which could guide further drug development and improvement. See the commentary by eLife Insight featuring our work.
Most of current structural studies of protein aggregation miss the connection between atomic structures of fiber-forming peptide segments and full-length structure of amyloid proteins. I combined various computational methods to construct physical models of protein aggregates associated with human diseases, by de novo building of amyloid fibril models from atomic structure of fibrillar peptide segments. Furthermore, I utilized structural modeling and molecular dynamics simulation to explore structural dynamics and conversion between different amyloid states along aggregation pathway. Together with structural determination and toxicity assay from my colleagues, we proposed a distinct amyloid aggregation pathway mediated by out-of-register β-sheets, progressing from monomer to oligomer, to out-of-register fiber. This work culminated a recent publication in PNAS.
Enzymes catalyze millions of chemical reactions with high efficiency and specificity under mild conditions. De novo creation of novel enzymes is a grand challenge to scientific community and industry.
As a graduate student in Baker Liboratory in University of Washington, seattle, I am the first lab member working on developing a general protocol for novel enzyme design that can generate new enzymes with desired catalytic activity in any given chemical reaction system. Using this method, I designed two families of enzymes with two different novel catalytic activities, neither of which is catalyzed by natural occurring enzymes.
First, I designed Kemp-elimination catalysts, catalyzing the single step reaction of proton transfer from carbon, with measured rate enhancements over background of up to 10,000 with multiple turnovers. Application of in vitro evolution methodologies (Tawfik laboratory, Weizmann Institute of Science), to enhance the computational design produced a >200 fold increase in kcat/KM.
Many common chemical reactions consist of multiple transitions and can not be efficiently catalyzed by natural occurring enzymes. One example is the retro-aldol reaction, the breaking of a carbon-carbon bond, which the nature did not create an enzyme for. However, this reaction could be extremely useful, applicable in industries that involve breaking long-chain organic compounds into shorter compounds. I tested our methodology by designing novel retro-aldolases in a non-natural substrate, on different protein scaffolds. My designs achieved rate enhancements over background of up to 10,000 with multiple turnovers. Mutational analysis also confirmed that catalysis depends on the computationally designed active sites, and their high-resolution crystal structures suggest that the designs have close to atomic accuracy. Further optimization through site-directed mutagenesis and laboratory evolution (Hilvert Liboractory,ETH Zurich) can afford additional increases (up to 1,000 fold, in some cases) in activity.
These proof-of-principle studies open a new possibility for designing enzymes with catalytic activities we desire. These research works have resulted in one US/International patent and five journal papers including Science and Nature.
Modelling with discrete water molecules is another great challenge in protein computation due to their crucial roles at protein-protein interfaces and protein environment, and their abundant existence. I developed a “solvated rotamer” approach to efficiently predict the positions of water molecules at protein surfaces and interfaces. This computational approach aimed for modeling the often critical contributions of specifically bound water molecules in protein design algorithms, which were too computationally expensive to simulate in previous methods. In addition, this approach has applications beyond protein computation. It should also be useful for modeling protein-nucleic acid interactions, which often involve highly solvated interfaces. See the cover story highlighting my work in the Proteins-Structure, Function and Bioinformatics (Volume 58, Issue 4, March 2005).
Carbon hydrogen (CH) and oxygen (O) atoms are essential components of any protein. CH can form weak hydrogen bonds with oxygen, named as CH•••O hydrogen bond. One hydrogen bond per se is quite weak, but it exists in protein-protein interfaces in a massive quantity, indicating its potential critical role at protein interfaces, especially in hydrophobic interactions. A reliable method to quantify the significance of this type of bond at protein interfaces is essential for making accurate protein modelling and design.
In my B.S. and M.S. research in Lai Labortatory in Peking University, Beijing, I developed a statistical potential to quantitatively describe the CH•••O hydrogen bonding interaction at the protein-protein interface. This method successfully calculated the contribution of different types of hydrogen bonds in different environments and protein complexes, which showed that the contribution of the CH•••O H-bond could reach as high as ∼40–50% in some protein-protein complexes. And it is the first time that the importance of CH•••O hydrogen bond was quantified, making it clear that the contribution of this bond has to be considered and reasonably estimated to yield accurate computation results. Our research provided a simple, efficient and flexible tool that computational biologists can apply in the protein interaction computation in the vast majority of protein systems.
I am currently looking for highly motivated graduate students to join my lab. If you are interested in joining the Jiang lab for graduate studies, please feel free to contact me (see contact page).
You can find information about graduate studies in Biochemistry, Biophysics, and Structural Biology (BBSB) Home Areai within the Graduate Programs in Bioscience and the Molecular Biology Interdepartmental Ph.D. Program at UCLA.
* authors contributed equally to this work
I am always looking for highly motivated postdocs and graduate students to join my lab.
Please visit "Join the Lab" for more details.