Welcome to Jiang Laboratory!

Target protein aggregation in neurodegenerative disease

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.


Current Research

Amyloid Inhibitor Design

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.

SEVI Inhibitor Design 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.

Amyloid Pharmacophore 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.


Past Research Highlights

Computational modeling of protein aggregates

Model of Aggregation Pathway 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.

De Novo Enzyme Design

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.

Computational Enzyme design 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.

Designed Aldol design 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.

"Solvated Rotamer" Approach to study protein-water interaction

Solvated Rotamer Movie 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).

CH...O Hydrogen Bonds at protein interfaces

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.

CH...O Hydrogen Bonds 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.


Principal Investigator (PI)

Lin Jiang Ph.D,     NRB 475B,   301-206-0908,   linjiang at mednet dot ucla dot edu

Biography

Jiang Photo Jiang started his journey in science when he went to Peking University, where he earned a B.S. degree in Chemistry and a M.S. degree in Physical Chemistry with Distinction. He did research in protein interactions with Luhua Lai at Peking University and found his passions toward structure-based protein modeling and drug design research. He then went to the University of Washington for Ph.D in Biochemical Science. There he worked on enzyme design in the laboratory of David Baker, using computational and experimental methods to engineer protein catalysts for those chemical transformations that naturally occurring enzymes cannot catalyze. After completing his Ph.D work, he pursued postdoctoral training with David Eisenberg at UCLA, applying his computational methods to develop new therapeutics for protein aggregation diseases. He joined the UCLA faculty in 2015 and is currently an Assistant Professor in Residence of Neurology. He has published 19 original research articles in peer-reviewed journals with over two thousand citations. Four articles published have been selected for Faculty of 1000 Biology; seven articles have been selected for editorial commentary or cover story in the corresponding issue of the particular journal. His research work has led to three US/international patents and one pending patent, which had been commercialized in multiple biotechnology companies. His research accomplishments have been recognized with invitations to present at international conferences, including Gordon Research Conference, FASEB Science Research Conference and Biophysical Society Annual Meeting.

Curriculum Vitae pdf


Joining Jiang Lab

Potential Post-Docs

I am actively seeking to fill collaborative post-doctoral associate positions focused on structure of protein aggregation and drug design of neurodegenerative disorders. I am always interested in potential post-doctoral candidates, and if your research interests align well with mine, I would be happy to discuss possibilities for post-doctoral positions. If you are interested in post-doctoral studies in my lab, please email me (see contact page), attach a CV, and give me a brief sketch of your research interests.

Potential Graduate Students

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.


Contact Info

Neuroscience Reserach Building

PI Office:
    Lin Jiang
    Department of Neurology
    Molecular Biology Institute, Brain Research Institute
    Neuroscience Research Building, Room 475B
    Phone: 310-206-0908
    Email: linjiang at mednet.ucla.edu
Laboratory Location:
    Neuroscience Research Building, Room 455
    635 Charles E Young Drive South
    Los Angeles, CA 90095
Directions:
    The Neuroscience Research Building (NRB) is accessed from a driveway that runs from Charles Young Drive South to the North. Once in front of the building, enter and walk diagonally toward the back right wall of the building, past the lecture hall. Take the elevator to the 4th floor. Turn right into the hallway and use the phone at the end of it to call to let you in (the extension is 60908).
Map Resources:
    NRB Google Map
    UCLA Campus Map


Publications

Full Publications in Google Scholar   PubMed-NCBI

Selected Articles:

  1. L. Jiang*, C. Liu*, D. Leibly, M.R. Sawaya, M. Zhao, M. Landau, M.P. Hughes, D. Eisenberg (2013) "Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta" eLife. Jul. 16, 2:e00857
    1. eLife commented my research work “Lifting the veil on amyloid drug design”
    2. ELife featured my research work as “Editors’ choice of the week”
    3. UCLA Newsroom reported my research work of amyloid inhibitor design

  2. C. Liu*, M. Zhao*, L. Jiang*, J. Park, P. Cheng, M.R. Sawaya, D. Guo, A. Berk, J.S. Nowick, D. Eisenberg (2012) "Out-of-register beta-sheets suggest a pathway to toxic amyloid aggregates" PNAS. Dec. 18; 109(51):20913-8 [Co-first author]

  3. S.A. Sievers*, J Karanicolas*, H.W. Chang*, A. Zhao*, L. Jiang*, O. Zirafi, J.T. Stevens, J. Munch, D. Baker, D. Eisenberg. (2011) Structure-based design of non-natural amino acid inhibitors of amyloid fibrillation. Nature. Jun 15;475(7354):96-100. [Co-first author]
    1. Nature Methods commented my research work as “Research Highlights”
    2. UCLA Newsroom
    3. Faculty of 1000 score: 8

  4. L. Jiang*, E.A. Althoff*, F.R. Clemente, L. Doyle, D. Rothlisberger*,A. Zanghellini, J.L. Gallaher, J.L. Betker, F. Tanaka, C.F. Barbas III, D. Hilvert, K.N. Houk, B. Stoddard and D. Baker. (2008) De novo computational design of retro-aldol enzymes. Science. Mar 7; 319(5868): 1387-1391.
    1. BBC podcast live programme (“The Naked Scientists” by Dr. Chris Smith) reported the research work of "Artificial Enzymes" on March 9th, 2008. [Download Audio File]
    2. Featured by Nature in “Rearch Highlights in Biochemistry: Catalytic creator”, "A celebration of 2008", Nature, Dec. 2008
    3. “Cutting edge chemistry in 2008”, by Chemistry World, selected as the best papers published in chemistry in 2008
    4. News Reports and Highlights by scientific magazine:
      1. Chemistry World
        Chemical & Engineering
        Technology Review
    5. Faculty of 1000 score: 10

  5. D. Rothlisberger*, O. Khersonsky*, A.M. Wollacott*, L. Jiang, J. DeChancie, J. Betker, J.L. Gallaher, E.A. Althoff, A. Zanghellini, O. Dym, S. Albeck, K.N. Houk, D.S. Tawfik, D. Baker. (2008) Novel Kemp elimination catalysts by computational enzyme design. Nature. May 8; 453 (7192): 190-195.
    1. Featured by Nature in “The year in Nature: Artificial Enzymes”, "A celebration of 2008", Nature, Dec. 2008
    2. Faculty of 1000 score: 22

  6. L. Jiang, B. Kuhlman, T. Kortemme, D. Baker. (2005) A "solvated rotamer" approach to modeling water-mediated hydrogen bonds at protein-protein interfaces. Proteins. Mar 1; 58(4): 893-904.
    1. Featured cover story
    2. Faculty of 1000 score: 6

  7. L. Jiang and L. Lai. (2002) CH...O hydrogen bonds at protein-protein interfaces. J. Biol. Chem. Oct 4; 277(40): 37732-40.
    1. Google Scholar Citations: 110+

    * authors contributed equally to this work

Patents:

  1. "PHARMACOPHORES FOR AMYLOID FIBERS INVOLVED IN ALZHEIMER'S DISEASE", US Patent App. No. 61/507, 810; International App. No. PCT/US2012/046945, Filing on Jul. 2011; Pub. No. WO/2013/010176, Jan 2013.
  2. “Synthetic enzymes derived from computational design” US Patent App. No. 12/334,360, 2008; Pub. No. 2009/0191607, Jun 2009; Pub. No. US8340951 B2, Publication Date. Dec 25, 2012. [Download pdf]
  3. “SYNTHETIC ENZYMES DERIVED FROM COMPUTATIONAL DESIGN” International App. No. PCT/US2008/086715, December 2008; Pub. No. WO/2009/076655, Jun 2009.
    1. Commercialized in the biocatalysis company Arzeda Corp., Seattle, WA

Book Chapter:

  1. L. Jiang, K. Fan and J. Liang. “Mysteries of the Nanotechnique” Peking University Press, Beijing, ISBN 7-301-050860-0/H.0640, July 2001. [Download pdf]


[What's New]

I am always looking for highly motivated postdocs and graduate students to join my lab.
Please visit "Join the Lab" for more details.


Historical Notes

2013, eLife Insight commented my amyloid inhibitor research, and UCLA Newsroom also featured this work

2011, my Google Scholar Citations reached the first One Thousand.

As for 2011, four of my publications were selected by Faculty of 1000.

2011, UCLA Newsroom reported my research published on Nature and Plos Biology.

2011, Nature Methods commented my research work as “Research Highlights”.

2008, BBC podcast live programme reported my work on March 9th.

In 2008 and 2009, Nature, Nat. Chem. Biol., Angew. Chem. Int. Ed. and Chemistry & Biology commented my emzyme design work in Science and Nature paper.

In 2008, Chemistry World, Chemical & Engineering, Technology Review highlighted my emzyme design work in Science paper.

Dec. 2008, Nature selected my Science paper as "Research Highlights in Biochemistry" in "A celebration of 2008".

Dec. 2008, Nature selected my Nature paper as "The year of Nature" in "A celebration of 2008".

Dec. 2008, Chemistry World selected my Science paper as “Cutting edge chemistry in 2008”.

2008, my enzyme design work in Baker lab was recognized as "Top breakthroughs in computational science" by Department of Energy, along with my colleagues.

2005, Proteins featured my work as the cover story.