U.S. Department of Health and Human Services
Robert Tycko
 

 Contact Info

 
Tel: 301-402-8272
Email: robertty@mail.nih.gov
 

 Select Experience

 
  • Senior InvestigatorLCP, NIDDK, NIH1994-present
  • Member of Technical Staff (Principal Investigator)Physical Chemistry Research Department, AT&T Bell Laboratories1986-1994
  • Postdoctoral ResearcherUniversity of Pennsylvania1984-1986
  • Ph.D.University of California at Berkeley1984
  • A.B.Princeton University1980
 

 Related Links

 

    Specialties
    • Biomedical Engineering/Biophysics/Physics

    Research Summary

    Research Goal

    The purpose of this research is to expand the capabilities of experimental techniques for probing structural properties of molecules with central roles in biology and human disease.  We also seek to provide concrete structural information about proteins involved in Alzheimer's disease, diabetes, and AIDS.

    Current Research

    We are pursuing the development of solid-state nuclear magnetic resonance (NMR) methods for structural studies of biopolymers and the application of these methods to problems in biophysical chemistry and structural biology.  Solid-state NMR methods provide structural information at atomic-level detail in systems that cannot be characterized by other structural methods, including x-ray diffraction and liquid-state NMR.  Examples of such systems include proteins that associate with biological membranes, amyloid fibrils and other noncrystalline aggregates, and frozen solutions of large biomolecular assemblies.  Our work is often exploratory and interdisciplinary, drawing heavily on experimental and theoretical techniques of the physical as well as biological sciences.  We combine solid-state NMR measurements with electron microscopy, atomic force microscopy, and other complementary techniques.

    Development of general solid-state NMR methods for structural characterization of peptides and proteins

    Techniques developed in our group have been applied successfully in studies of HIV-related peptide/antibody complexes, amyloid fibrils associated with Alzheimer's disease, and other systems.  Of particular interest recently are techniques for measuring interatomic distances and dihedral angles in uniformly 15N,13C-labeled proteins.  We are also interested in techniques for sensitivity enhancement in solid-state NMR, including indirect detection methods, hyperpolarization methods, and low-temperature solid-state NMR technology.

    Structural studies of amyloid fibrils

    Amyloid fibrils are of great interest in both the biomedical and the biophysical research communities, because of their association with diseases such as Alzheimer's disease and type 2 diabetes, and because amyloid fibrils are a common structural state of proteins and peptides that has been poorly understood.  We have shown that solid-state NMR methods are uniquely capable of providing molecular-level structural constraints on amyloid fibrils, which are inherently noncrystalline and insoluble.  We developed the first detailed, experimentally based molecular structural models for fibrils formed by the beta-amyloid peptide associated with Alzheimer's disease and by the amylin (or IAPP) peptide associated with type 2 diabetes.  Current work is directed at structural characterization of amyloid fibrils that form in vivo in human tissue.

    Solid-state NMR investigations of protein folding

    Although the highly ordered, folded structures of thousands of proteins have been determined to be high resolution by x-ray crystallography and liquid-state NMR methods, relatively little is known about the structures and structural distributions of proteins in their unfolded states.  The structural properties of unfolded and partially folded proteins are important as determinants of folding kinetics and thermodynamics, and as factors that affect protein aggregation in amyloid diseases.  We are exploring the use of solid-state NMR in conjunction with submillisecond freeze-quenching as an approach to quantitative characterization of unfolded and partially folded proteins.  Recent results show that we can determine site-specific conformational distributions in unfolded proteins and identify unanticipated kinetic intermediates in a rapid protein-folding process.

    Solid-state NMR studies of AIDS-related proteins

    Recent work includes characterization of transmembrane oligomers formed by the HIV-1 Vpu protein, structural studies of HIV-1 Rev protein assemblies, and determination of bound peptide conformations in AIDS-related peptide/antibody complexes.  We are currently exploring the application of solid-state NMR in studies of HIV-1 capsid protein assembly, with the goals of identifying the intermolecular interactions that stabilize capsids and elucidating the mechanism of capsid formation.

    Ultra-low-temperature dynamic nuclear polarization

    Applications of solid-state NMR to biological problems are frequently limited by low signal-to-noise ratios.  To improve sensitivity, we have developed a new technology for ultra-low-temperature (<30 K) biomolecular solid-state NMR.  We are now combining this technology with dynamic nuclear polarization (DNP), a phenomenon in which high-frequency microwave irradiation of paramagnetically doped samples leads to large enhancements of nuclear spin polarizations, and hence, NMR signals.  Recent results show that sensitivity enhancements greater than 400X can be achieved with compact and relatively inexpensive microwave sources.  Applications of DNP-enhanced, ultra-low-temperature, solid-state NMR in studies of amyloid precursors, protein-folding intermediates, and membrane proteins are planned for the near future.​

    Applying our Research

    Detailed structural information at the molecular level is essential for the development of a correct understanding of interactions between biological macromolecules that are required for human health or that lead to human disease.  Such information can guide the development of new drugs and new approaches to diagnosis, prevention, and treatment.

    Need for Further Study

    In the case of amyloid diseases such as Alzheimer's disease and type 2 diabetes, we need to identify and characterize the precise structural entities that develop in human tissue and investigate connections between structural variations and variations in disease development.