The National Institute of Diabetes & Digestive & Kidney Diseases

Dr. Tycko received his A.B. from Princeton University in 1980, and his Ph.D. in chemistry from the University of California at Berkeley in 1984. His thesis work focused on new theoretical methods for analyzing excitation sequences in nuclear magnetic resonance (NMR) spectroscopy. After postdoctoral research in biological NMR at the University of Pennsylvania from 1984 to 1986, he joined the Physical Chemistry Research Department of AT&T Bell Laboratories in Murray Hill, New Jersey. At Bell Labs, Dr. Tycko carried out NMR studies of novel materials such as fullerenes and superconducting alkali fullerides. Using optically pumped NMR, he carried out the first experimental studies of skyrmions in semiconductor quantum wells. In 1994, Dr. Tycko moved to the Laboratory of Chemical Physics, a physical chemistry and biophysics research department in NIDDK. At the NIH, he has made numerous contributions to solid state NMR methodology for structural studies of proteins and other complex molecular systems. A major project in recent years has been the elucidation of the molecular structures of protein fibrils that are associated with amyloid diseases, especially Alzheimer's disease. Other ongoing projects include structural studies of HIV-1 proteins and fundamental studies of protein folding using solid state NMR methods.

Dr. Tycko received the American Physical Society's Earle K. Plyler Prize for Molecular Spectroscopy in 2005, the Chemical Society of Washington’s Hillebrand Prize in 2007, and an NIH Director’s Award in 2001.  He is a Fellow of the American Physical Society, the American Association for the Advancement of Science, and the International Society of Magnetic Resonance. Dr. Tycko has served on the editorial boards of the Journal of Chemical Physics, the Journal of Magnetic Resonance, the Journal of Biomolecular NMR, and Molecular Physics. He chaired the Gordon Research Conference on Magnetic Resonance in 2001.

1. 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.

2. Structural studies of amyloid fibrils. Due to the involvement of amyloid fibrils in amyloid diseases and the recent realization that amyloid formation is a common property of polypeptides with diverse amino acid sequences, these systems are of great current interest in both the biomedical and the biophysical research communities. We have shown that solid state NMR methods are uniquely capable of providing structural constraints on amyloid fibrils, which are inherently noncrystalline and insoluble. We have developed the first detailed, experimentally-based molecular structural models for fibrils formed by the beta-amyloid peptide associated with Alzheimer's disease. Current work is directed at refinement and extensions of these structural models, investigations of the structures of amyloid fibrils associated with type 2 diabetes and yeast prions, and structural characterization of amyloid fibrils that form in vivo in human tissue.

3. Solid state NMR investigations of protein folding. Although the highly ordered, folded structures of thousands of proteins have been determined to 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 sub-millisecond 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.

4. 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.

5. Ultra-low-temperature dynamic nuclear polarization. Applications of solid state NMR to biological problems are frequently limited by low signal-to-noise.  To improve sensitivity, we have developed 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-tempearture solid state NMR in studies of amyloid precursors, protein folding intermediates, and membrane proteins are planned for the near future.

         1.    Qiang WQW, Yau WM, Tycko R (2011) Structural evolution of Iowa mutant beta-amyloid fibrils from polymorphic to homogeneous states under repeated seeded growth. J. Am. Chem. Soc. 133:4018-4029.
2.    Lu JX, Yau WM, Tycko R (2011) Evidence from solid state NMR for nonhelical conformations in the transmembrane domain of the amyloid precursor protein. Biophys. J. 100:711-719.
3.    Kryndushkin DS, Wickner RB, Tycko R (2011) The core of Ure2p prion fibrils is formed by the N-terminal segment in a parallel cross-beta structure: Evidence from solid state NMR. J. Mol. Biol. 409:263-277.
4.    Hu KN, Qiang W, Tycko R (2011) A general Monte Carlo/simulated annealing algorithm for resonance assignment in NMR of uniformly labeled biopolymers. J. Biomol. NMR 50:267-276.
5.    Chen B, Tycko R (2011) Simulated self-assembly of the HIV-1 capsid: Protein shape and native contacts are sufficient for two-dimensional lattice formation. Biophys. J. 100:3035-3044.
6.    Tycko R, Savtchenko R, Ostapchenko VG, Makarava N, Baskakov IV (2010) The alpha-helical C-terminal domain of full-length recombinant PrP converts to an in-register parallel beta-sheet structure in PrP fibrils: Evidence from solid state nuclear magnetic resonance. Biochemistry 49:9488-9497.
7.    Thurber KR, Yau WM, Tycko R (2010) Low-temperature dynamic nuclear polarization at 9.4 T with a 30 m microwave source. J. Magn. Reson. 204:303-313.
8.    Thurber KR, Tycko R (2010) Prospects for sub-micron solid state nuclear magnetic resonance imaging with low-temperature dynamic nuclear polarization. Phys. Chem. Chem. Phys. 12:5779-5785.
9.    Lu JX, Sharpe S, Ghirlando R, Yau WM, Tycko R (2010) Oligomerization state and supramolecular structure of the HIV-1 Vpu protein transmembrane segment in phospholipid bilayers. Protein Sci. 19:1877-1896.
10.    Hu KN, Yau WM, Tycko R (2010) Detection of a transient intermediate in a rapid protein folding process by solid state nuclear magnetic resonance. J. Am. Chem. Soc. 132:24-25.
11.    Hu KN, Tycko R (2010) What can solid state NMR contribute to our understanding of protein folding? Biophys. Chem. 151:10-21.
12.    Chen B, Tycko R (2010) Structural and dynamical characterization of tubular HIV-1 capsid protein assemblies by solid state nuclear magnetic resonance and electron microscopy. Protein Sci. 19:716-730.
13.    Tycko R, Sciarretta KL, Orgel J, Meredith SC (2009) Evidence for novel beta-sheet structures in Iowa mutant beta-amyloid fibrils. Biochemistry 48:6072-6084.
14.    Thurber KR, Tycko R (2009) Measurement of sample temperatures under magic-angle spinning from the chemical shift and spin-lattice relaxation rate of (79)Br in KBr powder. J. Magn. Reson. 196:84-87.
15.    Paravastu AK, Qahwash I, Leapman RD, Meredith SC, Tycko R (2009) Seeded growth of beta-amyloid fibrils from Alzheimer's brain-derived fibrils produces a distinct fibril structure. Proc. Natl. Acad. Sci. U. S. A. 106:7443-7448.
16.    Hu KN, Tycko R (2009) Zero-quantum frequency-selective recoupling of homonuclear dipole-dipole interactions in solid state nuclear magnetic resonance. J. Chem. Phys. 131:045101.
17.    Hu KN, Havlin RH, Yau WM, Tycko R (2009) Quantitative determination of site-specific conformational distributions in an unfolded protein by solid state nuclear magnetic resonance. J. Mol. Biol. 392:1055-1073.
18.    Chen B, Thurber KR, Shewmaker F, Wickner RB, Tycko R (2009) Measurement of amyloid fibril mass-per-length by tilted-beam transmission electron microscopy. Proc. Natl. Acad. Sci. U. S. A. 106:14339-14344.
19.    Thurber KR, Tycko R (2008) Biomolecular solid state NMR with magic-angle spinning at 25 K. J. Magn. Reson. 195:179-186.
20.    Shewmaker F, Ross ED, Tycko R, Wickner RB (2008) Amyloids of shuffled prion domains that form prions have a parallel in-register beta-sheet structure. Biochemistry 47:4000-4007.
21.    Paravastu AK, Leapman RD, Yau WM, Tycko R (2008) Molecular structural basis for polymorphism in Alzheimer's beta-amyloid fibrils. Proc. Natl. Acad. Sci. U. S. A. 105:18349-18354.
22.    Tycko R (2007) Symmetry-based constant-time homonuclear dipolar recoupling in solid state NMR. J. Chem. Phys. 126:064506.
23.    Tycko R (2007) Stochastic dipolar recoupling in nuclear magnetic resonance of solids. Phys. Rev. Lett. 99:187601.
24.    Luca S, Yau WM, Leapman R, Tycko R (2007) Peptide conformation and supramolecular organization in amylin fibrils: Constraints from solid state NMR. Biochemistry 46:13505-13522.
25.    Havlin RH, Blanco FJ, Tycko R (2007) Constraints on protein structure in HIV-1 Rev and Rev-RNA supramolecular assemblies from two-dimensional solid state nuclear magnetic resonance. Biochemistry 46:3586-3593.
26.    Baxa U, Wickner RB, Steven AC, Anderson DE, Marekov LN, Yau WM, Tycko R (2007) Characterization of beta-sheet structure in Ure2p(1-89) yeast prion fibrils by solid state nuclear magnetic resonance. Biochemistry 46:13149-13162.
27.    Shewmaker F, Wickner RB, Tycko R (2006) Amyloid of the prion domain of Sup35p has an in-register parallel beta-sheet structure. Proc. Natl. Acad. Sci. U. S. A. 103:19754-19759.
28.    Sharpe S, Yau WM, Tycko R (2006) Structure and dynamics of the HIV-1 Vpu transmembrane domain revealed by solid state NMR with magic-angle spinning. Biochemistry 45:918-933.
29.    Petkova AT, Yau WM, Tycko R (2006) Experimental constraints on quaternary structure in Alzheimer's beta-amyloid fibrils. Biochemistry 45:498-512.
30.    Petkova AT, Leapman RD, Guo ZH, Yau WM, Mattson MP, Tycko R (2005) Self-propagating, molecular-level polymorphism in Alzheimer's beta-amyloid fibrils. Science 307:262-265.
31.    Sharpe S, Kessler N, Anglister JA, Yau WM, Tycko R (2004) Solid state NMR yields structural constraints on the V3 loop from HIV-1 gp120 bound to the 447-52d antibody Fv fragment. J. Am. Chem. Soc. 126:4979-4990.
32.    Petkova AT, Buntkowsky G, Dyda F, Leapman RD, Yau WM, Tycko R (2004) Solid state NMR reveals a pH-dependent antiparallel beta-sheet registry in fibrils formed by a beta-amyloid peptide. J. Mol. Biol. 335:247-260.
33.    Oyler NA, Tycko R (2004) Absolute structural constraints on amyloid fibrils from solid state NMR spectroscopy of partially oriented samples. J. Am. Chem. Soc. 126:4478-4479.
34.    Blanco FJ, Hess S, Pannell LK, Rizzo NW, Tycko R (2001) solid state NMR data support a helix-loop-helix structural model for the n-terminal half of HIV-1 rev in fibrillar form. J. Mol. Biol. 313:845-859.
35.    Tycko R, Blanco FJ, Ishii Y (2000) Alignment of biopolymers in strained gels: A new way to create detectable dipole-dipole couplings in high-resolution biomolecular NMR. J. Am. Chem. Soc. 122:9340-9341.
36.    Ishii Y, Tycko R (2000) Sensitivity enhancement in solid state N-15 NMR by indirect detection with high-speed magic angle spinning. J. Magn. Reson. 142:199-204.
37.    Balbach JJ, Ishii Y, Antzutkin ON, Leapman RD, Rizzo NW, Dyda F, Reed J, Tycko R (2000) Amyloid fibril formation by Abeta(16-22), a seven-residue fragment of the Alzheimer's beta-amyloid peptide, and structural characterization by solid state NMR. Biochemistry 39:13748-13759.
38.    Weliky DP, Bennett AE, Zvi A, Anglister J, Steinbach PJ, Tycko R (1999) Solid state NMR evidence for an antibody-dependent conformation of the V3 loop of HIV-1 gp120. Nat. Struct. Biol. 6:141-145.
39.    Michal CA, Tycko R (1999) Stray-field NMR imaging and wavelength dependence of optically pumped nuclear spin polarization in InP. Phys. Rev. B 60:8672-8679.
40.    Tycko R (1998) Optical pumping in indium phosphide: P-31 NMR measurements and potential for signal enhancement in biological solid state NMR. Solid State Nucl. Magn. Reson. 11:1-9.
41.    Michal CA, Tycko R (1998) Nuclear spin polarization transfer with a single radio-frequency field in optically pumped indium phosphide. Phys. Rev. Lett. 81:3988-3991.
42.    Tycko R, Barrett SE, Dabbagh G, Pfeiffer LN, West KW (1995) Electronic states in gallium arsenide quantum wells probed by optically pumped NMR. Science 268:1460-1463.
43.    Barrett SE, Dabbagh G, Pfeiffer LN, West KW, Tycko R (1995) Optically pumped NMR evidence for finite-size skyrmions in GaAs quantum wells near Landau-level filling nu=1. Phys. Rev. Lett. 74:5112-5115.
44.    Tycko R, Dabbagh G, Rosseinsky MJ, Murphy DW, Ramirez AP, Fleming RM (1992) Electronic properties of normal and superconducting alkali fullerides probed by C-13 nuclear magnetic resonance. Phys. Rev. Lett. 68:1912-1915.
45.    Tycko R, Dabbagh G, Fleming RM, Haddon RC, Makhija AV, Zahurak SM (1991) Molecular dynamics and the phase transition in solid C60. Phys. Rev. Lett. 67:1886-1889.
46.    Tycko R, Dabbagh G, Duchamp JC, Zilm KW (1990) C-13 zero-field NMR in high field. J. Magn. Reson. 89:205-209.
47.    Tycko R, Dabbagh G (1990) Measurement of nuclear magnetic dipole-dipole couplings in magic angle spinning NMR. Chem. Phys. Lett. 173:461-465.
48.    Tycko R (1990) Zero-field nuclear-magnetic-resonance in high field. J. Chem. Phys. 92:5776-5793.
49.    Sleator T, Tycko R (1988) Observation of individual organic molecules at a crystal surface with use of a scanning tunneling microscope. Phys. Rev. Lett. 60:1418-1421.
50.    Tycko R, Opella SJ (1987) Overtone NMR spectroscopy. J. Chem. Phys. 86:1761-1774.
51.    Tycko R (1987) Adiabatic rotational splittings and Berry's phase in nuclear quadrupole resonance. Phys. Rev. Lett. 58:2281-2284.
52.    Schneider DM, Tycko R, Opella SJ (1987) High-resolution solid state triple nuclear magnetic resonance measurement of C-13-N-15 dipole dipole couplings. J. Magn. Reson. 73:568-573.
53.    Tycko R, Pines A, Guckenheimer J (1985) Fixed-point theory of iterative excitation schemes in NMR. J. Chem. Phys. 83:2775-2802.