The National Institute of Diabetes & Digestive & Kidney Diseases

Dr. Tycko was awarded the American Physical Society's Earle K. Plyler Prize for Molecular Spectroscopy in 2005, and is a Fellow of the American Physical Society and the American Association for the Advancement of Science. He received an NIH Director's Award in 2001, and was the Norman Hascoe Distinguished Lecturer (University of Connecticut, 2001), the Max T. Rogers Distinguished Lecturer (Michigan State University, 2003), and the R.W. Vaughan Lecturer (Rocky Mountain Conference on Analytical Chemistry, 2004). 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.

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 can provide local 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 peptides and proteins that associate with biological membranes, amyloid fibrils and other noncrystalline aggregates, and frozen solutions of biopolymers with molecular weights in excess of 100 kD. The field of biomolecular solid state NMR is at a relatively early stage of development. As a result, our work tends to be highly exploratory and interdisciplinary, drawing heavily on experimental and theoretical techniques of the physical, as well as biological, sciences. Some ongoing projects include the following:

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 specific interatomic distances and specific dihedral angles in samples that contain multiple uniformly 15N,13C-labeled residues. 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 fibril 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 truly 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 experimental tests of various hypotheses regarding the interactions that stabilize amyloid structures.

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 freeze-quenching as an approach to site-specific, quantitative characterization of unfolded and partially folded proteins. Initial results indicate that site-specific variations in conformational distributions and in folding equilibria are readily apparent in solid state NMR data.

4. Solid state NMR studies of membrane proteins. We are currently investigating the molecular structure of the HIV-1 Vpu protein, a relatively small transmembrane protein involved in the HIV-1 life cycle, with the goal of understanding how its structure and oligomerization state affect its biological function and its in vitro ion channel activity. We have also carried out studies of peptide/antibody complexes associated with AIDS, motivated in part by their utility as model systems for membrane-associated peptide/receptor complexes. As methods for producing micromole-scale quantities of membrane proteins improve, and as the sensitivity of solid state NMR measurements improves, studies of the structure, function, and interactions of membrane proteins by solid state NMR will accelerate.

5. Optical pumping effects in solid state NMR. In certain materials, notably III-V semiconductors such as gallium arsenide and indium phosphide, irradiation with light at low temperatures produces enormous enhancements of nuclear spin polarizations and hence enormous enhancements of NMR signals. We are interested in understanding the physical mechanisms and exploring the generality of these optical pumping effects, with the goal of developing optical pumping methods that are useful in structural studies of organic and biological systems.

Havlin RH, Blanco FJ, Tycko R Constraints on Protein Structure in HIV-1 Rev and Rev-RNA Supramolecular Assemblies from Two-Dimensional Solid State Nuclear Magnetic Resonance. Biochemistry , 2007. [Full Text/Abstract]

Bu Z, Shi Y, Callaway DJ, Tycko R Molecular alignment within beta-sheets in Abeta(14-23) fibrils: solid-state NMR experiments and theoretical predictions. Biophys J (92): 594-602, 2007. [Full Text/Abstract]

Tycko R Symmetry-based constant-time homonuclear dipolar recoupling in solid state NMR. J Chem Phys (126): 064506, 2007. [Full Text/Abstract]

Shewmaker F, Wickner RB, Tycko R Amyloid of the prion domain of Sup35p has an in-register parallel beta-sheet structure. Proc Natl Acad Sci U S A (103): 19754-9, 2006. [Full Text/Abstract]

Tycko R Characterization of amyloid structures at the molecular level by solid state nuclear magnetic resonance spectroscopy. Methods Enzymol (413): 103-22, 2006. [Full Text/Abstract]

Lazar KL, Kurutz JW, Tycko R, Meredith SC Encapsulation and NMR on an aggregating peptide before fibrillogenesis. J Am Chem Soc (128): 16460-1, 2006. [Full Text/Abstract]

Petkova AT, Yau WM, Tycko R Experimental Constraints on Quaternary Structure in Alzheimer's beta-Amyloid Fibrils. Biochemistry(45): 498-512, 2006. [Full Text/Abstract]

Paravastu AK, Tycko R Frequency-selective homonuclear dipolar recoupling in solid state NMR. J Chem Phys (124): 194303, 2006. [Full Text/Abstract]

Tycko R Molecular structure of amyloid fibrils: insights from solid-state NMR. Q Rev Biophys (39): 1-55, 2006. [Full Text/Abstract]

Paravastu AK, Petkova AT, Tycko R Polymorphic fibril formation by residues 10-40 of the Alzheimer''s beta-amyloid peptide. Biophys J (90): 4618-29, 2006. [Full Text/Abstract]

Tycko R Solid-state NMR as a probe of amyloid structure. Protein Pept Lett (13): 229-34, 2006. [Full Text/Abstract]

Sharpe S, Yau WM, Tycko R Structure and Dynamics of the HIV-1 Vpu Transmembrane Domain Revealed by Solid-State NMR with Magic-Angle Spinning. Biochemistry (45): 918-33, 2006. [Full Text/Abstract]

Sciarretta KL, Gordon DJ, Petkova AT, Tycko R, Meredith SC Abeta40-Lactam(D23/K28) models a conformation highly favorable for nucleation of amyloid. Biochemistry (44): 6003-14, 2005. [Full Text/Abstract]

Sharpe S, Yau WM, Tycko R Expression and purification of a recombinant peptide from the Alzheimer's beta-amyloid protein for solid-state NMR. Protein Expr Purif(42): 200-10, 2005. [Full Text/Abstract]

Buchete NV, Tycko R, Hummer G Molecular dynamics simulations of Alzheimer's beta-amyloid protofilaments. J Mol Biol(353): 804-21, 2005. [Full Text/Abstract]

Chan JC, Oyler NA, Yau WM, Tycko R Parallel beta-sheets and polar zippers in amyloid fibrils formed by residues 10-39 of the yeast prion protein Ure2p. Biochemistry (44): 10669-80, 2005. [Full Text/Abstract]

Havlin RH, Tycko R Probing site-specific conformational distributions in protein folding with solid-state NMR. Proc Natl Acad Sci U S A (102): 3284-9, 2005. [Full Text/Abstract]

Petkova AT, Leapman RD, Guo Z, Yau WM, Mattson MP, Tycko R Self-propagating, molecular-level polymorphism in Alzheimer's beta-amyloid fibrils. Science(307): 262-5, 2005. [Full Text/Abstract]

Oyler NA, Tycko R Absolute structural constraints on amyloid fibrils from solid-state NMR spectroscopy of partially oriented samples. J Am Chem Soc (126): 4478-9, 2004. [Full Text/Abstract]

Chan JC, Tycko R Broadband rotational resonance in solid state NMR spectroscopy. J Chem Phys (120): 8349-52, 2004. [Full Text/Abstract]

Gordon DJ Balbach JJ Tycko R Meredith SC Increasing the amphiphilicity of an amyloidogenic peptide changes the beta-sheet structure in the fibrils from antiparallel to parallel. Biophys J (86): 428-34, 2004. [Full Text/Abstract]

De Dios AC, Sears DN, Tycko R NMR studies of peptide T, an inhibitor of HIV infectivity, in an aqueous environment. J Pept Sci (10): 622-30, 2004. [Full Text/Abstract]

Tycko R Progress towards a molecular-level structural understanding of amyloid fibrils. Curr Opin Struct Biol (14): 96-103, 2004. [Full Text/Abstract]

Tycko R Sensitivity enhancement in two-dimensional solid-state NMR spectroscopy by transverse mixing. Chemphyschem (5): 863-8, 2004. [Full Text/Abstract]

Petkova AT Buntkowsky G Dyda F Leapman RD Yau WM Tycko R Solid state NMR reveals a pH-dependent antiparallel beta-sheet registry in fibrils formed by a beta-amyloid peptide. J Mol Biol (335): 247-60, 2004. [Full Text/Abstract]

Sharpe S, Kessler N, Anglister JA, Yau WM, Tycko R 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): 4979-90, 2004. [Full Text/Abstract]

Tycko R Ishii Y Constraints on supramolecular structure in amyloid fibrils from two-dimensional solid-state NMR spectroscopy with uniform isotopic labeling. J Am Chem Soc (125): 6606-7, 2003. [Full Text/Abstract]

Tycko R Insights into the amyloid folding problem from solid-state NMR. Biochemistry (42): 3151-9, 2003. [Full Text/Abstract]

Antzutkin ON Balbach JJ Tycko R Site-specific identification of non-beta-strand conformations in Alzheimer''s beta-amyloid fibrils by solid-state NMR. Biophys J (84): 3326-35, 2003. [Full Text/Abstract]

Chan JC Tycko R Solid-state NMR spectroscopy method for determination of the backbone torsion angle psi in peptides with isolated uniformly labeled residues. J Am Chem Soc (125): 11828-9, 2003. [Full Text/Abstract]

Petkova AT Ishii Y Balbach JJ Antzutkin ON Leapman RD Delaglio F Tycko R A structural model for Alzheimer''s beta -amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci U S A (99): 16742-7, 2002. [Full Text/Abstract]

Petkova AT Tycko R Sensitivity enhancement in structural measurements by solid state NMR through pulsed spin locking. J Magn Reson (155): 293-9, 2002. [Full Text/Abstract]

Antzutkin ON Leapman RD Balbach JJ Tycko R Supramolecular structural constraints on Alzheimer''s beta-amyloid fibrils from electron microscopy and solid-state nuclear magnetic resonance. Biochemistry (41): 15436-50, 2002. [Full Text/Abstract]

Balbach JJ Petkova AT Oyler NA Antzutkin ON Gordon DJ Meredith SC Tycko R Supramolecular structure in full-length Alzheimer''s beta-amyloid fibrils: evidence for a parallel beta-sheet organization from solid-state nuclear magnetic resonance. Biophys J (83): 1205-16, 2002. [Full Text/Abstract]

Tycko R Biomolecular solid state NMR: advances in structural methodology and applications to peptide and protein fibrils. Annu Rev Phys Chem (52): 575-606, 2001. [Full Text/Abstract]

Ishii Y Markus MA Tycko R Controlling residual dipolar couplings in high-resolution NMR of proteins by strain induced alignment in a gel. J Biomol NMR (21): 141-51, 2001. [Full Text/Abstract]

Ishii Y Yesinowski JP Tycko R Sensitivity enhancement in solid-state (13)C NMR of synthetic polymers and biopolymers by (1)H NMR detection with high-speed magic angle spinning. J Am Chem Soc (123): 2921-2, 2001. [Full Text/Abstract]

Blanco FJ Hess S Pannell LK Rizzo NW Tycko R 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): 845-59, 2001. [Full Text/Abstract]

Tycko R Solid-state nuclear magnetic resonance techniques for structural studies of amyloid fibrils. Methods Enzymol (339): 390-413, 2001. [Full Text/Abstract]

Tycko R, Blanco FJ, Ishii Y. Alignment of biopolymers in strained gels: a new way to create detectable dipole-dipole couplings in high resolution biomolecular NMR. Journal of the American Chemical Society , 2000.

Balbach JJ Ishii Y Antzutkin ON Leapman RD Rizzo NW Dyda F Reed J Tycko R Amyloid fibril formation by A beta 16-22, a seven-residue fragment of the Alzheimer''s beta-amyloid peptide, and structural characterization by solid state NMR. Biochemistry (39): 13748-59, 2000. [Full Text/Abstract]

Antzutkin ON Balbach JJ Leapman RD Rizzo NW Reed J Tycko R Multiple quantum solid-state NMR indicates a parallel, not antiparallel, organization of beta-sheets in Alzheimer''s beta-amyloid fibrils. Proc Natl Acad Sci U S A (97): 13045-50, 2000. [Full Text/Abstract]

Balbach JJ Yang J Weliky DP Steinbach PJ Tugarinov V Anglister J Tycko R Probing hydrogen bonds in the antibody-bound HIV-1 gp120 V3 loop by solid state NMR REDOR measurements. J Biomol NMR (16): 313-27, 2000. [Full Text/Abstract]

Ishii Y Tycko R Sensitivity enhancement in solid state (15)N NMR by indirect detection with high-speed magic angle spinning. J Magn Reson (142): 199-204, 2000. [Full Text/Abstract]

Tycko R Solid-state NMR as a probe of amyloid fibril structure. Curr Opin Chem Biol (4): 500-6, 2000. [Full Text/Abstract]

Tycko R Berger AE Dual processing of two-dimensional exchange data in magic angle spinning NMR of solids. J Magn Reson (141): 141-7, 1999. [Full Text/Abstract]

Tycko R Selection rules for multiple quantum NMR excitation in solids: derivation from time-reversal symmetry and comparison with simulations and (13)C NMR experiments. J Magn Reson (139): 302-7, 1999. [Full Text/Abstract]

Weliky DP Bennett AE Zvi A Anglister J Steinbach PJ Tycko R Solid-state NMR evidence for an antibody-dependent conformation of the V3 loop of HIV-1 gp120. Nat Struct Biol (6): 141-5, 1999. [Full Text/Abstract]

Michal CA, Tycko R. Nuclear spin polarization transfer with a single radio-frequency field in optically pumped indium phosphide. Physical Review Letters(81): 3988, 1998.

Tycko R Optical pumping in indium phosphide: 31P NMR measurements and potential for signal enhancement in biological solid state NMR. Solid State Nucl Magn Reson (11): 1-9, 1998. [Full Text/Abstract]