Research

Technique Development: Protein Structure by Solid State NMR

There are two established methods of protein structure determination: X-ray crystallography and solution NMR. Both methods have drawbacks. The protein must crystallize in order to use x-rays, and the protein must both be solvent in some liquid and not too large for study by solution NMR. Solid State NMR suffers from neither of these restrictions and could conceivably be used to study a large range of protein strucutres. Since solid state NMR has only recently begun to be applied to problems of biological interest, the field still lacks the arsenal of techniques available to any mature analytical technique. Consequently, we must develop these techniques in the laboratory as we carry on studies of proteins.

• Y. Ishii, J.J. Balbach, R. Tycko,
  "Measurement of dipole-coupled lineshapes in a many-spin system by constant-time two-dimensional solid state NMR with high-speed magic-angle spinning"
  Chemical Physics 266 (2-3): 231-236 May 15 2001
• R. Tycko, O.N. Antzutkin, J.J. Balbach,
  "Multiple quantum solid-state NMR indicates a parallel, not antiparallel, organization of beta-sheets in Alzheimer's beta-amyloid fibrils"
  Proceedings of the National Academy of Science 97 (24): 13045-13050 November 21 2000

Aggregate Protein Structure

There are biologically important cases of protein aggregation that are well suited for study by SSNMR. Our research will initially focus on amyloid-forming proteins. Amyloid fibrils are kinds of aggregate (polymolecular) structures that are not well understood, since they cannot be studied by either X-ray crystallography or solution NMR. The most well known protein in this group is the beta-amyloid peptide, which has been recognized as being important to Alzheimer's Disease. Other disease related proteins in this group are amylin (type II diabetes), the prion protein (spongiform encephalopathy), transthyretin (certain cardiac problems resulting from senile systemic amyloidosis) and amyloid A (rheumatoid arthritis among other diseases).

Another biomolecular structural problem which is not tractable by other means in some cases is the issue of antibody binding. It can be an important part of drug design to understand both the location and the structure of the receptor site in antibody-protein interactions (or any protein-protein interaction). SSNMR can be used to probe these issues, and provide information that cannot be obtained by any other method.

• R. Tycko, A. Petkova, N. Oyler, C.C. Chan, J. Balbach,
  "Probing the molecular structure of amyloid fibrils with solid state NMR" Biophysical Journal 82 (1): 913 Part 2 January 2002
• J.J. Balbach, J. Yang, D.P. Weliky, P.J. Steinbach, V. Turganov, J. Anglister, R. Tycko, "Probing hydrogen bonds in the antibody-bound HIV-1 gp120 V3 loop by solid state NMR REDOR measurements", Journal of Biomolecular NMR, 16 p. 313 (2000).

Teaching

• Fall 2002 - Physics 1
• Spring 2003 - Physics 2