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My research uses nuclear magnetic resonance spectroscopy, optical spectroscopy, and computational methods to probe structural and dynamical aspects of protein function. Within the past decade, advances in NMR spectroscopy have made possible the determination of the three-dimensional structures of peptides, short nucleic acid sequences and small proteins. In addition, NMR also is a powerful method for investigating dynamic properties of biological molecules and molecular systems. Areas currently of interest include the following:

 Enzyme dynamics. Numerous experimental and theoretical techniques have indicated that proteins have a complex dynamic behavior over many amplitude and temporal scales. However, current experimental knowledge of the details of the internal dynamics of proteins is fragmentary. Nuclear magnetic resonance spectroscopy is being used to globally characterize the internal dynamics of the enzyme ribonuclease H from microbial and viral sources. The results are being interpreted using molecular dynamics simulations and theoretical models to characterize the conformational space accessible to the proteins.

Protein-DNA Interactions. A number of small structural motifs, including helix-turn-helix, bZip domains, and zinc fingers, have been implicated in specific recognition of nucleic acids. Changes in the conformational flexibility of proteins may contribute to thermodynamics of DNA binding. To investigate this hypothesis, intramolecular dynamics of bZip peptides in the free state and bound to DNA are being measured by nuclear magnetic resonance spectroscopy and optical spectroscopy.

Protein-RNA Interactions. In collaboration with Max Gottesman, the structures of complexes between the Hong Kong 022 phage protein Nun and the phage Box B RNA hairpin are being determined by NMR spectroscopy. Box B is a short sequence within the Nun sites of the phage genome. Binding of Nun to the Box B site within the nascent RNA transcript promotes termination at downstream termination sites. Nun contains an "arginine rich motif" that comprises the putative RNA binding site. The structure determination makes use of three and four dimensional NMR spectroscopy and 13C/15N enriched Nun and Box B RNA.

Methods development. Many of the above projects pose problems that require the development of new experimental methods in NMR spectroscopy. At present, new approaches are being pursued for characterizing microsecond-millisecond motions in proteins by a combination of NMR spectroscopy and computational techniques.

Selected Publications

A. M. Mandel, M. Akke and A. G. Palmer, Dynamics of ribonuclease H: Temperature dependence of motions on multiple time scales, Biochemistry 35, 16009-16023 (1996).

M. Philippopoulos, A. M. Mandel, A. G. Palmer and C. Lim, Accuracy and precision of NMR relaxation experiments and MD simulations for characterizing protein dynamics, Proteins: Struct., Func. Genet. 28, 481-493 (1997).

P. A. Carr, H. P. Erickson, and A. G. Palmer, Backbone dynamics of homologous fibronectin type III cell adhesion domains from fibronectin and tenascin, Structure 5, 949-959 (1997).

M. Akke, J. Liu, J. Cavanagh, H. P. Erickson, and A. G. Palmer, Pervasive conformational fluctuations on microsecond time scales in a fibronectin type III domain, Nat. Struct. Biol. 5, 55-59 (1998).

C.D. Kroenke, J.P. Loria, L.K. Lee, M. Rance, and A.G. Palmer, Longitudinal and transverse ¹H-¹⁵N dipolar/¹⁵N chemical shift anisotropy relaxation interference: Unambiguous determination of rotational diffusion tensors and chemical exchange effects in biological macromolecules, J. Am. Chem. Soc. 120, 7905-7915 (1998).

C. Bracken, P.A. Carr, J. Cavanagh, and A.G. Palmer, Temperature dependence of intramolecular dynamics of the basic region leucine zipper of GCN4: Implications for the entropy of association with DNA, J. Mol. Biol. 285, 2133-2146 (1999).

J.P. Loria, M. Rance and A.G. Palmer, A relaxation-compensated Carr-Purcell-Meiboom-Gill sequence for characterizing chemical exchange by NMR spectroscopy, J. Am. Chem. Soc. 121, 2331-2332 (1999).

R. S. Watnick, S. C. Herring, A. G. Palmer, and M. E. Gottesman, The C-terminus of phage HK022 Nun includes a novel zinc-binding motif and a tryptophan required for transcription termination, Genes and Development 14, 731-739 (2000).

O. Millet, J. P. Loria, C. D. Kroenke, M. Pons, and A. G. Palmer, The static magnetic field dependence of chemical exchange linebroadening defines the NMR chemical shift time scale, J. Am. Chem. Soc. 122, 2867-2877 (2000).

R. B. Hill, C. Bracken, W. F. DeGrado, and A. G. Palmer, Molecular motions and protein folding: Characterization of the backbone dynamics and folding equilibrium of a2D using 13C NMR spin relaxation, J. Am. Chem. Soc. 122, 11610-11619 (2000).