This research will be carried out primarily in San Luis-Argentina at the San Luis University in collaboration with Jorge A. Vila as an extension of NIH Grant Number: GM-14312. Protein and peptide conformational shifts, which are defined as the deviations of the 13Calpha and 13Cbeta chemical shifts from their corresponding statistical-coil values, can be used in many different ways in structural analysis. Possible applications include: (i) secondary structure mapping; (ii) generating structural constraints; (iii) three-dimensional structural refinement; and (iv) three-dimensional structural generation. Such a wide capability of NMR-derived data could play an important role in determination of protein structure in solution, and lead to a broad scope of possible theoretical applications. In particular, this proposal will focus on both the quantum-chemical computation of the Boltzmann-averaged values of the 13C( and 13C( chemical shifts for all the naturally occurring amino acids in water at neutral pH for a model peptide in both the canonical alpha-helical and beta-sheet conformations, respectively, and on the prediction of the tertiary structure of proteins with the help of 13C NMR chemical shift information. To accomplish these goals efficiently, a new protocol to explore the accessible conformational space more efficiently will be introduced. It is expected that the results derived from this investigation may be useful for both knowledge-based approaches and ab initio methods developed to predict the structures of globular proteins, as well as may contribute to our understanding of how statistical-coil states can be inter-related with the conformational preferences of more-structured states, such as alpha-helical and beta-sheet conformations. Although the conversion of chemical shift information into quantifiable structural information is a relatively new field, the results provided by this proposed research would provide additional assistance for an accurate tertiary protein structure prediction and, consequently, make a significant contribution to the solution of the, as yet unsolved, protein folding problem.

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Small Research Grants (R03)
Project #
5R03TW006335-03
Application #
6923629
Study Section
International and Cooperative Projects 1 Study Section (ICP)
Program Officer
Michels, Kathleen M
Project Start
2003-08-15
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2007-07-31
Support Year
3
Fiscal Year
2005
Total Cost
$33,560
Indirect Cost
Name
Cornell University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Vila, Jorge A; Scheraga, Harold A (2008) Factors affecting the use of 13C(alpha) chemical shifts to determine, refine, and validate protein structures. Proteins 71:641-54
Vila, Jorge A; Ripoll, Daniel R; Scheraga, Harold A (2007) Use of 13Calpha chemical shifts in protein structure determination. J Phys Chem B 111:6577-85
Vila, Jorge A; Villegas, Myriam E; Baldoni, Hector A et al. (2007) Predicting 13Calpha chemical shifts for validation of protein structures. J Biomol NMR 38:221-35
Niv, Masha Y; Ripoll, Daniel R; Vila, Jorge A et al. (2007) Topology of Type II REases revisited;structural classes and the common conserved core. Nucleic Acids Res 35:2227-37
Villegas, Myriam E; Vila, Jorge A; Scheraga, Harold A (2007) Effects of side-chain orientation on the 13C chemical shifts of antiparallel beta-sheet model peptides. J Biomol NMR 37:137-46
Makowska, Joanna; Rodziewicz-Motowidlo, Sylwia; Baginska, Katarzyna et al. (2006) Polyproline II conformation is one of many local conformational states and is not an overall conformation of unfolded peptides and proteins. Proc Natl Acad Sci U S A 103:1744-9
Ripoll, Daniel R; Vila, Jorge A; Scheraga, Harold A (2005) On the orientation of the backbone dipoles in native folds. Proc Natl Acad Sci U S A 102:7559-64
Vila, Jorge A; Ripoll, Daniel R; Arnautova, Yelena A et al. (2005) Coupling between conformation and proton binding in proteins. Proteins 61:56-68
Vila, Jorge A; Baldoni, Hector A; Scheraga, Harold A (2004) Position dependence of the 13C chemical shifts of alpha-helical model peptides. Fingerprint of the 20 naturally occurring amino acids. Protein Sci 13:2939-48
Ripoll, Daniel R; Vila, Jorge A; Scheraga, Harold A (2004) Folding of the villin headpiece subdomain from random structures. Analysis of the charge distribution as a function of pH. J Mol Biol 339:915-25

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