The long term objective of this project is to understand quantitatively the stereochemical and physico-chemical basis of alpha-helix termination. This means better understanding the mechanism of protein folding, one of the most basic problems in biomedical research. The health-related significance of this work is that the information obtained could be used for the design of new protein structures and the improvement of stabilities of biologically active proteins. The following questions will be answered: 1) Which residues in the C-capping box are important for the formation of the alphal helix termination motif? 2) What are the thermodynamic propensities of different residues at solvent exposed (C2, C1, Ccap & C ) positions of the C-capping box in an alpha-helix? 3) Do these propensities correlate with thermodynamic propensity scales obtained in other systems (alpha-helix propensities, beta-sheet propensities) or structural parameters (peptide backbone amide hydrogen exchange factors, buried and exposed surface area, etc.)? 4) What is the role of the bracketing hydrophobic interactions in formation and stabilization of the alphal motif? These questions will be answered by study of specific mutations in the C-capping box of the alpha-helix of ubiquitin using a combination of experimental methods, providing both structural (CD, fluorescence, and NMR spectroscopies and X-ray crystallography) and thermodynamic (microcalorimetry,) information on the system. From these data, we will evaluate the structural and energetic contributions of various amino acid residues at different positions of C-capping box.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular and Cellular Biophysics Study Section (BBCA)
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Texas Tech University
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Wafer, Lucas N; Tzul, Franco O; Pandharipande, Pranav P et al. (2014) Structural and thermodynamic characterization of the recognition of the S100-binding peptides TRTK12 and p53 by calmodulin. Protein Sci 23:1247-61
Wafer, Lucas N; Tzul, Franco O; Pandharipande, Pranav P et al. (2013) Novel interactions of the TRTK12 peptide with S100 protein family members: specificity and thermodynamic characterization. Biochemistry 52:5844-56
Wafer, Lucas N; Streicher, Werner W; McCallum, Scott A et al. (2012) Thermodynamic and kinetic analysis of peptides derived from CapZ, NDR, p53, HDM2, and HDM4 binding to human S100B. Biochemistry 51:7189-201
Sgourakis, Nikolaos G; Merced-Serrano, Myrna; Boutsidis, Christos et al. (2011) Atomic-level characterization of the ensemble of the A?(1-42) monomer in water using unbiased molecular dynamics simulations and spectral algorithms. J Mol Biol 405:570-83
Wafer, Lucas N R; Streicher, Werner W; Makhatadze, George I (2010) Thermodynamics of the Trp-cage miniprotein unfolding in urea. Proteins 78:1376-81
Patel, Mayank M; Sgourakis, Nikolaos G; Garcia, Angel E et al. (2010) Experimental test of the thermodynamic model of protein cooperativity using temperature-induced unfolding of a Ubq-UIM fusion protein. Biochemistry 49:8455-67
Sgourakis, Nikolaos G; Patel, Mayank M; Garcia, Angel E et al. (2010) Conformational dynamics and structural plasticity play critical roles in the ubiquitin recognition of a UIM domain. J Mol Biol 396:1128-44
Streicher, Werner W; Lopez, Maria M; Makhatadze, George I (2010) Modulation of quaternary structure of S100 proteins by calcium ions. Biophys Chem 151:181-6
Day, Ryan; Paschek, Dietmar; Garcia, Angel E (2010) Microsecond simulations of the folding/unfolding thermodynamics of the Trp-cage miniprotein. Proteins 78:1889-99
Streicher, Werner W; Lopez, Maria M; Makhatadze, George I (2009) Annexin I and annexin II N-terminal peptides binding to S100 protein family members: specificity and thermodynamic characterization. Biochemistry 48:2788-98

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