Protein misfolding and abnormal aggregation is known to be characteristic of many diseases and often coincident with peptide mutations. Our long-term goal is to understand the effects of peptide mutations upon the relative energies of the various peptide secondary structures and how they are related to these diseases, with particular emphas placed on diseases related to collagen structure and Alzheimer's disease. With respect to the collagen related diseases, we suggest that these mutations cause errors in the H-bonding patterns of normal collagen. With respect to Alzheimer's disease, we suspect that mutations affect the relative amounts and positions of local alpha-helical structure in the protein, tau, which can change its propensity to be phosphoylated. Hyperphosphorylation has been directly related to the abnormal aggregation of tau which is a physiological symptom of Alzheimer's Disease.
The specific aims of the proposed work will be the elucidation the structural factors that determine that determine the secondary structures of peptides using density functional and semi empirical molecular orbital theory, both in isolated (gas phase) and solvated completely geometrically optimized oligopeptides. This work will be coordinated with NMR structural determinations of the same peptides where possible.
A second aim will be the application of these and other similar energetic studies to the improved understanding of the details of several diseases that involve mutated, misfolded and/or unnaturally aggregated peptides and proteins. The specific foci of these studies will be collagen-like triple helices (related to osteogenesis imperfecta, Ehlers-Danlos syndrome, Alport syndrome, Schmid metaphyseal chondrodysplasia and dystrophic epidermolysis bullosa) and the protein tau (involved in Alzheimer's disease). First principles (quantum mechanical) calculations will be used to determine the relative energies of the secondary structures of different peptides. The knowledge gleaned from these studies will be applied to determining the properties misfolded proteins that cause several diseases.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Enhancement Award (SC1)
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Special Emphasis Panel (ZGM1-MBRS-X (CH))
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Velazquez, Jose M
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Hunter College
Schools of Arts and Sciences
New York
United States
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Plumley, Joshua A; Ali-Torres, Jorge; Pohl, Gabor et al. (2014) Capping amyloid ?-sheets of the tau-amyloid structure VQIVYK with hexapeptides designed to arrest growth. An ONIOM and density functional theory study. J Phys Chem B 118:3326-34
Pohl, Gabor; Asensio, Amparo; Dannenberg, J J (2014) Capping parallel ?-sheets of acetyl(Ala)6NH2 with an acetyl(Ala)5ProNH2 can arrest the growth of the sheet, suggesting a potential for curtailing amyloid growth. An ONIOM and density functional theory study. Biochemistry 53:617-23
Pohl, Gabor; Plumley, Joshua A; Dannenberg, J J (2013) The interactions of phenylalanines in ?-sheet-like structures from molecular orbital calculations using density functional theory (DFT), MP2, and CCSD(T) methods. J Chem Phys 138:245102
Roy, Dipankar; Marianski, Mateusz; Maitra, Neepa T et al. (2012) Comparison of some dispersion-corrected and traditional functionals with CCSD(T) and MP2 ab initio methods: dispersion, induction, and basis set superposition error. J Chem Phys 137:134109
Marianski, Mateusz; Oliva, Antoni; Dannenberg, J J (2012) A reinvestigation of the dimer of para-benzoquinone and pyrimidine with MP2, CCSD(T), and DFT using functionals including those designed to describe dispersion. J Phys Chem A 116:8100-5
Marianski, Mateusz; Dannenberg, J J (2012) Aqueous solvation of polyalanine *-helices with specific water molecules and with the CPCM and SM5.2 aqueous continuum models using density functional theory. J Phys Chem B 116:1437-45
Roy, Dipankar; Pohl, Gabor; Ali-Torres, Jorge et al. (2012) Density functional theory study of ?-hairpins in antiparallel ?-sheets, a new classification based upon H-bond topology. Biochemistry 51:5387-93
Kobko, Nadya; Marianski, Mateusz; Asensio, Amparo et al. (2012) A Density Functional Theory Evaluation of Hydrophobic Solvation: Ne, Ar and Kr in a 50-Water Cluster. Implications for the Hydrophobic Effect. Comput Theor Chem 990:214-221
Ali-Torres, Jorge; Dannenberg, J J (2012) The folding of acetyl(Ala)28NH2 and acetyl(Ala)40NH2 extended strand peptides into antiparallel ýý-sheets. A density functional theory study of ýý-sheets with ýý-turns. J Phys Chem B 116:14017-22
Marianski, Mateusz; Asensio, Amparo; Dannenberg, J J (2012) Comparison of some dispersion-corrected and traditional functionals as applied to peptides and conformations of cyclohexane derivatives. J Chem Phys 137:044109

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