This proposal represents an extended investigation into the application of the generalized-ensemble approach for protein-folding simulations. It is a continuation of the work that the PI did over the last few years. The PI intends to apply the novel techniques that were developed in his group a) to a study of folding transitions and the relation between secondary and tertiary structure formation in a few carefully selected proteins that have either only alpha-helices or beta-sheets as secondary structure elements. The following peptides will be considered: HP-36 (36 residues, all-helical), Beta3s (20 residues, all-beta-sheet), the B domain of staphylococcal protein A (45 residues, all-helical), and Anthopleurin A (49 residues, all-beta-sheet); b) to study the ensemble of low-energy structures, energy landscape and folding of the 62-residue IgG-binding domain of protein L and the 56-residue segment B1 of streptococcal protein G. These two small fast-folding proteins have both helix and beta-sheets and therefore allow one to probe results of the above investigation for complex examples of small proteins; c) and to research in some protein fragments, the transition from an alpha-helix to a beta-sheet, that is thought to be responsible for the outbreak of various neurodegenerative diseases. It is hoped that such research of the thermodynamic of folding and other structural transitions in proteins will lead to an improved understanding of the mechanism of folding. This would allow one to understand better the outbreak of various diseases associated with the malfunction of certain proteins and could lead to more efficient ways of drug design.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular and Cellular Biophysics Study Section (BBCA)
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Wehrle, Janna P
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Michigan Technological University
Schools of Arts and Sciences
United States
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Alred, Erik J; Phillips, Malachi; Berhanu, Workalemahu M et al. (2015) On the lack of polymorphism in A?-peptide aggregates derived from patient brains. Protein Sci 24:923-35
Alred, Erik J; Scheele, Emily G; Berhanu, Workalemahu M et al. (2014) Stability of Iowa mutant and wild type A?-peptide aggregates. J Chem Phys 141:175101
Berhanu, Workalemahu M; Hansmann, Ulrich H E (2014) Stability of amyloid oligomers. Adv Protein Chem Struct Biol 96:113-41
Ya?ar, Fatih; Sieradzan, Adam K; Hansmann, Ulrich H E (2014) Folding and self-assembly of a small heterotetramer. J Chem Phys 140:105103
Ya?ar, Fatih; Jiang, Ping; Hansmann, Ulrich H E (2014) Multicanonical Molecular Dynamics Simulations of the N-terminal Domain of Protein L9. Europhys Lett 105:30008
Berhanu, Workalemahu M; Hansmann, Ulrich H E (2014) Inter-species cross-seeding: stability and assembly of rat-human amylin aggregates. PLoS One 9:e97051
Berhanu, W M; Jiang, P; Hansmann, U H E (2013) Folding and association of a homotetrameric protein complex in an all-atom Go model. Phys Rev E Stat Nonlin Soft Matter Phys 87:014701
Berhanu, Workalemahu M; Ya?ar, Fatih; Hansmann, Ulrich H E (2013) In silico cross seeding of A? and amylin fibril-like oligomers. ACS Chem Neurosci 4:1488-500
Bernhardt, Nathan A; Berhanu, Workalemahu M; Hansmann, Ulrich H E (2013) Mutations and seeding of amylin fibril-like oligomers. J Phys Chem B 117:16076-85
Berhanu, Workalemahu M; Hansmann, Ulrich H E (2013) The stability of cylindrin *-barrel amyloid oligomer models-a molecular dynamics study. Proteins 81:1542-55

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