Abstract
Protein conformational transition from alpha-helices to beta-sheets precedes aggregation of proteins implicated in many diseases, including Alzheimer and prion diseases. Direct characterization of such transitions is often hindered by the complicated nature of the interaction network among amino acids. A recently engineered small protein-like peptide with a simple amino acid composition features a temperature-driven alpha-helix to beta-sheet conformational change. Here we studied the conformational transition of this peptide by molecular dynamics simulations. We observed a critical temperature, below which the peptide folds into an alpha-helical coiled-coil state and above which the peptide misfolds into beta-rich structures with a high propensity to aggregate. The structures adopted by this peptide during low temperature simulations have a backbone root mean square deviation less than 2 A from the crystal structure. At high temperatures, this peptide adopts an amyloid-like structure, which is mainly composed of coiled anti-parallel beta-sheets with the cross-beta-signature of amyloid fibrils. Most strikingly, we observed conformational conversions in which an alpha-helix is converted into a beta-strand by proximate stable beta-sheets with exposed hydrophobic surfaces and unsaturated hydrogen bonds. Our study suggested a possible generic molecular mechanism of the template-mediated aggregation process, originally proposed by Prusiner (Prusiner, S. B. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 13363-13383) to account for prion infectivity.
Highlights
Protein conformation diseases, including Alzheimer, Lou Gehrig, and prion diseases [1], involve the aggregation of soluble proteins into insoluble amyloid fibrils following major conformational rearrangements
An intriguing conformational transition from ␣-helices to -sheets occurs en route to the aggregation of natively ␣-helical proteins, such as prion proteins [3] in Creutzfeldt-Jakob disease and the A peptide in Alzheimer disease [4]
It has been shown that aggregation into amyloid fibrils is a common property of polypeptides [5, 6]
Summary
Protein conformation diseases, including Alzheimer, Lou Gehrig, and prion diseases [1], involve the aggregation of soluble proteins into insoluble amyloid fibrils following major conformational rearrangements. Lipfert et al [12] employed a reaction path annealing algorithm to study the misfolding and amyloid formation of a short seven-residue peptide from the yeast prion protein in the presence of pre-made -sheets. In this algorithm, the initial and final states are fixed, and the energy is computed along the pathway by multiple constrained simulations. These hypothetical peptide sequences were designed in silico to feature a metastable -sheet state in addition to the ␣-helical ground state These studies provide computational evidence for the template model of propagating conformational changes proposed by Prusiner [3] that explains the lethal infection of pathological prions. An unconstrained study of an experimentally characterized protein system is necessary to understand the ␣-helix to -sheet transition and to directly “observe” the template hypothesis proposed by Prusiner [3]
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