Pauling and Corey's α-pleated sheet structure may define the prefibrillar amyloidogenic intermediate in amyloid disease

Abstract

Transthyretin, ␤2-microglobulin, lysozyme, and the prion protein are four of the best-characterized proteins implicated in amyloid disease. Upon partial acid denaturation, these proteins undergo conformational change into an amyloidogenic intermediate that can self-assemble into amyloid fibrils. Many experiments have shown that pH-mediated changes in structure are required for the formation of the amyloidogeneic intermediate, but it has proved impossible to characterize these conformational changes at high resolution using experimental means. To probe these conformational changes at atomic resolution, we have performed molecular dynamics simulations of these proteins at neutral and low pH. In low-pH simulations of all four proteins, we observe the formation of ␣-pleated sheet secondary structure, which was first proposed by L. Pauling and R. B. Corey [(1951) Proc. Natl. Acad. Sci. USA 37, 251-256]. In all ␤-sheet proteins, transthyretin and ␤2-microglobulin, ␣-pleated sheet structure formed over the strands that are highly protected in hydrogen-exchange experiments probing amyloidogenic conditions. In lysozyme and the prion protein, ␣-sheets formed in the specific regions of the protein implicated in the amyloidogenic conversion. We propose that the formation of ␣-pleated sheet structure may be a common conformational transition in amyloidosis.

Potentially amyloidogenic conformational intermediates populate the unfolding landscape of transthyretin: Insights from molecular dynamics simulations

“…Employing classical and geometry-based methods as well as several property-fluctuation analyses and cluster analysis, we shed new light on the molecular mechanism of amyloidogenesis by TTR and extend the observations by other authors. [31][32][33][34] Our simulations corroborate experimental observations correlating the conformational stability of monomeric TTR species and their amyloidogenic potential, 8 and highlight some of the amino acid residues that may have a relevant role in the early stages of amyloid formation. Additionally, our simulations allow the identification of unfolding events leading to aggregationprone intermediates, and thus allow the discrimination between amyloidogenic and nonamyloidogenic behavior.…”

Characterization of a possible amyloidogenic precursor in glutamine-repeat neurodegenerative diseases

“…In the ␤-sheet protein transthyretin (TTR), the ␣-sheet formed over the strands that are highly protected in hydrogen-exchange experiments probing amyloidogenic conditions (7). In lysozyme and the prion protein, ␣-sheets formed in the specific regions of the protein that are implicated in the amyloidogenic conversion (8). Given that amyloidogenic proteins of diverse sequences can form amyloid fibrils of similar architecture, there may be some common structural elements of the prefibrillar amyloidogenic intermediate.…”

Prion and water: Tight and dynamical hydration sites have a key role in structural stability

“…MD calculations have also been used to estimate the effects of water binding on protein flexibility (19). Although a number of MD studies have been carried out on the PrP, most of them have concentrated on modeling the structural processes leading to the scrapie PrP (PrP Sc ) form, for which limited structural data are available (6,(20)(21)(22).…”