期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：32
页码：11622-11627
DOI：10.1073/pnas.0401781101
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Transthyretin, {beta}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 {alpha}-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 {beta}-sheet proteins, transthyretin and {beta}2-microglobulin, {alpha}-pleated sheet structure formed over the strands that are highly protected in hydrogen-exchange experiments probing amyloidogenic conditions. In lysozyme and the prion protein, {alpha}-sheets formed in the specific regions of the protein implicated in the amyloidogenic conversion. We propose that the formation of {alpha}-pleated sheet structure may be a common conformational transition in amyloidosis.
