Amyloid Properties of Asparagine and Glutamine in Prion-like Proteins

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• 作者：Yuan Zhang ; Viet Hoang Man ; Christopher Roland ; Celeste Sagui
• 刊名：ACS Chemical Neuroscience
• 出版年：2016
• 出版时间：May 18, 2016
• 年：2016
• 卷：7
• 期：5
• 页码：576-587
• 全文大小：817K
• 年卷期：0
• ISSN：1948-7193

文摘

Sequences rich in glutamine (Q) and asparagine (N) are intrinsically disordered in monomeric form, but can aggregate into highly ordered amyloids, as seen in Q/N-rich prion domains (PrDs). Amyloids are fibrillar protein aggregates rich in β-sheet structures that can self-propagate through protein-conformational chain reactions. Here, we present a comprehensive theoretical study of N/Q-rich peptides, including sequences found in the yeast Sup35 PrD, in parallel and antiparallel β-sheet aggregates, and probe via fully atomistic molecular dynamics simulations all their possible steric-zipper interfaces in order to determine their protofibril structure and their relative stability. Our results show that polyglutamine aggregates are more stable than polyasparagine aggregates. Enthalpic contributions to the free energy favor the formation of polyQ protofibrils, while entropic contributions favor the formation of polyN protofibrils. The considerably larger phase space that disordered polyQ must sample on its way to aggregation probably is at the root of the associated slower kinetics observed experimentally. When other amino acids are present, such as in the Sup35 PrD, their shorter side chains favor steric-zipper formation for N but not Q, as they preclude the in-register association of the long Q side chains.