Early-stage human islet amyloid polypeptide aggregation [electronic resource] : Mechanisms behind dimer formation

• Ngôn ngữ: eng
• Ký hiệu phân loại: 576.8 Evolution
• Thông tin xuất bản: Arlington, Va. : Oak Ridge, Tenn. : National Science Foundation (U.S.) ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2018
• Mô tả vật lý: Size: Article No. 025101 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260193
• Chủ đề: 1. 59 basic biological sciences; 2. 60 applied life sciences

Tóm tắt

Amyloid aggregates of human islet amyloid polypeptide (hIAPP or human amylin) have long been implicated in the development of type II diabetes. While hIAPP is known to aggregate into amyloid fibrils, it is the early-stage prefibrillar species that have been proposed to be cytotoxic. A detailed picture of the early-stage aggregation process and relevant intermediates would be valuable in the development of effective therapeutics. Here, we use atomistic molecular dynamics simulations with a combination of enhanced sampling methods to examine the formation of the hIAPP dimer in water. Bias-exchange metadynamics calculations reveal relative conformational stabilities of the hIAPP dimer. Finite temperature string method calculations identify pathways for dimer formation, along with relevant free energy barriers and intermediate structures. We show that the initial stages of dimerization involve crossing a substantial free energy barrier to form an intermediate structure exhibiting transient beta-sheet character, before proceeding to form an entropically stabilized dimer structure.