Pathways and interactions accounting for the oligomerization of amyloid peptides

淀粉样肽寡聚化的途径和相互作用

• 批准号: 10804128
• 负责人: Cristiano Luis Dias
• 金额: $ 6.38万
• 依托单位: NEW JERSEY INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10804128
• 关键词: Accounting; Address; Affect; Alzheimer' s Disease; Amino Acid Sequence; Amyloid; Amyloid Fibrils; Amyloid Proteins; Amyloid beta-Protein; Amyloidosis; Binding; Biochemical; Biophysics; Brain; Cell membrane; Chemistry; Comparative Study; Complement; Computer Simulation; Computers; Development; Disease; Drug Design; Event; FDA approved; Goals; Group Meetings; Individual; Kinetics; Knowledge; Length; Light; Lipids; Membrane Lipids; Methods; Mutate; Neurodegenerative Disorders; Neurofibrillary Tangles; Parkinson Disease; Pathway interactions; Patients; Peptides; Performance; Pharmaceutical Preparations; Positioning Attribute; Preventive treatment; Process; Research; Research Project Grants; Running; Senile Plaques; Solvents; Surface; Testing; Time; Toxic effect; Translating; Universities; abeta oligomer; amyloid peptide; biophysical chemistry; cost; experimental study; improved; innovation; insight; interest; molecular dynamics; monomer; peptide A; prevent; protein aminoacid sequence; rational design; simulation; supercomputer; tau Proteins; temporal measurement; undergraduate student

The aggregation of amyloid peptides into soluble oligomers and fibrils is a hallmark of Alzheimer’s disease. The interaction of these aggregates with the cell membrane accounts for an important mechanism of toxicity wherein oligomers can form pores in lipid membranes and amyloid fibrils can induce lipid loss. As monomers, i.e., individual peptides, have been found to be mostly nontoxic, the development of strategies to inhibit aggregation has the potential to translate into the development of new preventive treatments for Alzheimer’s disease. These efforts require, however, a deep understanding of the interactions accounting for amyloid aggregation. Previously, the aggregation of peptides in bulk solution, i.e., primary nucleation, was assumed to be the main mechanism accounting for the formation of oligomers. More recently, this assumption was reassessed by careful kinetic experiments, which can only be explained quantitatively assuming that most oligomers form on the surface of existing fibrils in a process known as secondary nucleation. Currently, there is a critical lack of understanding of the molecular interactions and pathways accounting for secondary nucleation. This remains a serious impediment for the rational design of drugs that can inhibit oligomerization on the fibril surface. This proposal uses innovative all-atom molecular dynamics simulations complemented with biophysical and biochemical experiments to fill this knowledge gap. It takes advantage of improvements in the development of force fields as well as in the enhanced performance of today’s supercomputers that can now track the position of many atoms (~250,000 atoms) for a long-time (>10 μs). Moreover, this project provides opportunities for undergraduate students to participate in all aspects of this research including setting up, running, and analyzing simulations in different supercomputer clusters. All-atom simulations will be used in aim 1 of this project to determine how the peptide sequence affects pathways and interactions accounting for oligomerization in bulk solution. Simulations in aims 2 and 3 will be performed in large boxes containing a seeded fibril. In aim 2, a systematic study will be carried out to shed light into effects of the fibril surface and the peptide sequence on fibril elongation. Oligomerization pathways at the fibril surface, i.e., secondary nucleation, will be studied in aim 3. A comparative study of oligomerization pathways in primary and secondary nucleation will be performed to determine the interactions enabling the fibril surface to catalyze the aggregation process.

淀粉样多肽聚集成可溶低聚物和纤维是阿尔茨海默氏症的一个特征 疾病。这些聚集体与细胞膜的相互作用是一个重要的 低聚物可在脂膜中形成毛孔，淀粉样纤维可 导致脂肪流失。由于单体，即单个多肽已被发现大多无毒，因此 制定抑制聚集的战略有可能转化为发展 阿尔茨海默病的新预防疗法。然而，这些努力需要深入的 了解淀粉样蛋白聚集的相互作用。 以前，多肽在本体溶液中的聚集，即一次成核，被认为是 低聚物形成的主要机理。最近，这一假设是 通过仔细的动力学实验重新评估，这只能定量地假设 大多数低聚物在现有纤维的表面形成，这一过程被称为二次成核。 目前，对分子相互作用和通路核算的理解严重不足。 用于二次成核。这仍然严重阻碍了合理设计能够 抑制原纤维表面的齐聚。这项提议使用了创新的全原子分子动力学。 模拟与生物物理和生化实验相辅相成，以填补这一知识空白。它 利用力场发展方面的改进以及在增强的 今天的超级计算机的性能，现在可以跟踪许多原子的位置(~250,000 原子)很长时间(&gt；10μS)。此外，该项目还为本科生提供了机会 学生参与本研究的方方面面，包括建立、运行和分析 在不同的超级计算机集群中进行模拟。 在本项目的目标1中，将使用全原子模拟来确定多肽序列如何影响 本体溶液中齐聚反应的途径和相互作用。AIMS 2和3中的仿真 将在包含种子原纤维的大盒子中进行。在目标2中，将进行系统研究 揭示了纤维表面和多肽序列对纤维伸长的影响。 目标3将研究纤维表面的齐聚途径，即二次成核。 将对一次成核和二次成核中的齐聚途径进行比较研究 以确定使纤维表面能够催化聚集过程的相互作用。