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: 10580438
• 负责人: Cristiano Luis Dias
• 金额: $ 47.43万
• 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/10580438
• 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; Lead; 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; amyloid peptide; biophysical chemistry; cost; experimental study; innovation; insight; interest; molecular dynamics; monomer; peptide A; peptide B; 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.

淀粉样蛋白的聚集成固体寡聚和原纤维的聚集是阿尔茨海默氏症的标志 疾病。这些聚集体与细胞膜的相互作用是重要的 毒性机制，其中低聚物可以在脂质膜和淀粉样蛋白纤维中形成毛孔 诱导脂质损失。正如单体（即单个胡椒体）所发现的主要是无毒的， 制定抑制聚集的策略有可能转化为发展 阿尔茨海默氏病的新预防治疗。但是，这些努力需要深入 了解淀粉样蛋白聚集的相互作用。 以前，假定肽中肽在大量溶液中的聚集，即原代成核，假定为 解释寡聚物形成的主要机制。最近，这个假设是 通过仔细的动力学实验重新评估，只能在定量上说明，这只能假设 在称为二次核的过程中，大多数低聚物在现有原纤维表面形成。 目前，严重缺乏对分子相互作用和途径的了解 用于继发成核。对于可以合理设计的药物，这仍然是一个严重的障碍 抑制原纤维表面的寡聚。该建议使用创新的全原子分子动力学 通过生物物理和生化实验完成的模拟，以填补这一知识空白。 利用改进力场的发展以及增强的 当今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）长期（>10μs）。此外，该项目为本科提供了机会 学生参与这项研究的各个方面，包括建立，运行和分析 在不同的超级计算机簇中的仿真。 该项目的目标1将使用全原子模拟，以确定胡椒序列如何影响 途径和相互作用考虑了大量解决方案中的寡聚化。目标2和3中的模拟 将在包含种子原纤维的大盒子中进行。在AIM 2中，将进行系统的研究 将光散发到原纤维表面和辣椒序列对原纤维伸长的影响中。 原纤维表面的寡聚途径，即次级核，将在AIM 3中进行研究。 将进行初级和二级成核中寡聚途径的比较研究 确定使原纤维表面催化聚集过程的相互作用。