Collaborative Research: Dynamics of surfactant - amyloid beta protein interactions during self-assembly

蛋白质分子在“聚集”过程中的结块是细胞生物学中的一个常见问题。一种蛋白质聚集导致了一种叫做“淀粉样蛋白”的特殊结构的团块，被认为在包括阿尔茨海默病在内的许多神经退行性疾病中起着关键作用。最近，淀粉样蛋白也与正常的细胞功能有关。在聚集过程中形成各种各样的聚集体结构，其中许多会引起特定的生物反应。因此，了解聚集机制对人类健康至关重要。淀粉样蛋白的形成受到生物表面活性剂分子的影响，这些分子与许多淀粉样蛋白相关。在拟议的项目中，首席研究员将与一组合作者一起使用实验、计算机模拟和数学分析来了解表面活性剂如何调节淀粉样蛋白聚集，形成特定的聚集体。这将改变我们对这些在阿尔茨海默病中起作用的相互作用的理解。这项科学努力也将涉及许多学生，他们不仅将学习新的研究领域，而且还将为数据收集和结果解释做出贡献。与阿尔茨海默病有关的一种叫做淀粉样蛋白的蛋白质的自我结合，包括从其本质上无序的单体形式转变为以核依赖的方式组织良好的纤维状结构。在形成的聚集体中，低分子量低聚物已成为生理上重要的物种。形成的低聚物不一定是原纤维形成途径的专性中间体，它们可以沿着交替的“非通路”形成，这导致许多不同结构的β淀粉样蛋白菌株。许多因素都可以诱发非通路产物。在这些因素中，由生物表面活性剂（SAs）产生的界面由于其与淀粉样蛋白的永久关联而具有生理学相关性。最近来自主要研究者实验室的发现表明，非酯化脂肪酸SAs以浓度依赖的方式诱导通路外或通路上的聚集体。研究人员假设sa的浓度依赖性相变调节淀粉样蛋白聚集途径以产生不同的低聚物。在这项工作中，一个合作团队将用两个特定的目标来验证这一假设：Aim 1将使用各种阴离子sa研究β -淀粉样蛋白和sa之间的生物物理相互作用，Aim 2将使用数值模拟和降阶数学分析来模拟β - sa相互作用导致的低聚物的时间进化。一种涉及实验生物物理学、模拟和数学分析的跨学科方法，在实验（目标1）和模拟（目标2）之间提供协同反馈，将提供对β淀粉样蛋白和SAs之间异型相互作用的见解，并将弥合该领域现有的知识差距。考虑到非通路聚集体的功能作用与其各自的形态有关，了解淀粉样蛋白β - sa相互作用的理化性质将对破译淀粉样蛋白相关的细胞过程具有至关重要的意义。这项工作还将有助于更好地理解涉及淀粉样蛋白的更大、更复杂的反应网络中的聚集途径，从而可以在未来用于设计干预策略。拟议的项目将对来自南密西西比大学（USM）、弗吉尼亚联邦大学（VCU）和蒙特克莱尔州立大学（MSU）三所大学的本科生和研究生的科学和教育产生更广泛的影响，分别跨越分子生物物理学、计算系统生物学和数学生物学领域。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Clumping of protein molecules in a process called "aggregation" is a common problem in cellular biology. One kind of protein aggregation leads to a specific structure of the clumps called "amyloids" and is thought to play a key role in many neurodegenerative diseases including Alzheimer's disease. Recently, protein amyloids have also been associated with normal cellular functions. A wide variety of aggregate structures are formed during aggregation, and many of these cause a specific biological response. Hence, understanding the mechanisms of aggregation is critical for human health. Amyloid formation is influenced by biological surfactant molecules, which associate many amyloid proteins. In the proposed project, the principal investigator along with a team of collaborators will use experiments, computer simulations, and mathematical analysis to understand how surfactants modulate amyloid protein aggregation to form specific aggregate species. This will transform our understanding of these interactions which play a role in Alzheimer's disease. This scientific endeavor will also involve many students, who will not only learn new areas of research but will also contribute towards data collection and interpretation of results.Self-association of a protein called amyloid beta, associated with Alzheimer's disease, involves the conversion from its intrinsically disordered, monomeric form to well-organized, fibrillar structures in a nucleation-dependent manner. Among the aggregates formed, the low-molecular weight oligomers have emerged to be physiologically important species. The oligomers formed need not be the obligate intermediates of the fibril formation pathway, and they could be formed along alternate "off-pathways", which result in many distinct structural strains of amyloid beta. Many factors can induce off-pathway products. Among these factors, interfaces generated by biological surfactants (SAs) are physiologically relevant due to their perpetual association with amyloid beta. Recent findings from the principle investigator's lab indicate that non-esterified fatty acid SAs induce off- or on- pathway aggregates in a concentration dependent manner. The investigators hypothesize that concentration-dependent phase transitions of SAs modulate amyloid beta aggregation pathways to generate distinct oligomers. In this work, a collaborative team will test the hypothesis with two specific aims: Aim 1 will investigate biophysically the interactions between amyloid beta and SAs using a variety of anionic SAs, and Aim 2 will model temporal evolution of oligomers as a result of amyloid beta-SA interactions using numerical simulations and reduced order mathematical analysis. An interdisciplinary approach involving experimental biophysics, simulation and mathematical analysis with a synergistic feedback between the experiments (Aim 1) and simulations (Aim 2) will provide insights into the heterotypic interactions between amyloid beta and SAs and will bridge the existing knowledge gap in the field. Considering that the functional effects of off-pathway aggregates are related to their respective morphologies, understanding the physiochemical properties of amyloid beta-SA interactions will be of paramount significance in deciphering amyloid-related cellular processes. This work will also help in a better understanding of aggregation pathways in a larger, more complex network of reactions involving amyloids, which can then be utilized to design intervention strategies in the future. The proposed project will have broader impacts on science and education for undergraduate and graduate students from the three institutions of University of Southern Mississippi (USM), Virginia Commonwealth University (VCU), and Montclair State University (MSU) spanning the areas of molecular biophysics, computational systems biology and mathematical biology respectively.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.