Computational Studies on the Modulation of Peptide-lipid Interactions by Glycosaminoglycans

在化学部生命过程化学(CLP)项目的支持下，马里兰大学的Silvina Matysiak将在模拟细胞外基质的环境中研究促进或阻碍淀粉样蛋白形成的分子条件。细胞外基质是由蛋白质和碳水化合物组成的复杂网状结构，它与周围的细胞相连，将它们聚集在一起形成组织。淀粉样蛋白是蛋白质沉积/聚集体。淀粉样蛋白的形成是许多正常生物过程和神经退行性疾病(如阿尔茨海默病)的关键因素。科学界已经认识到碳水化合物和细胞膜表面在调节淀粉样蛋白形成中的重要性。然而，分离和量化特定的分子间相互作用如何影响或成核特定的淀粉样蛋白聚集态的形成一直是具有挑战性的。这项拟议中的研究将利用和扩展马蒂夏克博士实验室过去几年开发的计算模型，这些模型现在可以让马蒂夏克团队继续进行这类研究。这项研究还将允许研究生和本科生获得多尺度计算建模方面的专门培训。新的计算模型将用于基于课程的本科生研究经验(CURE)方法的计算建模课程的重新设计。该研究项目试图通过使用粗粒度和原子性模型来表征糖胺聚糖(GAG)在多肽-膜相互作用和多肽聚集中的作用。我们将在不同的条件下研究几种淀粉样多肽(功能性或毒性)的聚集情况。在不同组成和不同特定多糖结构存在的情况下，逐步研究不同组成的混合双层将有助于马里兰团队确定哪些相互作用可以增强或抑制多肽的折叠/误折叠和聚集。来自这项研究的信息有望为肽-脂、肽-寡糖和寡糖-脂相互作用如何调节特定淀粉样肽聚集形态的出现以及这些聚集过程的动力学提供新的见解。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemistry of Life Processes (CLP) program in the Chemistry Division, Silvina Matysiak from the University of Maryland will investigate the molecular conditions that promote or impede amyloid formation in an environment mimicking the extracellular matrix. The extracellular matrix is a complex mesh of proteins and carbohydrates, and it is connected to the cells it surrounds, holding them together to form a tissue. Amyloids are proteinaceous deposits/aggregates. Amyloid formation is a critical factor in many normal biological processes and in neurodegenerative diseases, such as Alzheimer's disease. The importance of carbohydrates and the surface of cell membranes in modulating amyloid formation have been recognized by the scientific community. However, it has been challenging to isolate and quantify how specific intermolecular interactions influence or nucleate the formation of particular amyloid aggregation states. The proposed research will exploit and extend computational models, developed over the last few years in Dr. Matysiak’s lab, that now enable the Matysiak group to pursue this type of research. This research will also allow graduate and undergraduate students to acquire specialized training in multiscale computational modeling. The new computational models will be used in the redesigning of a computational modeling course using a course-based undergraduate research experience (CURE) approach.This research project seeks to characterize the effects of glycosaminoglycans (GAGs) in peptide-membrane interactions and peptide aggregation by the usage of coarse-grained and atomistic models. The aggregation of several amyloidogenic peptides (functional or toxic) will be studied under various conditions. Stepping through mixed bilayers of different compositions and in the presence of different specific polysaccharide structures will help the Maryland team to ascertain what interactions can enhance or suppress peptide folding/misfolding and aggregation. Information from this study is expected to provide new insight into how peptide-lipid, peptide-oligosaccharide, and oligosaccharide-lipid interactions tune the emergence of specific amyloid peptide aggregation morphologies and into the kinetics of these aggregation processes.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.