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

University Of Maryland, College Park, College Park MD

Investigators

Abstract

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.