CAREER: Atomic resolution modeling of proteoglycans

University Of New England, Biddeford ME

Investigators

Abstract

Proteoglycans are a major part of the biological "glue" that holds cells together in many different animals and in people. Proteoglycans also help cells to sense what is going on outside of them. Because proteoglycans are very flexible and difficult to isolate as pure samples, their structure has been difficult to study using regular experiments. Therefore, this project will apply cutting-edge physics-based computer modeling to proteoglycans. As a result, this project will increase the understanding of the normal growth and development of humans and many other animals. During the project, twelve early university students will be exposed to career paths in science, an advanced university student will receive both research and educational training, five elementary school teachers will receive training in modern computer tools for teaching science, and 500 fourth and fifth grade students from a diverse range of ethnicities and socio-economic backgrounds will receive enriched science teaching and interact with university students studying science. The specific scientific goals of the project are to: (1) develop a high-precision public database of the conformational free energies for all carbohydrates found in proteoglycans to facilitate computer modeling; (2) understand the dynamics and thermodynamics of carbohydrate polymers and the non-covalent interactions between pairs of carbohydrate polymers as relevant to proteoglycans; and (3) transform the extracellular proteoglycan biglycan, the membrane-anchored glypican proteoglycan Dally-like, and fragments of the matrix proteoglycans aggrecan and versican into research platforms that reveal how interactions between protein, carbohydrate, ion, and lipid components affect the structure and dynamics, and therefore functions, of proteoglycans. Standard unbiased molecular dynamics simulations and enhanced sampling and free-energy methods including replica exchange molecular dynamics and Adaptive Biasing Force molecular dynamics will be used to meet these scientific goals, thereby contributing to an area where advancement has been hindered because of limitations in experimental approaches.