Multiscale Molecular Dynamics Simulations of Amyloidogenic Protein Binding and Folding on Lipid Rafts*

Amyloidogenic proteins, e.g., beta-amyloid, are a class of proteins that do not have a fixed three-dimensional structure. These proteins rapidly aggregate in solution and on membrane surfaces.  At present, very little is known about the binding behaviors and disordered-to-ordered transition of amyloidogenic protein aggregates on phase-separated lipid nanodomains, which mimic the structures of biological membranes. Using multiscale (atomistic and coarse-grained) simulations, we explore the structure, dynamics, and energetics of beta-amyloid aggregates of various sizes on highly dynamic and heterogeneous lipid nanodomains, or lipid rafts, at microsecond timescales with atomistic resolution. Our lipid rafts are composed of phase-separated cholesterol-enriched liquid-ordered (Lo) domains surrounded by liquid-disordered (Ld) regions. We are interested in the preference of beta-amyloid binding to the Lo, Ld, or Lo/Ld interfacial domain, and the subsequent surface-induced templated folding of protein on nanostructured surfaces. This work will allow us to have a better understanding of the physics of protein interactions and folding on nanostructured surfaces, and propose new protein structures for future anti-aggregation drug development to treat amyloid diseases.