Computer Simulations of Early Aggregation of Intrinsically Disordered Protein on Nano-Structured Surfaces at Different Spatial and Time Scales

Early aggregation of intrinsically disordered protein (IDP), e.g., beta-amyloid (Aß), on the surfaces of neurons is responsible for the progression of Alzheimer's. However, the molecular details of forming toxic and partially-ordered Aß aggregates on the surface of phase-separated lipid nanodomains, a model of neuronal membrane, are still not available. Using both atomistic and coarse-grained (CG) multiscale MD simulations, we explore early aggregation events of initially disordered Aß on multicomponent, phase-separated lipid membranes at different spatial resolutions and microsecond time scales. Our lipid membranes consist of highly dynamic and heterogeneous liquid-ordered (Lo), liquid-disordered (Ld), and mixed Lo/Ld nano-domains. Our work involves forward (atomistic-to-CG) and backward (CG-atomistic) mappings of protein/membrane complexes, as well as, domain preference of protein binding, characterizations of the domain size, area per lipid, and bilayer thickness of the lipid nano-domains at both atomistic and CG resolutions. Our results will provide new insights into understanding the molecular interactions of IDP on nanostructured surfaces, and protein-induced membrane disruption mechanisms of Aß on neurons leading to the early progression of Alzheimer's disease.