Microsecond Coarse-Grained MD Simulations of Beta-Amyloid Fibrils Binding to Phase Separated Lipid Raft Domains Reveal Diverse Membrane-bounded Conformations and Binding Kinetics of Protein Depending on the Fibril size and Lipid Domain Structure

An early event associated with several protein aggregation diseases is the binding of amyloidogenic fibrils to cell membranes. At present, the binding conformation and kinetics of these fibrils on structurally heterogeneous and dynamic cholesterol-enriched raft domains remain elusive. We have constructed 4 coarse-grained (CG) beta-amyloid fibrils, ranging from dimer to pentamer, and 5 phase-separated CG lipid rafts, containing phospholipid and cholesterol or tail- or headgroup modified cholesterol. Using CG-MD simulations, the binding conformation, kinetics and interaction energetics of each fibril from solution to the rafts were studied. Within 20 μs, all fibrils bound to the raft surface and formed stable fibril/raft complexes at the liquid-ordered and -disordered phase boundary. The dimer fibrils bound to the raft exclusively via its hydrophobic C-terminal (C-state). Other than the C-state, the larger fibrils bound to the rafts via the hydrophilic N-terminal (N-state) and termini (T-state) with weaker binding energies. Interestingly, a transmembrane inserted state (I-state) of a trimer fibril was found for the raft containing tailgroup modified cholesterol. Our study indicates diverse conformations, kinetics and energetics of fibril/raft interactions in cells.