Locking pathway for docked state D2 in Abeta fibril elongation

This video shows a reconstructed locking pathway of a monomer of Aβ1-42 docking to a protofibrillar end represented by four other chains. This structure is taken from the solution NMR structure derive by Riek's lab. The reconstruction relies on a network (Markov model) analysis of a set of simulations generated by the progress index-guided sampling (PIGS) method, and the overall process happens on a high microsecond time scale. The construction is geometrically continuous but not kinetically authentic. The indicated values refer to the so-called committor probabilities toward the locked (fibrillar) state, which are the probabilities that a randomly initiated trajectory initiated at a given point will reach the locked state before it recurs to the docked starting state. Here, we show the video for one of the three analyzed docked states (D2).

In detail, by tracing back the PIGS reseeding history, we extracted a geometrically continuous, time-reversed trajectory converting D2 to the fibrillary state (~30 ns). The movie shows a view of the odd end (left) with hydrophobic residues as either sticks (top) or smooth surface (bottom). In addition, angled top and bottom views of the β2- and β1-side of the pentamer (right) are provided in surface representation. Coloring is by chain with chain A in blue. Visualization was done with VMD and the Tachyon ray tracer. Perspective rendering with a depth-of-field effect and shadows is meant to enhance depth perception. Trajectory jitter was removed with a smoothing window of 40 ps applied to a saving frequency of 2 ps.