Fibril elongation by A?(17-42): kinetic network analysis of hybrid-resolution molecular dynamics simulations.

ABSTRACT: A critical step of ?-amyloid fibril formation is fibril elongation in which amyloid-? monomers undergo structural transitions to fibrillar structures upon their binding to fibril tips. The atomic detail of the structural transitions remains poorly understood. Computational characterization of the structural transitions is limited so far to short A? segments (5-10 aa) owing to the long time scale of A? fibril elongation. To overcome the computational time scale limit, we combined a hybrid-resolution model with umbrella sampling and replica exchange molecular dynamics and performed altogether ?1.3 ms of molecular dynamics simulations of fibril elongation for A?17-42. Kinetic network analysis of biased simulations resulted in a kinetic model that encompasses all A? segments essential for fibril formation. The model not only reproduces key properties of fibril elongation measured in experiments, including A? binding affinity, activation enthalpy of A? structural transitions and a large time scale gap (?lock/?dock = 10(3)-10(4)) between A? binding and its structural transitions, but also reveals detailed pathways involving structural transitions not seen before, namely, fibril formation both in hydrophobic regions L17-A21 and G37-A42 preceding fibril formation in hydrophilic region E22-A30. Moreover, the model identifies as important kinetic intermediates strand-loop-strand (SLS) structures of A? monomers, long suspected to be related to fibril elongation. The kinetic model suggests further that fibril elongation arises faster at the fibril tip with exposed L17-A21, rather than at the other tip, explaining thereby unidirectional fibril growth observed previously in experiments.

SUBMITTER: Han W 

PROVIDER: S-EPMC4156860 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature