Molecular Dynamics Study of Fragmentation in Protofilaments of Amyloid Beta (16-42)
- Author(s): Tabatabaie-Raissi, Omid
- Advisor(s): Lu, Yunfeng
- et al.
Through the use of molecular dynamics simulations, we show that fragmentation of amyloid beta (16-42) protofilaments occurs through the formation of water-conducting glycine vents surrounding the inner pore which then propagate under the increased stress due to C-terminal wrapping. We find that longer protofilaments have an increased propensity to fracture and that the stress-induced propagation of glycine vents is alleviated by thickening of the protofilament to cover exposed hydrophobic residues and reduce C-terminal wrapping. Moreover, we propose that the intrinsic flexibility of glycine-29 in the loop region plays a critical role in the fragmentation of protofilaments. We support this hypothesis by conducting a 1 ns MD simulation on a G29P-mutated 20-mer protofilament. Our results indicate that the increased rigidity of the loop region due to the proline mutation forces the C-terminal to wrap in the opposite direction and therefore prevents the opening of glycine vents, effectively inhibiting fragmentation.