The F19W mutation reduces the binding affinity of the transmembrane Aβ11-40 trimer to the membrane bilayer

Alzheimer's disease is linked to the aggregation of the amyloid-beta protein (A beta) of 40 or 42 amino acids. Lipid membranes are known to modulate the rate and mechanisms of the A beta aggregation. Point mutations in A beta can alter these rates and mechanisms. In particular, experiments show that F19 mutations influence the aggregation rate, but maintain the fibril structures. Here, we used molecular dynamics simulations to examine the effect of the F19W mutation in the 3A beta(11-40) trimer immersed in DPPC lipid bilayers submerged in aqueous solution. Substituting Phe by its closest (non-polar) aromatic amino acid Trp has a dramatic reduction in binding affinity to the phospholipid membrane (measured with respect to the solvated protein) compared to the wild type: the binding free energy of the protein-DPPC lipid bilayer increases by 40-50 kcal mol(-1) over the wild-type. This is accompanied by conformational changes and loss of salt bridges, as well as a more complex free energy surface, all indicative of a more flexible and less stable mutated trimer. These results suggest that the impact of mutations can be assessed, at least partially, by evaluating the interaction of the mutated peptides with the lipid membranes.

Automated summary

Alzheimer's disease is associated with the aggregation of Aβ protein of 40 or 42 amino acids, with point mutations affecting the aggregation rate and mechanism. F19 mutations have been shown to impact aggregation rate while maintaining fibril structures. Substituting Phe with Trp leads to reduced binding affinity to lipid membranes and more flexible and less stable trimer structures.