Molecular determinants of the interaction between the C-terminal domain ofAlzheimer's beta-amyloid peptide and apolipoprotein E alpha-helices

In a previous work, we predicted and demonstrated that the 29-42-residue fr agment of beta-amyloid peptide (A beta peptide) has in vitro capacities clo se to those of the tilted fragment of viral fusion proteins. We further dem onstrated that apolipoprotein E2 and E3 but not apolipoprotein E4 can decre ase the fusogenic activity of A beta(29-42) via a direct interaction. There fore, we suggested that this fragment is implicated in the neurotoxicity of A beta and in the protective effects of apolipoprotein E in Alzheimer's di sease. Because structurally related apolipoproteins do not interact with th e A beta C-terminal domain but inhibit viral fusion, we suggested that inte ractions existing between fusogenic peptides and apolipoproteins are select ive and responsible for the inhibition of fusion, In this study, we simulat ed interactions of all amphipathic helices of apolipoproteins E and A-1 wit h A beta and simian immunodeficiency virus (SIV) fusogenic fragments by mol ecular modeling. We further calculated cross-interactions that do not inhib it fusion in vitro. The results suggest that interactions of hydrophobic re sidues are the major event to inhibit the fusogenic capacities of A beta(29 -42) and SIV peptides. Selectivity of those interactions is due to the ster ic complementarity between bulky hydrophobic residues in the fusogenic frag ments and hydrophobic residues in the apolipoprotein C-terminal amphipathic helices.