Self-association of beta-amyloid peptide (1-40) in solution and binding to lipid membranes.

The beta-amyloid peptide (beta AP), a 39 to 43 residue peptide, is the major component of Alzheimer plaques. Using circular dichroism spectroscopy, titration calorimetry, and analytical ultracentrifugation we have analyzed the self-association of beta AP(1-40) in aqueous solution and the binding of beta AP(1-40) to negatively charged lipid vesicles. The CD spectra of both aggregation and membrane binding are characterized by an isodichroic point at 212 nm, indicating a simple two-state equilibrium for both cases. In aqueous solution beta AP(1-40) exhibits a reversible, concentration-dependent random coil<-->beta-structure transition which can be described by a cooperative aggregation model with an association constant of s = 1.05 x 10(4)M-1 and a nucleation parameter of sigma = 0.012. A similar conformational change is observed upon addition of lipid. At a given peptide concentration, the addition of negatively charged, small unilamellar vesicles also induces a conformational change from a random coil conformation to a conformation with 40 to 60% beta-structure. The binding isotherm can be measured with high sensitivity titration calorimetry. It is approximately linear in the initial binding phase and exhibits an apparent saturation behaviour. The apparent binding constant decreases with concentration from Kapp approximately 2100 M-1 at low concentration to 700 M-1 at the highest concentration measured. Peptide penetration into the lipid membrane and peptide aggregation at the membrane surface are proposed as possible mechanisms to explain the lipid-induced random coil<-->beta-structure transition.