Specific Binding of Cholesterol to the Amyloid Precursor Protein: Structure of the Complex and Driving Forces Characterized in Molecular Detail

C99 is the C-terminal membrane-bound fragment of the amyloid precursor protein that is cleaved by gamma-secretase to release A beta peptides, the hallmark of Alzheimers disease (AD). Specific interactions of C99 with cholesterol have been proposed to underlie the recognized role of cholesterol in promoting amyloidogenesis. By using molecular dynamics simulations, we studied cholesterol binding to C99 in a lipid bilayer. We determined the free-energy profile of binding and analyzed the structure of C99/cholesterol complexes in two low-energy binding modes. We also examined the complexation driving forces and found, unexpectedly, that the interactions between the GxxxG dimerization motif and the cholesterol ring system are not sufficient for binding and that further stabilization mediated by the C99 N-terminal domain is essential. Taken together, our results strongly support the view that C99 specifically binds cholesterol in the cell membrane; the detailed information on the structure and energetics of the complex may assist in the design of new anti-AD drugs.