Molecular dynamics study of the monomers and dimers of N-AcAβ(13-23)NH2: on the effect of pH on the aggregation of the amyloid beta peptide of Alzheimer's disease

The region encompassed by residues 13-23 of the amyloid beta peptide (A beta(13-23)) of Alzheimer's disease is the self-recognition site that initiates toxic oligomerization and fibrillization and also is the site of interaction of A beta with many other proteins. We describe herein a study by molecular dynamics of N-AcA beta(13-23)NH2 (N-CH3C(O) HHQKLVFFAEDNH(2)) as a model of full-length A beta(1-40) or A beta(1-42) and of its dimers. The effect of pH at or below physiological (pH 7.4) is assessed by protonation of one or more of the His residues. The major conformation of the monomer of the systems is a flexible folded structure. Protonation of one or both His residues does not change the conformation in any significant way. The dimers of protonated and unprotonated systems exist almost exclusively as stable antiparallel beta-sheets anchored at both ends by intermolecular salt bridges between Lys(16) of one chain and the C-terminal residues Glu(22) and Asp(23) of the other. We also employ the technique of "umbrella sampling" whereby relative binding affinities of the complexes could be determined. In the case of unsymmetrically protonated species, each complex begins dissociation by releasing the weaker salt bridge, breaking interstrand hydrogen bonds, and losing the beta-sheet character. The stronger salt bridge is the last to release and presumably is the first to form in the reverse process of aggregation. Umbrella sampling yields the free energy profiles of the dissociation as a function of the separation of the centres of mass. For each system, the dissociation profile has only a shallow maximum. By implication, the reverse process of assembly has almost no barrier. This is an example of entropy-enthalpy compensation that arises naturally during the molecular dynamics - umbrella sampling simulation.