pH effects on the conformational preferences of amyloid β-peptide (1-40) in HFIP aqueous solution by NMR spectroscopy

The structure and aggregation state of amyloid beta-peptide (A beta) in membrane-like environments ore important determinants of pathological events in Alzheimer's disease. In fact, the neurotoxic nature of amyloid-forming peptides and proteins is associated with specific conformational transitions proximal to the membrane. Under certain conditions, the A beta peptide undergoes a conformational change that brings the peptide in solution to a competent state for aggregation. Conversion can be obtained at medium pH (5.0-6.0), and in vivo this appears to take place in the endocytic pathway. The combined use of H-1 NMR spectroscopy and molecular dynamics-simulated annealing calculations in aqueous hexafluoroisoproponol simulating the membrane environment, at different pH conditions, enabled us to get some insights into the aggregation process of A beta, confirming our previous hypotheses of a relationship between conformational flexibility and aggregation propensity. The conformational space of the peptide was explored by means of an innovative use of principal component analysis as applied to residue-by-residue root-mean-square deviations values from a reference structure. This procedure allowed us to identify the aggregation-prone regions of the peptide.