(311e) Simulation of pH-Dependent Edge Strand Rearrangement in Human Β-2 Microglobulin

Amyloid fibrils formed from unrelated proteins often share morphological similarities, suggesting common biophysical mechanisms for amyloidogenesis. Biochemical studies of human β-2 microglobulin (β₂M) have shown that its transition from a water-soluble protein to insoluble aggregates is triggered by low pH. Additionally, biophysical measurements of β₂M using NMR have identified residues of the protein that participate in the formation of amyloid fibrils. The crystal structure of monomeric human β₂M determined at pH 5.7 shows that one of its edge β-strands (strand D) adopts a conformation that differs from other structures of the same protein obtained at higher pH. This alternate β-strand arrangement lacks a β-bulge, which may facilitate protein aggregation through intermolecular β-sheet association. To explore whether the pH change may account for the observed conformational difference, molecular dynamics simulations of β₂M were performed. The effect of pH were modeled by specifying the protonation states of Asp, Glu, and His as well as the carboxy terminus of the main chain. The bulged conformation of strand D is preferred at medium pH (pH = 5 ? 7), whereas at low pH (pH < 4) the straight conformation is observed. Therefore, lowering pH may stabilize the straight conformation of edge strand D and thus increase the amyloidogenicity of β₂M.