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 can be 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 yield the observed conformational difference, molecular dynamics simulations of β₂M were performed. The effects of pH were modeled by specifying the protonation states of Asp, Glu, and His, as well as the C 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, low pH may stabilize the straight conformation of edge strand D and thus increase the amyloidogenicity of β₂M. Published by Cold Spring Harbor Laboratory Press.