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Simulation of pH‐dependent edge strand rearrangement in human β‐2 microglobulin

Amyloid fibrils formed from unrelated proteins often share morphological similarities, suggesting common biophysicalmechanisms 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.