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Energetics and mechanism of the normal-to-amyloidogenic isomerization of β2-microglobulin: on-the-fly string method calculations.

We use on-the-fly finite temperature string method in collective variables to study the transition from a normal to an amyloidogenic conformation of β2-microglobulin. We show that the protonation state of two histidine residues is of key importance and that under acidic (protonating) conditions, the transition to the amyloidgenic form is facilitated by both displacement of N-terminal residues to disrupt a hydrophobic pocket and by side-chain/side-chain electrostatic attraction, both of which facilitate a cis-trans prolyl isomerization. The free energy barriers for the normal-to-amyloidogenic isomerization are found to be 14.9 and 7.1 kcal/mol for the neutral and protonated cases, respectively, consistent with enhanced amyloidgenesis at low pH observed both in vitro and in hemodialysis-associated amyloidosis, and somewhat lower than experimentally determined barriers for bare prolyl cis-trans isomerization. We suggest specific mutagenesis experiments which could be used to further validate the mechanism observed.