Molecular dynamics simulations of the unfolding of β2‐microglobulin and its variants

In this study, we examined the unfolding processes of native β2‐microglobulin and two related variants, one with an N‐terminal hexapeptide deletion ΔN6 and another with Lys57–Asp58 cleavage, by high‐temperature molecular dynamics simulations. Three simulation models were used, molecular dynamics (MD) simulations with explicit water solvation, MD simulations with the CHARMM EEF1 force field and Langevin dynamics with the CHARMM EEF1 force field. Our simulations reproduce many of the experimentally observed structural changes. The most striking agreement is in the β‐strands to α‐helix transition. In our simulations, strands β3, β4 and β5 consistently change to α‐helix, whereas β8 changes to an α‐helix only briefly. Through comparisons of the conformational behavior of the native, the ΔN6 and the Lys‐cut β2‐m, using the three simulation methods, we identified the consensus conformational changes that differentiate between the native β2‐m and its two variants. We found that the main effect of the removal of the N‐terminal hexapeptide is to increase the separation between strands β2 and β6 and to facilitate the β to α transition. On the other hand, the lysine cleavage only increases the flexibility of strand β5 and does not affect the interactions between strands β2 and β6. These conformational changes may relate to polymerization tendencies of these variants.