Molecular dynamics simulations of human α-lactalbumin: Changes to the structural and dynamical properties of the protein at low pH

Abstract

Two 700-ps molecular dynamics simulations of human α-lactalbumin have been compared. Both were initiated from an X-ray structure determined at pH 6.5. One simulation was designed to represent native conditions and the other the protein in solution at pH 2.0 without a bound calcium ion. The low pH conditions were modelled by protonating the aspartate, glutamate, and histidine side chains and the protein C-terminus. Significant changes were observed for the C-terminal region of the sequence in the simulation at low pH. Most notably an α-helix, helix D, and the C-terminal 310 helix were substantially disrupted relative to the simulation at high pH. These perturbations to the native fold are similar to those observed in an X-ray structure of α-lactalbumin at pH 4.2. In addition, larger fluctuations about side chain torsion angles were observed in the low pH simulation than in that corresponding to the higher pH. These structural and dynamical changes might be representative of the early stages of the transition to the molten- globule state of the protein known to be formed under low pH conditions in solution.