Paired Simulations and Experimental Investigations into the Calcium-Dependent Conformation of Albumin

Serum albumin is the most abundant
protein in blood plasma, and
it is involved in multiple biological processes. Serum albumin has
recently been adapted for improving biomaterial integration with bone
tissue, and studies have shown the importance of this protein in bone
repair and regeneration. However, the mechanism of action is not yet
clear. In stark contrast, other studies have demonstrated that albumin
blocks cell adhesion to surfaces, which is seen as a limitation to
its bone healing role. These apparent contradictions suggest that
the conformation of albumin facilitates its bioactivity, leading to
enhanced bone repair. Serum albumin is known to play a major role
in maintaining the calcium ion concentration in blood plasma. Due
to the prevalence of calcium at bone repair and regeneration sites,
it has been hypothesized that calcium binding to serum albumin triggers
a conformational change, leading to bioactivity. In the current study,
molecular modeling approaches including molecular docking, atomic
molecular dynamics (MD) simulation, and coarse-grained MD simulation
were used to test this hypothesis by investigating the conformational
changes induced in bovine serum albumin by interaction with calcium
ions. The computational results were qualitatively validated with
experimental Fourier-transform infrared spectroscopy analysis. We
find that free calcium ions in solution transiently bind with the
three major loops in albumin, triggering a conformational change where
N-terminal and C-terminal domains separate from each other in a partial
unfolding process. The separation distance between these domains was
found to correlate with the calcium ion concentration. The experimental
data support the simulation results showing that albumin has enhanced
conformational heterogeneity upon exposure to intermediate levels
of calcium, without any significant secondary structure changes.