Calcium homeostasis is an essential physiological process requiring tight control in the
normal cell. The dysregulation of calcium homeostasis may play a key role in the onset of Alzheimer’s
disease (AD) and other disorders, whether through the loss of calcium binding or calcium
sensing capacity. Calbindin D28k (CB-D28k), a calcium binding protein composed of six EF-hands, four
of which can bind Ca2+, has been implicated in AD-related calcium dysregulation. In this study, docking
and molecular dynamics calculations were employed to refine the protein data base model in order
to understand the underlying structural variations between functional and non-functional EF-hands. Molecular modeling
calculations improved the modelled protein structure: helix-loop-helix sequences were formed in all hands and most canonical
interactions were formed in the four functional hands. The protein can also bind Zn2+, potentially altering the Ca2+
binding capability. Analysis of calculated structures of Zn2+ bound protein showed that only half of the correct EF-hand
canonical interactions of Ca2+ were formed with loop residues. These results have important implications for the understanding
of calcium dysregulation as well as for the development of novel therapeutic strategies in AD and other central
nervous system disease processes, or in conditions of brain injury where calcium homeostasis is compromised.
Keywords: Alzheimer's disease, Calbindin-D28k, Calcium binding protein, Calcium homeostasis, MD simulations, Zinc.
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