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

Patel, Dharmeshkumar; Haag, Stephanie L.; Patel, Jagdish Suresh; Ytreberg, F. Marty; Bernards, Matthew T.

doi:10.1021/acs.jcim.1c01104

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

Journal Article · 22 February 2022 · Journal of Chemical Information and Modeling

DOI: https://doi.org/10.1021/acs.jcim.1c01104 · OSTI ID:1981869

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^[2]; Ytreberg, F. Marty ^[2];

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University of Idaho, Moscow, ID (United States); Emory University, Atlanta, GA (United States)
University of Idaho, Moscow, ID (United States)

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.

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Research Organization:: Idaho National Laboratory (INL), Idaho Falls, ID (United States). Nuclear Science User Facility (NSUF)

Sponsoring Organization:: National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); USDOE Office of Nuclear Energy (NE)

Grant/Contract Number:: AC07-05ID14517

OSTI ID:: 1981869

Journal Information:: Journal of Chemical Information and Modeling, Journal Name: Journal of Chemical Information and Modeling Journal Issue: 5 Vol. 62; ISSN 1549-9596

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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

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