2017 Cardiovascular Research Day Abstract Book

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Coarse-Grained Molecular Dynamics Simulations of Kir2.2 Interactions with an Ensemble of
Cholesterol Molecules
Nicolas Barbera, MS 1 • Manuela Ayee, PhD 1 • Belinda Akpa, PhD 2 • Irena Levitan, PhD 3
1Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at
Chicago • 2 Department of Molecular Biomedical Sciences, North Carolina State University •
3Department of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of
Illinois at Chicago
Graduate Student
Hypercholesterolemia, elevated plasma levels of cholesterol, is a major risk factor in the
development of atherosclerosis. Our previous studies have shown that inwardly rectifying K+ (Kir)
channels, which play an important role in endothelial function, are suppressed by enriching cells
with cholesterol. Additionally, earlier work done by our group and others has shown that
cholesterol regulates Kir2 channels, a sub-family of Kir channels expressed in endothelial cells,
through direct interactions at non-annular interaction sites. However, while a putative binding site
has been identified, the dynamics of the binding process and cholesterol’s structural effect on the
protein remain poorly understood. To address these questions, we used coarse grained molecular
dynamics simulations of Kir2.2, a subfamily of Kir2, in model membranes containing cholesterol
and POPC to interrogate their molecular interactions at the microsecond timescale. Our simulations
show that rather than single ligand-channel binding, interactions between cholesterol and the
channel are both complex and numerous, with an average of 15-20 cholesterol molecules
interacting with the protein at any given time. These interactions occur at a range of timescales and
at distinct annular and non-annular sites on the surface of the protein. Additionally, we observed
spontaneous diffusion between these sites and between the protein surface and the surrounding
membrane. At present, we are exploring the functional significance of these various interactions
and the impact of this collective action on the structure-function relationships governing Kir2
channel activity.
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