Reduced Oxygen Permeability upon Protein Incorporation Within Phospholipid Bilayers

Abstract

Intracellular oxygenation is key to energy metabolism as well as tumor radiation therapy. Although integral proteins are ubiquitous in membranes, few studies have considered their effects on molecular oxygen permeability. Published experimental work with rhodopsin and bacteriorhodopsin has led to the hypothesis that integral proteins lessen membrane oxygen permeability, as well as the permeability of the lipid region. The current work uses atomistic molecular dynamics simulations to test the influence of an ungated potassium channel protein on the oxygen permeability of palmitoyloleoylphosphatidylcholine (POPC) bilayers with and without cholesterol. Consistent with experiment, whole-membrane oxygen permeability is cut in half upon adding 30 wt% potassium channel protein to POPC, and the apparent permeability of the lipid portion of the membrane decreases by 40%. Unexpectedly, oxygen is found to interact directly with the protein surface, accompanied by a 40% reduction of the apparent whole-membrane diffusion coefficient. Similar effects are seen in systems combining the potassium channel with 1:1 POPC/cholesterol, but the magnitude of permeability reduction is smaller by ~30%. Overall, the simulations indicate that integral proteins can reduce oxygen permeability by altering the diffusional path and the local diffusivity. This effect may be especially important in the protein-dense membranes of mitochondria.

Fig. 1

Simulation snapshot of the K⁺chan/POPC system, imaged at the end of the 300 ns production trajectory. (a-b) Side view and top view. Approximate thickness of the membrane, h, is indicated. Protein shown as black ribbons. POPC as white licorice/gray lines, water as small cyan spheres, and O₂ as larger red spheres. H atoms omitted for clarity. Blue circles and lines in panel b indicate approximate positions of “corner’ residues and pairwise distances used to estimate interfacial area for this face of the protein. (c) Side view of protein in surface representation, highlighting the O₂ molecules that contact the protein surface (red spheres). Blue spheres are O₂ molecules in the core of the protein or its water-filled “vestibule.’ Imaged with PyMOL [20].