Understanding Oxygen "Buffering" by Caveolae Using Coarse-Grained Molecular Dynamics Simulations.

The "oxygen paradox" embodies the delicate interplay between two opposing biological processes involving oxygen (O). O is indispensable for aerobic metabolism, fuelling oxidative phosphorylation in mitochondria. However, excess O can generate reactive species that harm cells. Thus, maintaining O balance is paramount, requiring the prioritisation of its benefits while minimising potential harm. Previous research hypothesised that caveolae, specialised cholesterol-rich membrane structures with a curved morphology, regulate cellular O levels. Their role in absorbing and controlling O release to mitochondria remains unclear. To address this gap, we aim to explore how the structural features of caveolae, particularly membrane curvature, influence local O levels. Using coarse-grained (CG) molecular dynamics simulations, we simulate a caveola-like curved membrane and select a CG bead as the O model. Comparing a flat bilayer and a liposome of 10 nm diameter, composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), allows us to study changes in the O free energy profile. Our findings reveal that curvature has a contrasting effect on the free energy of the outer and inner layers. These findings show the membrane curvature's impact on O partitioning in the membrane and O permeation barriers, paving the way towards our understanding of the role of caveolae curvature in O homeostasis.