Discerning Membrane Steady-State Oxygen Flux by Monte Carlo Markov Chain Modeling

Abstract

Molecular oxygen (O₂) permeability coefficients for lipid bilayers have previously been estimated using both electron paramagnetic resonance (EPR) oximetry and molecular dynamics simulation data. Yet, neither technique captures the fluxes that exist physiologically. Here, the dynamic steady state is modeled using a stochastic approach built on atomic resolution molecular dynamics simulation data. A Monte Carlo Markov chain technique is used to examine membrane-level fluxes of oxygen in lipid-water systems. At steady state, the concentration of oxygen is found to be higher inside the model membranes than in surrounding water, consistent with the known favorable partitioning of O₂ toward the lipid phase. Pure phospholipid 1-palmitoyl,2-oleoyl-phosphatidylcholine (POPC) bilayers accrue ~40% more O₂ molecules at steady state than POPC/cholesterol bilayers (1:1 molecular ratio) mimicking the red blood cell membrane. Steady-state levels of oxygen were reached inside both bilayer types within the same timeframe, but depletion of oxygen from the bilayer interior occurred 17% faster for POPC than for POPC/cholesterol. Likewise, first-order rate constants estimated for accrual to steady state were the same for POPC and POPC/cholesterol, at 190 μs⁻¹, while first-order rate constants for depletion of the accrued O₂ from the bilayers differed, at 95 μs⁻¹ for POPC and 81 μs⁻¹ for POPC/cholesterol (lower by 15%). These results are consistent with prior experiments in red blood cells (RBCs) with varying membrane cholesterol content, in which additional cholesterol slowed oxygen uptake and release. Further work is needed to understand whether differences in RBC membrane cholesterol content would affect the delivery of oxygen to tissues.