Myoglobin-Membrane Association Facilitates Oxygen Release via Active-Site Tuning

Abstract

Myoglobin, a heme protein abundant in striated muscle cells, plays acrucial role in oxygen delivery to mitochondria. In this study, we combinedspectroscopy, rapid kinetics and computer simulations to investigate how the interactionbetween oxymyoglobin and an outer mitochondrial membrane model - composed of 1:1POPC:POPE liposomes- impacts oxygen affinity. UV−visible and Resonance Ramanspectroscopy studies of metmyoglobin, deoxymyoglobin and oxymyoglobin reveal subtlestructural perturbations of the heme binding site, when oxymyoglobin interacts with themodel membrane. Stopped-flow kinetic measurements show that these distortions leadto a 2-fold increase in the rate constant for oxygen release. Furthermore, classical andmultiscale QM/MM simulations suggest that the increase in the O2 dissociation rate inthe presence of the liposomes is mainly due to proximal effects and heme planedistortions produced by specific interactions between oxymyoglobin and the membrane.Altogether, these results point to a fine-tuning in the active site conformation thatfacilitates oxygen release from oxymyoglobin upon membrane association, potentially enhancing mitochondrial oxygen availabilityand energy production in cells.