Binding of Carbon Monoxide to Hemoglobin in an Oxygen Environment: Force Field Development for Molecular Dynamics

Carbon monoxide (CO) is a byproduct of the incomplete combustion of carbon-based fuels, such as wood, coal, gasoline, or natural gas. As incomplete combustion in a fire accident or in an engine, massively produced CO leads to a serious life threat because CO competes with oxygen (O₂) binding to hemoglobin and makes people suffer from hypoxia. Although there is hyperbaric O₂ therapy for patients with CO poisoning, the nanoscale mechanism of CO dissociation in the O₂-rich environment is not completely understood. In this study, we construct the classical force field parameters compatible with the CHARMM for simulating the coordination interactions between hemoglobin, CO, and O₂, and use the force field to reveal the impact of O₂ on the binding strength between hemoglobin and CO. Density functional theory and Car-Parrinello molecular dynamics simulations are used to obtain the bond energy and equilibrium geometry, and we used machine learning enabled via a feedforward neural network model to obtain the classical force field parameters. We used steered molecular dynamics simulations with a force field to characterize the mechanical strength of the hemoglobin-CO bond before rupture under different simulated O₂-rich environments. The results show that as O₂ approaches the Fe²⁺ of heme at a distance smaller than ∼2.8 Å, the coordination bond between CO and Fe²⁺ is reduced to 50% bond strength in terms of the peak force observed in the rupture process. This weakening effect is also shown by the free energy landscape measured by our metadynamics simulation. Our work suggests that the O₂-rich environment around the hemoglobin-CO bond effectively weakens the bonding, so that designing of O₂ delivery vector to the site is helpful for alleviating CO binding, which may shed light on <i>de novo</i> drug design for CO poisoning.