Mechanics of Carbon Monoxide Binding to Hemoglobin in Oxygen-Rich Environment Revealed by Molecular Dynamics Simulation with Advanced Force Field

Carbon monoxide (CO) is a byproduct of the incomplete combustion of carbon-based fuels like 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. We construct the classical force field parameters compatible with CHARMM for simulating the coordination interactions between hemoglobin, CO and O₂, and use the advanced force field to reveal the impact of an O₂-rich environment on the binding strength between hemoglobin and CO. We use density functional theory calculations and Car-Parrinello molecular dynamics simulations to obtain the bond energy and equilibrium geometry, considering essential spin states. Machine learning enabled via a feedforward neural network model is then used to obtain the classical force field parameters for our molecular dynamics simulations. Steered molecular dynamics simulations with our advanced force field are applied to characterize the mechanical strength of the hemoglobin-CO bond before rupture under different simulated O₂-rich environments, represented by bias potentials confining an O₂ molecule at different radiuses from Fe²⁺ of heme. The results show that as O₂ approaches the Fe²⁺ at a distance smaller than ~2.8 Å, the coordination bond between CO and Fe²⁺ is reduced to 50% bond strength in terms of peak force observed in the rupture process. The free energy landscape measured by our metadynamics simulation also shows this weakening effect. Our work suggests that the O₂-rich environment around the hemoglobin-CO bond effectively weakens the bonding, so designing an O₂ delivery vector to the site helps alleviate CO binding, which may shed light on de novo drug design for CO poisoning.