Effect of toxic ligands on O2 binding to heme and their toxicity mechanism

Abstract

Heme, as the cofactor and active site of Hb, enables Hb to carry out the necessary function required for O₂ management for life, that is, reversible O₂ binding for transport. In this paper, the microscopic mechanism of heme-associated poisoning has been elucidated from the perspective of electronic interaction by performing first-principles calculations. The results show that the functional groups (–CHO, –COOH, –NO₂, –NH₂) and CN exhibit a stronger affinity for heme than O₂ and are more likely to occupy the O₂ binding site, which results in the loss of the ability of heme to carry O₂. Moreover, the addition of functional groups, CO and CN to heme at the side site can cause a pronounced enhancement toward the O₂ binding characteristics of heme, which prevents heme from releasing O₂ to oxygen-consuming tissues as the blood circulates. The reversible O₂ binding function of heme is disrupted by the presence of these toxic ligands in the heme binding pocket, which greatly affects O₂ transport in the blood. The inability of tissues to obtain O₂ leads to tissue hypoxia, which is the main cause of poisoning. Based on the energy, geometry and electronic properties, the hypoxia mechanism proposed by us coincides well with experiment, and the research has the potential to provide a theoretical reference for the relevant areas of bioscience.