Effects Of Small Molecules And Heavy Metals On The Interaction Between Heme And Oxygen

In biological system,heme,as the active site and coenzyme of hemoglobin(Hb),myoglobin(Mb)and cytochrome oxidase,is crucial for oxygen-based life on earth.Heme performs the functions of oxygen binding and activation under the management of oxygen of life,in which Hb and Mb reversibly bind oxygen to achieve the purpose of oxygen transport and storage,while during aerobic respiration,oxygen is reduced to water molecules under the catalysis of cytochrome oxidase and accompanied by the generation of energy.In these vital chemical processes,Hb binds to oxygen at the central Fe as the active site.In theory,the nature of Fe-O₂ bond in the heme with bound oxygen system(oxy-heme)has attracted extensive attention,and three models have been proposed,i.e.,Pauling's resonance theory,Weiss's electron transfer model and Mc Clure and Goddard's ozon-like model.Heme possesses multiple spin states with closed energy,so the researchers calculated the energy and structural parameters of different spin states by using various functional methods based on density functional theory(DFT)and compared them with experimental data.Correctly predicting the ground state of heme is a challenge to the accuracy and reliability of functional methods based on DFT.In the experiment,the structural modification of heme(substitute the axial ligand of heme)was applied to study the changes of its electronic structure and function.Furthermore,inspired by the biocatalytic function of heme,both the carbon nanotubes with covalently grafted heme and the ultra-small hydroxyapatite with embedded heme show superior oxygen reduction activity,and these biomimetic materials have potential application value in biofuel cells.In biology,carbon monoxide(CO),cyanide(CN)and heavy metal poisoning are generally manifested as dyspnea,shortness of breath and disorders.These clinical symptoms are related to the affected structural and functional of heme.However,the microscopic mechanisms of CO,CN and heavy metal poisoning are unclear and there is a lack of researches on heme-associated poisoning on the basis of first principles calculations.Herein,we have constructed a simplified heme model and systematically investigated the energy,geometric parameters and electronic structure of heme and oxy-heme by performing first principles calculations based on density functional theory.Secondly,the effects of CO,CN and heavy metals(Cr,Ni and As)on the energy,geometric structure and electronic structure of heme and oxy-heme have been studied.The main conclusions can be summarized as follows:1.In the heme system,the central Fe coordinates with five N atoms(four N atoms in the plane of porphyrin,namely pyrrole N and one axial N).The electronic local function indicates that the Fe-N bond is ionic while C-N and C-C bonds are covalent.In the vicinity of the Fermi level(E_F),the Fe-3d orbital overlaps strongly with N-2p orbital,suggesting that the interaction between Fe and N is strong and Fe can be stably deposited in the porphyrin ring.2.In the oxy-heme system,the oxygen binding process is exothermic,and the calculated oxygen binding energy is 0.11 eV.The O-O bond elongated from 1.23(?)to 1.24(?),and the corresponding vibration frequency decreased from 1562.29 cm^-1 to 1437.94 cm^-1.Oxygen acts as the charge acceptor to obtain a small number of electrons(0.04 e)from heme,with a small amount of charge distributed between Fe and oxygen.The hybridization between Fe-3d orbital and O₂-2p orbital is not obvious near E_F,indicating that the weak interaction between Fe and oxygen.The moderate interaction between heme and oxygen ensures reversible oxygen binding during blood oxygen transport.3.The inability of heme to release oxygen causes hypoxia.The combination of CO at heme side induces the binding energy of oxygen increse from 0.11 eV to 0.18 eV and more electron(0.28 e)transfer from heme to oxygen.The transferred electrons occupy the antibonding orbital of oxygen which leads the elongation of O-O bond(1.27(?))and the reduction of frequency by 216 cm^-1.Fe-3d and O₂-2p states are strongly mixed,showing that interaction between heme and oxygen is increased when CO binds to heme side.The binding energy and charge transfer of oxygen and the hybridization of Fe-3d and O₂-2p orbitals are significantly enhanced after Cr and Ni binds to heme,indicating that oxygen is bound more tightly to heme.The combination of CO,Cr and Ni with heme makes the charge transfer between heme and oxygen more significant,the activation and polarization of oxygen and the orbital hybridization of Fe-3d and O₂-2p more obvious,which makes the release of oxygen more difficult,resulting in the aerobic tissue can not obtain oxygen,that is hypoxia.4.The inability of heme to bind oxygen results in hypoxia.CN binds to heme at top site with binding energy of 2.15 eV and gets more electrons(0.54 e)from heme,which are larger than those of oxygen.The charge distribution between Fe and CN is obvious,indicative of covalent interactin of Fe-CN bond.Electrons transfer from the occupied state of Fe-3d to the empty antibonding orbital of CN-2p,causing the elongation of CN bond length(0.03(?))and the weakening of vibration frequency.The strong coupling of Fe-3d and CN-2p orbitals near E_Fsuggests that the interaction between heme and CN is stronger and CN is more likely to occupy the binding site of oxygen in the binding pocket,which prevents heme from binding oxygen.The combination of As with heme induces severe deformation of the structure of heme and redistribution of charge,which makes the function of oxygen binding of heme lost and causes hypoxia.