Capture, transport, and release of oxygen in the body is managed by one single molecular system. This is possible thanks to a delicate mechanism allowing fast and reversible modification of electron spins.
Foto: Shutterstock
Denne artikel er fra DTU Kemi Årsrapport 2018. Læs den fulde rapport her.
It is common knowledge that our blood transports oxygen. But only recently it has transpired that this vital biological function is based on a delicate mechanism based on the electron spin properties of the key molecule involved, the protein hemoglobin.
“The extraordinary property of hemoglobin is not so much its ability to bind oxygen, but rather its ability to bind and release oxygen quickly and reversibly with a small free energy difference as required for oxygen transport. Such fast, reversible oxygen binding is not commonly seen in chemistry. Life as we know it directly relies on the almost miraculous quantum mechanical properties of this single molecular system,” says Professor Kasper Planeta Kepp, DTU Chemistry. Given the extreme importance of the biological mechanisms involved in oxygen transport, the group at DTU Chemistry is obviously not alone in the field. However, the group has uniquely addressed the heme system across all its organization levels from fundamental quantum mechanics of individual atoms to the full protein structures and all the way up to studying cells and physiological implications of heme modifications, e.g. in diving whales and seals.
How iron captures oxygen
Hemoglobin is a so-called metalloprotein with iron (Fe) inside the protein directly involved in the oxygen binding. Besides the fact that iron is abundant on Earth, this element has several other attractive properties. Iron has a moderate effective nuclear charge, borderline Lewis acid properties, and is not too oxo-philic, nor too thio-philic and thus routinely forms complexes with a variety of ligands. Further contributing to flexibility, iron exists in several oxidation states.
Moreover, once associated with other atoms the richness and modest energy separations of the various electronic configurations of the d-orbitals of iron produce high degrees of freedom and spin-crossover properties. In other words, iron is uniquely suited for the highly flexible task of capturing, transporting, and releasing oxygen.
In hemoglobin, the iron atom is situated in a part of the molecule termed heme. Heme is a coordination complex consisting of an iron ion coordinated to a porphyrin ligand. Porphyrins are macrocyclic organic compounds. When iron(III) binds to porphyrin ligands in a weak ligand field, it produces a highly paramagnetic state having a half-filled d-shell with only spin-forbidden d-d transitions. In a stronger ligand field,however, rich transitions are offered. This is also the case for iron(II) complexes in both weak and strong ligand fields.
Bringing color to the world
Porphyrins have large ring-shaped structures. They typically absorb strongly in the visible region of the electromagnetic spectrum and are thus colored.
“Our ancestors largely associated the red color of blood with courage, war, danger, and suffering. Incidentally, similar transitions within the porphyrin-derived chlorophylls are responsible for the green color of plants, associated with nature, life, and hope. Thus, it is fair to say that electronic transitions in porphyrins have had vast cultural consequences, ”notes Kasper Planeta Kepp.
On the technical side, recent findings published by the group of Kasper Planeta Kepp at DTU Chemistry describe the spin crossover process of iron in complete detail, while another paper in the same journal introduces the first way to quantify oxo-philicity. These studies among many others have contributed to the overall under standing of the fundamental mechanism of oxygen transport in living organisms.
According to the current consensus, the iron-oxygen (Fe-O2) bond largely results from so-called back-bonding. Here, electrons move from an atomic orbital of one atom to an appropriate symmetry anti-bonding orbital on a ligand. In other words, electrons from iron are used to bond to the ligand.
Making forbidden binding possible
Still, forming the iron-oxygen bond is only the first step in the function of hemoglobin as an oxygen transporter. The really big question is: How does the heme system facilitate fast and reversible binding of O2, considering the spin-forbidden nature of this process?
To understand the answer to this question, one needs to take a closer look at the oxygen (O2) molecule. O2 has a triplet ground state with two unpaired, parallel-spin electrons. Inconveniently, the first excited singlet state lies far above this ground state in terms of energy (approx. 1 eV). The unpaired electron density of the π* orbitals is reluctant to react with organic molecules, partly because of the low spin-orbit coupling of the involved atoms and partly because of the high energy of excited singlet oxygen species on the potential energy surfaces (PES) of oxidation reactions, which prevent reaction even if the spin-orbit coupling were moderate. In 2004, Kasper Planeta Kepp and his Ph.D. supervisor Ulf Ryde computed the first fully relaxed PES for O2 binding to heme and showed spin-forbidden ligand binding to be mainly facilitated by allowing the spin states to be close in energy at dissociation and association. This remarkably produces abroad crossing region, maximizing crossover probability.
“This mechanism, referred to as the “broad crossing mechanism” remains a useful design principle for spin-forbidden ligand binding to transition metals,” Kasper Planeta Kepp concludes.
Optimized by evolution
The close-lying spin states of hemes occur not only in hemoglobin, but also in various states of heme enzymes. Amazingly, the balance between spin state energies and back-bonding leads to a dual ability of heme to function either as an oxygen transporter (at low back-bonding) or an oxygen activator (at high back-bonding), enabling both the transport (in globins) and use (in heme enzymes) of oxygen in the molecular infrastructure of oxygen-based life forms. “The spin-forbidden binding of heme has been the subject of substantial evolutionary optimization as this step could otherwise be slow and rate-limiting. However, the broad crossing regions are probably still required to facilitate fast reactions. In my opinion,the most important reactivity gain lies in the facilitation of spin inversion by the broad crossing region caused by close-lying spin states that accelerate binding rates by orders of magnitude. ”In conclusion, fundamental quantum mechanics, in the form of the controlled spin-forbidden binding of O2 to heme, has played a dominant role in the evolution of life. “Without the porphyrin ring, it is hard to imagine how life as we know it could have existed. We now know that all the three defining features of photo-sensitizing, electron transfer, and spin crossover are present within the very same porphyrin ring. The binding of O2 to heme is a truly quantum mechanical phenomenon with vast consequences for life on this planet!”