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Discovery of the Magnetic Behavior of Hemoglobin: a Beginning of Bioinorganic Chemistry Kara L

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Discovery of the Magnetic Behavior of Hemoglobin: a Beginning of Bioinorganic Chemistry Kara L PERSPECTIVE PERSPECTIVE Discovery of the magnetic behavior of hemoglobin: A beginning of bioinorganic chemistry Kara L. Brena, Richard Eisenberga,1, and Harry B. Grayb,c aDepartment of Chemistry, University of Rochester, Rochester, NY 14627; bDivision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125; and cBeckman Institute, California Institute of Technology, Pasadena, CA 91125 Edited by Michael A. Marletta, University of California, Berkeley, CA, and approved September 18, 2015 (received for review August 7, 2015) Two articles published by Pauling and Coryell in PNAS nearly 80 years ago described in detail the magnetic properties of oxy- and deoxyhemoglobin, as well as those of closely related compounds containing hemes. Their measurements revealed a large difference in magnetism between oxygenated and deoxygenated forms of the protein and, along with consideration of the observed diamagnetism of the carbonmonoxy derivative, led to an electronic structural formulation of oxyhemoglobin. The key role of hemoglobin as the main oxygen carrier in mammalian blood had been established earlier, and its allosteric behavior had been described in the 1920s. The Pauling–Coryell articles on hemoglobin represent truly seminal contributions to the field of bioinorganic chemistry because they are the first to make connections between active site electronic structure and the function of a metalloprotein. heme | bioinorganic | magnetism | oxygen transport | metalloproteins Hemoglobin occupies a very special place in four unpaired electrons per Fe atom. This re- directly to the function of the protein as the the annals of chemistry. Work on the protein sult would have major implications in estab- principal oxygen carrier in mammalian blood. began in the early 1800s, when it was found to lishing the role of the protein as an oxygen Duringthedecadeafterthedevelopmentof be a major component of mammalian blood transporter in the red blood of mammalian quantum mechanics, great strides were made cells and, importantly, found to contain iron. systems. In this Perspective, we discuss the in understanding bonding in molecules. In Isolation of hemoglobin was achieved by Pauling–Coryell articles and their role in the 1931, Pauling authored a compelling article Hünefeld in 1840 (1); shortly thereafter, it subsequent molecular-based understanding of entitled “The Nature of the Chemical Bond” was determined to have four one-iron sub- oxygen transport, as well as in the binding of that brought together the concepts of quan- units, each with a relative molecular mass of other small molecules to heme iron centers. tum mechanics, the electron pair bond, and 16,000 (an unprecedentedly large value at the The measurements by Pauling and Coryell the structures of molecules (5). The title of time). Research aimed at discovery of other were conducted using a Gouy balance in this paper would be used by Pauling in sub- properties of hemoglobin followed almost im- which the weight of a sample was determined sequent publications, including his classic mediately, including observations in 1845 by in the absence and presence of a magnetic field. textbook on the subject. In his 1931 treatise, Michael Faraday that it was not magnetic, in Thefieldwasprovidedbyanelectromagnet, which appeared in the Journal of the Amer- contrast to most other iron-containing matter and sample weights were measured at two ican Chemical Society,Paulingintroduced (2). These measurements were conducted by different field strengths. The specific examples the notion of hybridization of metal atomic placement of a sample between the poles of a examined included ferroheme, ferriheme, orbitals and different hybridization schemes magnet and measuring its change in weight. oxyferroheme, carbonmonoxyferroheme, and that correlated with observed or implied struc- Magnetic samples were drawn into the field, a variety of other heme compounds. The tures of metal-containing compounds. Most giving an increase in weight; nonmagnetic balance that was used for these measure- notable were the d2sp3 scheme that generated (diamagnetic) materials were repelled by the ments resides in the Chair’s office of the six equivalent hybrids directed to the vertices field, accompanied by a negligible or slight Division of Chemistry and Chemical En- of an octahedron and dsp2 hybridization that decrease in weight. In this context, remember gineering at the California Institute of gave four equivalent orbitals directed to the thatitwasfully80yearslaterthatthenotion Technology (Caltech) (Fig. 1). In the data of electron spin would be proposed as the analysis, the samples were corrected for Author contributions: K.L.B., R.E., and H.B.G. wrote the paper. principal basis of magnetic behavior. their small inherent diamagnetism. Based The authors declare no conflict of interest. Our story is based on the work of Linus on these measurements, the previously This article is a PNAS Direct Submission. Pauling and Charles Coryell, who, in 1936, observed diamagnetism of hemoglobin This article is part of the special series of PNAS 100th Anniversary published two articles in PNAS on the in the form of oxyferroheme, as well as articles to commemorate exceptional research published in PNAS magnetic properties of hemoglobin and re- that of carbonmonoxyferroheme, was con- over the last century. See the companion articles, “The magnetic lated substances (3, 4). Pauling and Coryell firmed whereas deoxyferroheme was deter- properties and structure of the hemochromogens and related sub- confirmed earlier findings that oxygenated mined to possess magnetism characteristic stances” on page 159 in issue 3 of volume 22, and “The magnetic properties and structure of hemoglobin, oxyhemoglobin and as well as carbonmonoxy forms of hemoglo- of unpaired electrons. Therefore, arterial and carbonmonoxyhemoglobin” on page 210 in issue 4 of volume 22. bin were diamagnetic but discovered that the venous blood were found to have different 1To whom correspondence should be addressed. Email: deoxygenated protein was magnetic, having magnetic properties, the basis of which related [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1515704112 PNAS | October 27, 2015 | vol. 112 | no. 43 | 13123–13127 Downloaded by guest on October 9, 2021 corners of a square, in striking contrast with iron atom is not attached to the four porphy- surface arranged in a square formation (9). the sp3 hybrids of tetrahedral carbon in satu- rin nitrogen atoms and the globin molecule by Cooperativity induced by ligand binding to rated organic compounds. covalent bonds, but is present as a ferrous ion, the hemes in this arrangement would re- In this context, the electronic structure of the bonds to the neighboring atoms being es- quire communication between and among carbonmonoxyhemoglobin was easiest to sentially ionic bonds.” The particular nature of the sites over relatively large distances. understand. The porphyrin ring of the protein the neighboring atoms is not specified, but The first X-ray crystal structure of human was known to contain four pyrrole N atoms discussion of the magnetic properties of fer- hemoglobin, one of low resolution (5.5 Å) capable of binding to Fe in a plane, with rous compounds is presented, suggesting that determined by Perutz in 1959, provided a test one axial bond to the globin and the other significant quenching of orbital angular mo- of Pauling’s predictions (10). Although the connecting to carbon monoxide. The six mentum to the total magnetic moment is seen hemes were found to be encapsulated by d2sp3 hybrids of Fe were used to form these in such Fe(II) compounds. The authors added, globinandnotonthesurface,Pauling bonds, leaving the remaining three d or- “It is not yet possible to discuss the significance was correct in the sense that they were bitals to accommodate the six electrons of of these structural differences in detail, but not in direct contact and, indeed, were Fe(II). A completely spin-paired arrange- they are without doubt closely related to and more than 25 Å apart. Furthermore, changes ment was thus achieved, consistent with in a sense responsible for the characteristic in quaternary structure as a function of the observed diamagnetism of carbonmo- properties of hemoglobin (for oxygen trans- heme ligation state were observed. The de- noxyhemoglobin. The diamagnetic behavior port).” (4) termination of the hemoglobin structure of oxygenated hemoglobin was similarly ac- One of the most important of the char- was the basis for the 1962 Nobel Prize commodated, but, according to Pauling and acteristic properties was discovered in the in Chemistry to Perutz, which he shared “ Coryell, The oxygen molecule undergoes a 1920s: namely, that the hemoglobin/O2 with John Kendrew, who had solved the profound change in electronic structure on equilibrium was affected by pH and that structure of myoglobin. Incidentally, these combination with hemoglobin” in light of the the four heme subunits of hemoglobin structures played a role in confirming the = S 1 paramagnetism of the O2 ground state did not bind O2 with the same formation details of an unrelated 1951 prediction by (4). The coordination of O2 to Fe was repre- constant. In work by Adair (6, 7) and Ferry Pauling in the Proceedings of the National sented in terms of two “resonating” structures and Green (8), oxygen binding was found Academy of Sciences by revealing the struc- shown below, but without any discussion of to proceed in a cooperative
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