science/technology the American Chemical Society's national meeting in Boston last month, de Dios and his colleague, Julio C. Facelli, director of the Center for High Performance Computing at the University of Utah, Salt Lake City, chaired a symposium on modeling NMR chemical shifts sponsored by the Computers in Chemistry and Physical Chemistry Divisions. Quite a few things had changed. "This was a meeting long awaited," de Dios says. There were some striking demographic differences. Instead of exclusively theorists, the audience and speaker list were studded with experimentalists, who now routinely use NMR modeling to augment their experiments. "Modeling of NMR shifts is now seen with almost every type of chemical system: proteins, zeolites, inorganic catalysts, nucleic acids, Theoretical modeling of NMR chemical shifts of catalytic carbohydrates," de systems—such as the pictured acetone adsorbed on a zeolite Dios says. As an addacid site—can help identify crucial intermediates. ed illustration of the field's progress, de between structures and chemical shifts Dios notes that during the period of June 1997 through May 1998, more than 150 need to be worked out in detail. At the time of the Maryland meeting, papers were published in this area. "The methods just keep getting fastcomputers were starting to flex their computational muscles, and the theoreti- er and faster," says John B. Nicholas, a cal techniques had become sophisticated theoretical chemist at Pacific Northenough to make NMR chemical shift pre- west National Laboratory, Richland, diction a commonplace reality. Howev- Wash., who spoke at the meeting. "We er, there was still a way to go. "In 1992, there were big gaps between theory and experiment," says Cynthia J. Jameson, a chemistry professor at the University of Illinois, Chicago. Back then, she says, "what was needed was more gas phase data; we needed to know how to deal with proteins, zeolites, and other extended networks." And the question of relativistic effects on chemical shifts in heavy atoms had barely been touched upon. De Dios (left) and Facelli chaired symposium on modeling NMR chemical shifts. Six years later, at
NMR METHODS BLOSSOM
Modeling of chemical shifts is leading to ability to predict complex structures Elizabeth K. Wilson C&EN West Coast News Bureau
I
n 1992, a group of theorists gathered in Maryland to take stock of the recent stunning progress in their field: modeling NMR (nuclear magnetic resonance) spectroscopy chemical shifts. Although NMR has been chemists' most widely used spectroscopic tool for decades, crunching through the quantum mechanical links between the tiny magnetic and electronic environments of nuclei, the external magnetic fields, and the macroscopic quantity that reveals molecular structure—the chemical shift—was another story entirely. The mathematical framework for calculating chemical shifts has existed since the advent of quantum mechanics, but until the past decade the complexity of such calculations prevented their ready use. The chemical shifts of small molecules could be approximated, but those of larger systems such as peptides, proteins, and catalysts were all but impossible to calculate with the computers of the 1970s and '80s. The chemical shift arises when the environment surrounding a nucleus shields or deshields it from the external magnetic field, altering the nucleus' resonant frequency. "The NMR chemical shift is intimately dependent on the structure and environment of the nucleus under study," says Angel C. de Dios, assistant professor of chemistry at Georgetown University in Washington, D.C. "Before we started modeling, you simply 'filled in the tables,' but nobody put meaning into them because they didn't know how to interpret them. By way of modeling, we have a way of interpreting the chemical shifts we see in terms of structure," he says. Even more appealing is the possibility that chemical shifts might be used to go beyond empirical data, to predict structures—especially those of large, complex molecules such as proteins. To do this, the fundamental mathematical relationships
SEPTEMBER 28, 1998 C&EN 2 5
science/technology
You've got to speak the language Theorists modeling nuclear magnetic resonance chemical shifts use these common words and acronyms: Chemical shift tensor—a tensor rep resentation of the chemical shift. The nine elements of the tensor, commonly represented as a 3 x 3 matrix, describe the magnitude of thefieldfelt at the site of the nucleus along the α direction, in duced by electronic currents brought about by an applied magnetic field along the β direction. Chemical shift tensors are required to describe the nu clear shielding effects in solid-state NMR, but also can be used in liquid and gasNMR. Density functional theory—a method of calculating molecular energies devel oped in the 1960s, based on electron densities rather than the wavefunctions used in Hartree-Fock (see below). The method is much faster, but some say less accurate, than Hartree-Fock. GIAO—Gauge including atomic orbitals. A groundbreaking theory, based on Har tree-Fock, that allowed theorists to calcu late chemical shift tensors of larger mole cules with relative speed and accuracy. Hartree-Fock—also known as the selfconsistent field theory, Hartree-Fock is
have faster computers. We have people looking at new methods so we can treat bigger systems." At the meeting, Jameson previewed some of the new advances: newer, faster theoretical methods to minimize comput er time while preserving predictive accu racy; the ability to do routine calculations with much larger molecules; new insights into the relativistic effects of heavy ele ments—a long-standing problem in NMR; and exciting progress in using NMR chem ical shifts to predict the structure of pro teins and catalysts. The steps from molecular description to chemical shift are anything but sim ple. Theoretical chemists typically model a system by solving the Schrodinger equation, which describes the energies of the system. The effects of the external NMR magnetic field on the nucleus of in terest is added into the equations as a "perturbation." They can then calculate the chemical shift, which is related math ematically to the total molecular energy, the applied magnetic field, and the nu clear magnetic moment. The electromagnetic environment in the vicinity of a nucleus affects its chemi cal shift, which depends on its orientation 26 SEPTEMBER 28, 1998 C&EN
the most widely used method for solv ing the Schrodinger equation for molec ular systems in theoretical chemistry. It is the basis for many of the theories used to calculate NMR chemical shifts. IGLO—Individualized gauge for local ized orbitals. Another theory, based on Hartree-Fock, used to calculate chemical shifts. IGLO requires less computational time than GIAO. Isotropic chemical shift—in a gas or liquid, the constant tumbling motion of molecules averages out the directional dependence of the magneticfieldon nu clear shielding; thus, there is one single, isotropic value for the chemical shift. LORG—Localized orbitals, local ori gin. Chemical shift calculation theory similar to IGLO. MP2—M0ller-Plesset perturbation theory, a theoretical augmentation that allows theorists to account for a chemi cal shift-altering property known as electron correlation. Shielding constant—simply related to the chemical shift, the shielding constant represents the amount of magnetic shielding felt by a nucleus. The shielding in turn causes a shift, downward or up ward, of the nucleus' resonant frequency.
in the magnetic field. Thus, rather than a single isotropic chemical shift, chemists frequently calculate a chemical shift "ten sor," often represented by a 3 x 3 matrix that describes all the directional aspects of shielding and deshielding at a nucleus. The chemical shift tensor is particularly important in solid-state NMR. The granddaddy of Schrodinger equa tion-solving theories, known as HartreeFock, provides the basis for many of the NMR chemical shift-calculating methods. But applying it hasn't been easy. In this theory, the mathematical description of the chemical shift is split into two terms, which are labeled the paramagnetic and diamagnetic terms. The diamagnetic term is easy to solve; the paramagnetic part, however, is incredibly difficult. For decades, theorists have wrangled with possible solutions to this intractable equation. A method known as gauge in cluding atomic orbitals (GIAO) eventual ly became the first comprehensive theo ry for calculating the NMR chemical shift. However, even with modern com puters, GIAO was still relatively timeconsuming and therefore expensive, al lowing calculations only on smaller, sim pler molecules.
Newer methods—such as individual gauge for localized orbitals (IGLO) and localized orbitals, local origin (LORG)— are faster. Another theoretical standby appropriated by chemists from physi cists, density-functional theory (DFT), uses electron density rather than the wavefunctions of Hartree-Fock as its foundation. The resulting calculations are much faster. Now, chemistry profes sor Peter Pulay of the University of Ar kansas, Fayetteville, has improved the GAIO method so that it is competitive with both IGLO and LORG. The ACS symposium largely focused on calculating chemical shift tensors as well as applications not only in solid state, but also in gas and solution. Other structural determination tech niques that involve NMR do exist. For the past 15 years, chemists have been using the nuclear Overhauser effect (NOE) in NMR to help predict stmctures of mole cules such as proteins in solution. This ef fect occurs in nuclei that are close togeth er—one excited nucleus transfers energy to the other, which enhances the NMR signal of the second nucleus. These signal enhancements can be used to determine spatial relationships between atoms.
The close proximity of the highest occupied molecular orbitals (HOMOs, shown as solid red and blue) of ethene and methane may lead to compression of the ethene orbital, which may cause the deshielding observed for a proton directly above. In the system shown, one proton of methane is just 2.0 À above the center of the carbon-carbon double bond. The HOMO of ethene alone is superimposed as a wire mesh for contrast.
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•science/technology
Jameson: new advances in NMR
Nicholas: meti ods keep getting faster
"NOE is the traditional way of getting I structure from NMR," says David A. Case, a professor in the molecular biology department at Scripps Research Institute, La Jolla, Calif. However, this method only works in solution, de Dios points out. Additionally, a technique such as X-ray crystallography can only be used for determining solid structures. But once it's fully developed, the chemical shift tensor could be used for all types of systems. "Using the chemical shift to help get structures is still in the very early days," Case notes. "How much the extra information is worth is still a matter that we're trying to figure out." A topic of particular interest at the meeting was the problems raised by doing NMR with heavy elements. The electronic and magnetic behavior of atoms in NMR is complicated enough, but with atoms further down on the periodic table—around the third row—the picture gets even more inextricable. As a nucleus gets heavier, its positive charge increases, which slings electrons around in orbits at speeds much closer to the speed of light than electrons in lighter elements. Theorists wanting to model the chemical shifts of nuclei under the influence of a heavy atom, or the nucleus of a heavy atom itself, must contend with relativistic effects generated by the ultrafast electrons. In the 1950s, scientists noticed that light atoms with a neighboring heavy element, such as hydrogen in hydrogen halides and carbon-13 in iodomethanes, were shifted far upfield, way out of character for what was expected. This is called the normal halogen dependence. Eventually, in 1969, Japanese theorists determined the effect was due to spin-orbit coupling: where electron spin interacts electromagnetically with the elec28 SEPTEMBER 28, 1998 C&EN
Pulay: improved GAIO methods
iron's orbit. Under the influence of the external NMR magnetic field, this interaction transmits readily through bonds and affects the resonance behavior of the light nucleus. "The spin-orbit effect is the dominant effect for explaining the chemical shift of these series of compounds," notes Hiroshi Nakatsuji, a member of the engineering faculty at the University of Kyoto in Japan. When the resonant nucleus is itself a heavy element, "scalar" relativistic effects
such as changes in mass with near-speedof-light velocity come into play. Nakatsuji's ab initio method of calculating spin-orbit coupling effects in hydrogen and methyl halides is the first of its kind and was developed in the past few years, he says. Pekka Pyykko, a chemistry professor at the University of Helsinki in Finland, described his work studying the effect of iodine on carbon-13 shifts. His study helps confirm that spin-orbit coupling is responsible for the heavy-element chemical shift. He also pointed out that spin-orbit coupling in NMR bears a surprising resemblance to the effect of nuclear spin-spin coupling. Georg Schreckenbach, a theoretical chemist at Los Alamos National Laboratory, Los Alamos, N.M., described his recent calculation of NMR shielding for early actinide elements. Hiroyuki Fukui, of the Kitami Institute of Technology, Kitami, Japan, showed that calculation of a relativistic mass correction increased NMR shielding of halogen nuclei owing to the relativistic contraction effect that concentrates electrons in the vicinity of a heavy nucleus.
Exposition showcases software In addition to nuclear magnetic reso- allowing the user to search for substrucnance software packages, software tures and reactions via a web browser. companies at the exposition at the • Wavefonction showcased its MolecuAmerican Chemical Society's Boston lar Modeling Workbook for Organic meeting offered new products and up- Chemistry, a supplement to organic dates, including the following: chemistry textbooks that allows instruc• Molecular Simulations Inc. (MSI) has tors to design molecular-modelingnew versions of its quantum mechanics intensive organic courses. codes CASTEP and DMol3, which together • Gaussian98, the latest version of are used for studying surface and solid- Gaussian's electronic structure prostate chemistry and catalytic processes. grams, includes computation of NMR C2. MesoDyn and C2.DPD are new model- shielding tensors and chemical shifts at ing tools for studying polymer blends the M0ller-Plesset perturbation (MP2) and solutions, colloids, emulsions, and level, Raman intensity prediction using other complex soft materials. density-functional theory (DFT) and • Jaguar 3.5, the latest release of Schrô- MP2 methods, and several new DFT dinger's electronic structure theory soft- fonctionals. ware, includes geometry scans for gen- • Oxford Molecular's new version of erating potential-energy surfaces, a new its electronic structure modeling softmethod for scaling vibrational frequen- ware, DGauss, now runs on Windows cies, and improved initial guess wave- NT, interfaces to CAChe Desktop Chemfunctions for systems containing transi- istry Products, includes support for the tion metals. Cray T3E supercomputer, and has en• Fujitsu's new WinMOPAC 2.0, a graph- hanced NMR software capabilities. ical user interface andfoilWindows ver- • Synopsys has released version 3.0 of sion of its semiempirical molecular orbit- its chemical spreadsheet, Accord, for al program MOPAC, also contains an in- Microsoft Excel97. The version takes adterface and Windows implementation of vantage of the chemical data manageMOS-F—a semiempirical molecular orbit- ment capabilities of the Accord 3.0 al program for spectroscopy. Chemistry Engine and the Accord Ac• The Institute for Scientific Informa- tiveXChemistry Control within the Extion has released the ISI Chemistry Server, cel97 spreadsheet environment.
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science/technology NMR software: Everybody's doing it In chemistry, nowhere is the growing friendship between theory and experiment better illustrated than in thefieldof nuclear magnetic resonance spectroscopy. "Five years ago, only hardcore theoreticians were calculating NMR chemical shielding functions," Angel C. de Dios, assistant chemistry professor at Georgetown University in Washington, D.C., says. "That has changed a lot now— whenever experimentalists measure something new, there is also a calculation portion that goes with the paper." The dizzying acceleration of computer data processing speeds as well as theoretical and software advances are making once-stultifying calculations routine and, thus, available to almost anyone, even if they only have a desktop computer. A number of academic and commercial computational chemistry software packages contain programs that predict NMR spectra from known molecular structures. NMR software takes varied approaches, and scientists have a number of computational routes to choosefrom,depending on how much time and money they have, as well as the nature of their task. The most rigorously accurate way to model NMR chemical shifts is to start with the bare basics—solving the Schrôdinger equation, which describes the energies of a molecular system. This ab initio method^-from first principles— makes use of various modifications of theoretical standbys: Hartree-Fock or density-functional theory. By adding in the effects of the external magnetic field on the nucleus of interest, it's then possible to calculate the chemical shift, which is related mathematically to the total molecular energy,
"There are still many things to be done for accurate calculations," Nakatsuji tells C&EN. "Of course, larger computers will be helpful, but we still have many theoret ical aspects to be clarified." Among its many applications, NMR chemical shift modeling has aided re search on catalytic systems. Theoretician Nicholas collaborates with James F. Haw, a chemistry professor at the University of Southern California, in studying zeolites as well as various Lewis acid catalysts. "There's a tremendous amount of controversy about whether carbeniumlike species can be formed on zeolites," Nicholas says. "One of our greatest con tributions is to put hard limits on zeo lite acidity." Nicholas and Haw also 30 SEPTEMBER 28, 1998 C&EN
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This proton NMR spectrum of GLU 23 In the protein Crambln was calculated by H y perΝMR from Hypercube. The small window shows the protein with GLU 23 highlighted and the big window displays the NMR spectrum of that residue.
the applied magnetic field, and the nu clear magnetic moment. The electronic shielding felt by a nucle us in its molecular environment, and thus the chemical shift, depends on the direction of the magneticfieldrelative to the nucleus. So chemical shifts are fre quently expressed in terms of a chemical shift tensor, which describes—to make a complicated story short—the magnitude of the field felt at the site of the nucleus along the α direction, induced by elec tronic currents brought about by an ap plied magneticfieldalong the β direction.
have identified some unique carbenium species. As Nicholas explains their methodolo gy, he tries to model the catalyst system and studies it to see how a species might interact with the catalyst. "Once we've found a very likely structure, we then cal culate the NMR spectrum and see wheth er there's agreement." And it has worked out well for them. "We've been able to make theoretical pre dictions about which molecules will form stable carbenium species and which won't," he says. And NMR has helped them to "really verify some unusual things that are not commonly observed." Nicholas and Haw's collaboration is one of the shining examples of how ex
In gases and liquids, the continuous tumbling of molecules averages out the directional dependence of the chemical shift. But in solids, chemical shift tensor calculations become necessary. It is the elaborate business of these directional effects that many theorists are tackling as they try to elucidate cor relations between chemical shifts and complex structures such as proteins or catalysts. The Gaussian software from the Pitts burgh-based company of the same name is a popular choice, along with ac-
periment and theory can work together, Nicholas notes. "What it has done is allow us to make much better progress than each method alone," he says. "In some cases, we find new ways of doing things— there's a real nice synergy between the two methods." Also important in catalysis are transi tion-metal complexes. They have unusu al chemical shifts, but theorists have made empirical correlations between chemical shifts of the central metal atom and catalytic activity. Using DFT, Michael Buehl, a chemistry professor at the Uni versity of Zurich in Switzerland now has made the first theoretical prediction of a correlation between transition-metal NMR chemical shifts and rate constants.
ademic programs such as ACES Π and Below ab initio methods on the accu with an unusual or large complex molecule. Typically, a computer makes use of TEXAS, de Dios says. Gaussian's NMR racy ladder are semiempirical methods. databases of known structures and actools use a theory called gauge including Like ab initio, the semiempirical ap companying spectra. It receives the exatomic orbitals (GIAO), which is based proach attempts to solve the Schrôperimental spectrum and searches for a on Hartree-Fock, to calculate chemical dinger equation for a system; however, match. shift tensors. the equations used in the software already have been "parameterized"—that Empirical methods are "a computer The latest version of the software, is, initial assumptions about certain version of what an NMR expert might Gaussian98, includes in its code what's atomic properties already have been do in their head," notes Michael J. known as second-order, or M0llerplugged in, a step that saves large Frisch, president of Gaussian. "If it's a Plesset perturbation theory (MP2), amounts of calculation time. The more or less normal molecule, then it which increases the calculational com makes a pretty good guess." plexity to deal with tricky effects such Gainesville, Fla.-based software compaas electron correlation. This prob The speed of empirical methods lem arises when there are nearby ex I makes the method valuable to many cited electronic states that can con § experimentalists who want to flesh tribute to the NMR chemical shift, de |o out their gas-or solution-NMR results, Dios explains. Although electron ^ maintains Antony Williams, senior correlation effects aren't significant | product manager at Advanced Chemfor most organic compounds, they |o istry Development Labs, Toronto. do come into play when multiple ACD Lab's suite of NMR software bonds and lone pairs are present searches a database of molecule fragwithin the same region of a mole ments and their assigned spectra cule, or in heavier elements. "MP2 (rather than entire molecules), takes gets most of the hard cases," says into account intramolecular interacDouglas J. Fox, director of technical tions, and predicts a spectrum. support for Gaussian. Other companies with software Ab initio methods are undoubted packages that predict NMR spectra inly the most comprehensive, but they clude CherweÛ Scientific Inc. and Oxare more time consuming and ex ford Molecular, both based in Oxford, pensive, theorists say. The develop England. ment of a great number of theoreti A current flow diagram for benzene, with colors There's also plenty of software to cal tricks has been driven by the showing the magnitude of the current The high manage and process NMR spectra; need to cut down on computer time symmetry of benzene makes the current struc- Molecular Simulations Inc. (MSI), San tures easy to visualize. Current diagrams of more Diego, and Tripos Inc., St Louis, for and costs. Peter Pulay, a chemistry professor complicated molecules are difficult to Interpret example, have several NMR software at the University of Arkansas, Faymodules to help experimentalists do etteville, has applied parallelization ny Hypercube markets a semiempirithings such as assign spectral peaks. A techniques using clusters of Pentiumnew application for NMR is in the drugcal NMR package called HyperNMR, Pro processors, giving what he says can which can outpace ab initio packages discovery arena, where high-throughbe supercomputer performance at a such as Gaussian by two orders of magput screening meshes with NMR to genmoderate price. "We can carry out a cal nitude, according to Hypercube's preserate and compare spectra for whole arculation on a 100-atom organic mole ident and chief executive officer, Neil rays of compounds. cule overnight with reasonable accura S. Ostlund. "NMR is going through a renaissance cy, and the total cost of it may be about Finally, empirical methods are even right now," according to Scott D. Kahn, $20—not a large sum as research ex faster, but their accuracy suffers in com- director of life sciences marketing at penses go," Pulay says. parison with ab initio when dealing MSI.
Such predictability could be very useful to catalyst designers. "The expected reactivity or catalytic activity of a newly synthesized complex could be estimated from its NMR spectrum alone," Buehl says. Buehl envisions possibly being able to select target molecules based on NMR data from the literature—ligand or substituent effects on transition-metal chemical shifts in related compounds, for example. Isao Ando, a chemistry professor at Tokyo Institute of Technology, described his methods for calculating NMR shifts in polymers in the solid state, using the solid-state physics tight-binding molecular orbital theory. In this theory, the sys-
tem's wavefunction is treated as a sum of atomic wavefunctions centered about each atom in the system, multiplied by a phase factor. In the past, theorists have developed semiempirical tight-binding models, but Ando has taken the theory a step higher, to ab initio calculations. With this model, he's been able to use NMR to determine the structure of olefinic and vinyl polymers, conducting polymers, and polypeptides. Theorists also would like to be able to predict NMR spectra in crystals, says Thanh Truong, a chemistry professor at the University of Utah, Salt Lake City. "Rigorous theory of NMR chemical shifts has existed only for gas-phase systems,"
he notes. But even if a comparable rigorous theory did exist for crystals, it would be computationally expensive. For some time, theorists have used what's known as embedded cluster methods to attack this problem. In this theoretical approach, only a small area of interest (in this case, the resonant nucleus) is treated quantum mechanically, while the surrounding environment is modeled more simply by any number of methods. Truong also takes this approach, using the so-called Madelung field to describe the environment. In a crystal, this field is the potential exerted on a molecule or atom due to other molecules in the lattice. It is represented by a set of SEPTEMBER 28, 1998 C&EN 31
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science/technology point charges. Truong says he is accu rately able to represent the Madelung field in the region of the resonant nucle us, which had previously been a difficult task. Truong then harnessed this theoret ical description to calculate NMR chemi cal shifts. With it, he's been able to mod el the NMR chemical shift of the adsorp tion of NH3 in zeolites, he says. Ned H. Martin, a chemistry professor at the University of North Carolina, Wilmington, described his approach to an NMR anomaly. As Martin explained at the meeting, he and his students were using ab initio methods to predict NMR shielding above the plane of aromatic rings and alkenes. They found that above the carbon-carbon double bond of an alkene, some proton signals were deshielded. Conventional wisdom has held that the proton over a carbon-carbon double bond ought to be shielded. "However, what we've found is the opposite," Martin says. They found a dif ference in chemical shift between a hy drogen that's over a carbon-carbon dou ble bond and one in an otherwise com parable environment.
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Other chemists also were aware of this anomaly, noting that this unexpected deshielding occurs when the proton is very close to an aromatic ring—within 3 À. They hypothesized that this was due to a compression of the orbitals in the π system. Using the GAIO program in Gaussian94, Martin came up with a "mammoth" equation that predicts shielding incre ments for any proton position, given its
Oldfield: reason for discrimination
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xyz coordinates relative to the center of a carbon-carbon double bond. At the symposium, Martin showed what happens to an orbital that's only 2 À away from the proton: "The upper level is severely distorted; it's squooshed, bent away," he says. One of the most tantalizing possibilities of NMR is its potential to unlock the structures of peptides and proteins. Although empirical relationships have
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34
SEPTEMBER 28, 1998 C&EN
CIRCLE 1 ON READER SERVICE CARD
phyrins. But in proteins, CO binds been drawn between some struc only about 100 to 200 times as tures and chemical shifts, it's quite readily. This is good fortune, in another thing to use the chemical deed, because a human would shift values to derive structural Δσ, ppm quickly perish if oxygen were information. blocked from binding to hemoglo The consequences of protein bin and myoglobin. folding in NMR have been known The reason for this discrepancy for about 30 years: For example, an in binding affinity had been at unfolded protein will show one cartributed to a distal histidine in bon-13 peak for one particular kind the myoglobin and hemoglobin, of carbon, but once the protein is which blocks linear binding of folded, the spectrum from that CO, forcing it into an unfavorable carbon splits into many peaks. bent conformation. Numerous scientists are working on the problem, trying to understand However, Oldfield and col the differences between chemical leagues recently computed NMR shifts in a certain structure, based on chemical shifts and Mossbauer observation of both conventional iso spectra of CO-heme proteins. The tropic chemical shifts and chemical only way they could reproduce the -150^0150 shift anisotropics. These relation experimental spectra was to use a Colored surface shows how the chemical shielding ships can help chemists understand linear Fe-CO geometry. Further anlsotropy of the α carbon In a valine peptide var key aspects of molecules, such as work by de Dios and colleagues, in ies with backbone torsion angles ψ and φ. binding-site structures, which are which they added in effects of elec particularly important for drug de trostatic fields, also showed linear sign and discovery. between the nitrogen and aliphatic binding. To help explain the CO/0 2 dis A breakthrough in the study of these carbon, and ψ is the rotation about the crimination, Oldfield computed electro complex systems came about five years bond between the α carbon and the static potential surfaces for CO and 0 2 bound to hemes, which showed the ter ago, with introduction of fast RISC (re carbonyl carbon. duced instruction set computer) work Chemists can now readily generate minal oxygen in 0 2 is more electronega stations, says Eric Oldfield, a chemistry chemical shielding surfaces as a function tive than CO, and can therefore hydro professor at the University of Illinois, Ur- of these two torsion angles, showing gen bond to the distal histidine. bana-Champaign. Oldfield and de Dios, which pair of angles is likely, given a par In exploring chemical shift anisotro using Pulay's TEXAS program, were able ticular chemical shift tensor. pics, Judith Herzfeld, a professor of bio to predict carbon-13 and nitrogen-15 Oldfield's predictions have had inter physical chemistry at Brandeis University chemical shifts in some proteins for the esting applications: A long-standing ques in Waltham, Mass., made the assumption first time. tion has been how carbon monoxide that the electron current density induced The chemical shifts are a function of binds to hemoglobin and myoglobin. CO by an applied magnetic field is always the backbone torsion angles ψ and φ, binds 30,000 times more readily than perpendicular to the field. "The results where φ is the rotation about the bond molecular oxygen to model metallopor- were surprising and aesthetically pleas-
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SEPTEMBER 28, 1998 C&EN 3 5
software/database
science How does CO bind to myoglobin and hemoglobin? \ \\ CH HC^N/ H
0
III c 1
1
1
1
Fe
Fe
|
HC*N^CH 1 li HN C
1
Heme model
|
HC*N"CH 1 li HN C
1 CO-myoglobin
Carbon monoxide binds linearly to isolated iron porphyrins (left). In the binding of CO to myoglobin and hemoglobin, however, the distal histidine was thought to prevent linear binding, forcing the CO into an energetically unfavorable bent mode (right). This would explain why CO binding occurs infrequently in these biochemical systems relative to model metalloporphyrins. But recent NMR and Môssbauer studies show that CO may bind linearly to myoglobins and hemoglobins.
ing," she notes. She found that in this case, the shift tensor is symmetric, which implies that any asymmetry in the shift tensor arises from out-of-plane electron current density. Also, the anisotropy in the shift tensor is related directly to the variation of the isotropically averaged shift through space around that site. Herzfeld is testing the usefulness of the approximation that the currents are perpendicular to the applied field. Some compounds, such as phosphates, show good agreement between the approximate theory and experiment, but more research will be needed, she notes. Despite all the progress, there are challenges still to be tackled, researchers agree. Although inroads have been made on heavy-element NMR, significant questions remain, de Dios says. He also cites the importance of understanding molecular dynamics in intermolecular effects in NMR. Nicholas adds: "There's still very much a problem [modeling NMR in] transition metals; we still need much better algorithms so we can do big systems; and we probably need some methods to do this accurately within a solid-state framework. This is a very active area of research."^ 36 SEPTEMBER 28, 1998 C&EN
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