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Summary Conversion of aldo to keto sugars by the metalloenzyme D-xylose isomerase (XI) is a multistep reaction that involves hydrogen transfer. We have determined the structure of this enzyme by neutron diffraction in order to locate H atoms (or their isotope D). Two studies are presented, one of XI containing cadmium and cyclic D-glucose (before sugar ring opening has occurred), and the other containing nickel and linear D-glucose (after ring opening has occurred but before isomerization). Previously we reported the neutron structures of ligand-free enzyme and enzyme with bound product. The data show that His54 is doubly protonated on the ring N in all four structures. Lys289 is neutral before ring opening and gains a proton after this; the catalytic metal-bound water is deprotonated to hydroxyl during isomerization and O5 is deprotonated. These results lead to new suggestions as to how changes might take place over the course of the reaction.

Structural features of clusters involving a metal ion (Li+, Na+, Be2+, Mg2+, Zn2+, Al3+, or Ti4+) surrounded by a total of 18 water molecules arranged in two or more shells have been studied using density functional theory. Effects of the size and charge of each metal ion on the organization of the surrounding water molecules are compared to those found for a Mg[H2O]62+• [H2O]12 cluster that has the lowest known energy on the Mg2+• [H2O]18 potential energy surface (Markham et al. in J Phys Chem B 106:5118–5134, 2002). The corresponding clusters with Zn2+ or Al3+ have similar structures. In contrast to this, clusters with a monovalent Li+ or Na+ ion, or with a very small Be2+ ion, differ in their hydrogen-bonding patterns and the coordination number can decrease to four. The tetravalent Ti4+ ionizes one inner-shell water molecule to a hydroxyl group leaving a Ti4+(H2O)5 (OH−) core, and an H3O+• • • H2O moiety dissociates from the second shell of water molecules. These observations highlight the influence of cation size and charge on the local structure of hydrated ions, the high-charge cations causing chemical changes and the low-charge cations being less efficient in maintaining the local order of water molecules.

It is common knowledge that some metal ions prefer to bond to nitrogen atoms, others prefer oxygen and others select sulfur, although the mechanistic origin of this behaviour is not well understood. To provide quantitative data that can illuminate this characteristic difference, we have been performing ab initio molecular orbital calculations on complexes of a wide variety of main group and transition metal ions with simple ligands. In this paper we concentrate on metal ion complexes of NH3 and compare them with the corresponding complexes with H2O (Trachtman et al., 1998, Inorg. Chem., 37, 4221). The results reported here show that for each metal ion the bonding to ammonia in monoammines is intrinsically stronger than that to water in monohydrates, but that the enthalpy of formation of the amine complexes has a greater sensitivity to the nature of the metal ion. For both mono- and divalent transition metal cations the ligand-field stabilization energy (LFSE) in the monoammine complexes is larger than tha...

In this paper, we report the results of a study involving the coordination geometries of CuI, CuII, and CuIII crystal structures in the Cambridge Structural Database, and on Cu binding sites in proteins taken from the Protein Data Bank. The motifs used to bind two bridged Cu ions are also described. In addition, we report the results of ab initio molecular-orbital calculations performed on a variety of model CuI/CuII complexes (CuI/CuII⋅XnYm (X, Y=NH3, SH2); n+m=4; n=0–4) to provide data on the structural and energetic changes that occur in isolated complexes when the oxidation state of the Cu ion is changed from II to I while the coordination number is conserved. The use of such simple ligands in these calculations eliminates constraints on the geometric changes that may be imposed by more-complicated ligands.

The structures and binding enthalpies of a variety of gas-phase divalent magnesium ion hydrates containing up to 18 water molecules have been studied computationally. Second-order Moller−Plesset (MP2) perturbation theory and B3LYP hybrid density functional theory, using large basis sets containing both (multiple) polarization and diffuse functions, were employed. A comparison with experimental data is made by use of information on 36 Mg[H2O]62+ crystal structures listed in the Cambridge Structural Database. Computational studies indicate that Mg[H2O]52+ and Mg[H2O]62+ complexes with all the water molecules in the inner coordination sphere are lower in energy than structures with one or two of the water molecules placed in the second coordination sphere; these energy differences are larger for MP2 than for B3LYP calculations, when the same basis set is employed. Hydrated magnesium environments in crystal structures confirm the stability of the Mg[H2O]62+ grouping. A new model of a divalent magnesium ion co...

Linear relationships have been established between the dissociation enthalpies of the monohydrates of Li+, Na+, K+, Be2+, Mg2−, Ca2+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+, Al3+, Sc3+, Ti3+, V3+, Mn3+, Fe3+ and Ga3+ calculated at the MP2(FULL)/6-311++G**//MP2(FULL)/6-311++G** level, the hexahydrates of Na+, K+, Mg2+, Ca2+, Mn2+, Zn2+, Al3+, Sc3+, Fe3+ and Ga3+ calculated at the MP2(FULL)/6-311++G**//HF/6-311++G** level, and experimentally reported pKa values for the first ionization of the corresponding aqua-ions. In contrast to the results of Chang and Wang [Chem. Phys. Lett. 286 (1998) 46], we find that the 3+ ion hexahydrates are more (not less) stable than the 2+ ion hexahydrates.

SummaryD-xylose isomerase (XI) is capable of sugar isomerization and slow conversion of some monosaccharides into their C2-epimers. We present X-ray and neutron crystallographic studies to locate H and D atoms during the respective isomerization and epimerization of L-arabinose to L-ribulose and L-ribose, respectively. Neutron structures in complex with cyclic and linear L-arabinose have demonstrated that the mechanism of ring-opening is the same as for the reaction with D-xylose. Structural evidence and QM/MM calculations show that in the reactive Michaelis complex L-arabinose is distorted to the high-energy 5S1 conformation; this may explain the apparent high KM for this sugar. MD-FEP simulations indicate that amino acid substitutions in a hydrophobic pocket near C5 of L-arabinose can enhance sugar binding. L-ribulose and L-ribose were found in furanose forms when bound to XI. We propose that these complexes containing Ni2+ cofactors are Michaelis-like and the isomerization between these two sugars proceeds via a cis-ene-diol mechanism.

The binding of two metal ions that are in close proximity in proteins is examined using a combination of (1) crystallographic structural database analyses and (2) density functional theory calculations on model complexes. Divalent magnesium and manganese ions are the focus of the present study. It is found that in all proteins in the Protein Databank that have two closely positioned magnesium or manganese ions, these metal ions are generally bridged by at least one negatively charged oxygen-containing group—carboxylate, phosphate, or sulfate. This group transfers (negative) electron density to the metal ions and this helps to reduce electrostatic repulsion in the region. The geometry of the two-metal complex appears to depend on the nature of the negatively charged group between them. When a single oxygen atom is also in a bridging position, the two metal ions are found to be closer together than when only a carboxylate group binds them together. This suggests that this bridging oxygen atom may be negatively charged, e.g., a hydroxide ion rather than a water molecule. Details of the geometry of such bridges and the relevant motifs that are found in crystal structures are described.

1,4-Dimethylbenzo[c]phenanthrene (1,4-DMBcPh) is the dimethylated analogue of the benzo[c]phenanthrene (BcPh), where one of its two methyl groups resides in the highly congested fjord-region. A comparative X-ray crystallographic analysis, described herein, shows that BcPh is distorted out-of-plane so that there is an angle of 27° between the outermost rings. The additional methyl groups in 1,4-DMBcPh increase this nonplanarity to an angle of 37°. This methyl group-induced disruption of planarity results in P and M enantiomers of 1,4-DMBcPh, and this helicity is observed in a pronounced manner in its putative metabolites, the dihydrodiol and diol epoxide. Synthetically, photochemical cyclization offers convenient access to 1,4-DMBcPh as well as its metabolites. For this, Wittig reaction of 2,5-dimethylbenzyltriphenylphosphonium chloride and 2-naphthaldehyde provided a cis/trans mixture of alkenes which, when subjected to photolysis, provided 1,4-DMBcPh. Despite the high steric congestion in the fjord-regio...

The role of the cyclopropyl ring structure in the cyclization/fission mechanism for the 1,2 shift of the title radicals, whether as a local minimum on the potential energy surface or as a transition state, has been investigated using density functional theory calculations at the B3LYP/6-31+G*//B3LYP/6-31+G* computational level. The three-membered ring structure, C(1)−C(2)−C(3), has been identified for all the substituent groups, and the alteration in ring geometry that accompanies the changeover in its role has been characterizednotably an increase in the C(1)−C(3) and C(2)−C(3) bond lengths beyond a certain threshold value. The free energy of activation at 298 K for the cyclization/fission mechanism has been compared with that for the alternative fragmentation/recombination mechanism, in which breaking the C(2)−C(3) bond in the initial extended chain structure of the radical, giving an olefin and the radical derived from the substituent group, is followed by C(3)−C(1) bond formation. The difference, δΔG⧧...

The carcinogenicity of benzo[a]pyrene (BaP) derivatives varies with the substituents they contain. The effects of these substituents on the geometric structures of the PAHs have been examined by X-ray diffraction studies. Data presented include bond lengths and angles. deviations from planarity in the bay region, and non-bonded H˙˙˙˙H distances. Structures in the sequence BaP, 11-methylBaP and dibenzo[a, l]pyrene illustrate the increased nonplanarity of the PAHs as the carcinogenicity increases. For comparison, the geometry of 7,12-dimethylbenz[a]anthracene (DMBA) is also discussed. The structures of a diol epoxide of 5,6-dimethylchrysene and the product of the reaction of the diol epoxide of 5-methylchrysene with methanol are also presented. These show how the bay-region methyl group affects the structure, and presumably also the reactivity of the diol epoxide.

The various steps in a mechanism for the diol dehydrase reaction in which a carboxylic acid group of an amino acid residue at the active site of the enzyme serves as an additional cofactor have been investigated using density functional theory (B3LYP) calculations. This mechanism involves a neutral radical rather than a protonated radical (radical cation). 1,2-Dihydroxyethane was chosen as the substrate, and formic acid was selected as a model for the carboxylic acid group. The 1,2-dihydroxyeth-l-yl radical (produced by H-atom transfer from the substrate to the 5‘-deoxyadenosyl radical) forms a nine-membered ring structure with the formic acid. There are two intermolecular hydrogen bonds in this ring structureone with the OH of the ĊOH group in the radical as a hydrogen donor and the CO group in the formic acid as an acceptor, and the other with the OH of the COH group in the radical as an acceptor and the COH group of the formic acid as a hydrogen donor. Bond rearrangement within this hydrogen-bonded rin...

Divalent manganese, magnesium, and zinc fill unique roles in biological systems, despite many apparently similar chemical properties. A comparison of the liganding properties of divalent manganese, magnesium, and zinc has been made on the basis of data on crystal structures (from the Cambridge Structural Database and the Protein Databank) and molecular orbital and density functional calculations. The distribution of coordination numbers for divalent manganese in crystal structure determinations, and the identities of ligands, have been determined from analyses of data derived from the structural databases. Enthalpy and free energy changes for processes such as loss of water or ionization of water from hydrated cations have been evaluated from computational studies. The energy penalty for changing the hexahydrate of divalent manganese to a pentahydrate with one water molecule in the second coordination shell is intermediate between the high value for magnesium and the low value for zinc. The preferred coor...

The three-dimensional structure of a dihydrodiol epoxide of 5, 6-dimethylchrysene was elucidated by X-ray diffraction techniques. The effects of the steric overcrowding by the 5-methyl group in the bay region of this compound are described. The carbon atom of the 5-methyl group is found to lie out of the plane of the aromatic system, thereby avoiding the nearer C-H group of the epoxide ring; this C-H hydrogen atom is pushed in the opposite direction. As a result, the molecule is distorted so that the relative orientations of the epoxide group and the aromatic ring systems are very different for the diol epoxides of (nearly planar) benzo[a]pyrene (studied by Neidle and co-workers) and (distorted) 5, 6-dimethylchrysene (described here). The main effect of the 5-methyl group is to change the relative angle between the epoxide-bearing ring (the site of attack when the diol epoxide acts as an alkylating agent) and the aromatic ring system (which is presumed to lie partially between the DNA bases in the DNA adduct that is about to be formed). This may favor some specific alkylation geometry.

The three-dimensional structure of the carcinogenic nicotine-derived nitrosaminoketone, 4-(methyl-nitrosamino)-l-(3-pyridyl)-l-butanone, has been determined by X-ray crystallographic techniques. The molecule is essentially planar except for the methylnitrosamine group which is oriented at a dihedral angle of 68.7° to the pyridine ring. Molecules pack by way of —H⋯O interactions that involve the —NNO group.

The views of several well known crystallographers on how to teach the subject are presented with a description of teaching texts and schools available on a world-wide scale.

The formation and properties of a wide range of metal ion monohydrates, M(n)()(+)-OH(2), where n = 1 and 2, have been studied by ab initio molecular orbital calculations at the MP2(FULL)/6-311++G//MP2(FULL)/6-311++G and CCSD(T)(FULL)/6-311++G//MP2(FULL)/6-311++G computational levels. The ions M are from groups 1A, 2A, 3A, and 4A in the second, third, and fourth periods of the periodic table and the first transition series. Structural parameters, vibrational frequencies, bonding enthalpies, orbital occupancies and energies, and atomic charge distributions are reported. Trends in these properties are correlated with the progressive occupancy of the s, p, and d orbitals. Except for K(+)-OH(2) and Ca(2+)-OH(2), the O-H bond lengths and HOH angles are greater in the hydrates than in unbound water. The M-O bond lengths decrease proceeding from group 1A --> 4A but become larger in proceeding from the second --> fourth period. The bonding enthalpies, are found to be inversely linearly dependent on the M-O bond length M(n)()(+) according to equations of the form = A + B(1/M-O) for n = 1 and n = 2. Within each monohydrate the distribution of atomic charge reveals a small but definite transfer of charge from water to the metal ion. Compared to unbound water there is, in a metal-ion-bound water complex, an increase in the electronic (negative) charge on the oxygen atom, accompanied by a (significantly) larger decrease in the electronic charge on the hydrogen atoms. The bonding of the water molecule, although electrostatic in origin, is thus more complex than a simple interaction between a point charge on the metal ion, and the water dipole.

The effects of a metal ion-bound carboxylate group on the acidity of a water molecule bound to the same cation have been assessed by ab initio molecular orbital calculations. In the hexahydrate Mg[H2O]62+ the free energy required to deprotonate one coordinated water molecule is only 40% of that required to deprotonate a free water molecule, indicating that the presence of the magnesium ion facilitates the ionization of water. However, if one of the water molecules in this hexahydrate Mg[H2O]62+ is replaced by a carboxylate ligand, the energy required to dissociate a proton from a metal ion-bound water molecule is increased by approximately 80 kcal/mol and is intermediate between the energy required to deprotonate one water molecule in Mg[H2O]62+ and that for a free water molecule. This effect of the carboxylate group on the pKa of metal ion-bound water appears to be primarily the result of a reduction of the net positive charge of the overall Mg[H2O]52+−(RCOO-) complex rather than any changes in the elect...

The role of the lone pair of electrons of Pb(II) in determining the coordination geometry is analyzed from crystallographic studies and ab initio molecular orbital optimizations. Of particular interest are factors that contribute to the disposition of ligands around the lead with geometries that are (1) holodirected, in which the bonds to ligand atoms are distributed throughout the surface of an encompassing globe, and (2) hemidirected, in which the bonds to ligand atoms are directed throughout only part of an encompassing globe, i.e., there is an identifiable void in the distribution of bonds to the ligands. The preferred coordination numbers for lead were found to be 4 for Pb(IV) and 4 and 6 for Pb(II). All Pb(IV) structures in the CSD have a holodirected coordination geometry. Pb(II) compounds are hemidirected for low coordination numbers (2−5) and holodirected for high coordination numbers (9, 10), but for intermediate coordination numbers (6−8), examples of either type of stereochemistry are found. A...

The mechanism of action of the enzyme diol dehydrase has variously been suggested to involve a radical, a protonated radical (radical cation), or a carbocation in the apparent transfer of HO from one carbon atom to the other to give acetaldehyde and water. This adenosylcobalamin-requiring B12 enzyme catalyzes dehydration of 1,2-dihydroxyethane. Its active site is buried within a hydrophobic cavity. Each of the three possibilities are examined by ab initio molecular orbital calculations. Total molecular energies have been calculated with full geometry optimization at the MP2(FC)/6-31G* level and, in addition, single point energies using the MP2(FC)/6-311++G** basis set. Vibrational frequencies were also calculated. Transfer of an HO group within a HOCH−CH2OH⎤• radical (postulated to be formed by the initial reaction of the diol with the deoxyadenosyl radical via a bridge structure) was ruled out because the activation energy is much too high in relation to the observed rate constant for the enzyme reaction...

The crystal structure of the complex between the polycyclic aromatic hydrocarbon di-benz[a,c]anthracene and 1,3,5-trinitrobenzene is reported. The crystals are triclinic, space group P¯1 with unit cell dimensionsa=7.277(2) a,b=11.237(6) a, andc=13.902(5) a,α= 104.13(4)‡,Β=96.04(3)‡, and γ=95.15(2)‡. Diffraction data were measured at 121(2) K. The structure was determined and refined toR 1=0.046. The structure consists of layers containing both dibenz[a,c]anthracene and 1,3,5-trinitrobenzene molecules, interconnected within a layer by C-H⋯ O interactions. Layers stack on one another so that dibenz[a,c]anthracene molecules are sandwiched between 1,3,5-trinitrobenzene molecules and vice versa. The average distance between molecules in these sandwiches is 3.23 a.

Hydrogen bonding and the electron-withdrawing or electron-donating characteristics of substituent groups that are neighboring to epoxide groups can affect the reactivity of the epoxide ring. The crystal structure ofcis-2,3-epoxycyclooctanol has been determined as a saturated eight-membered ring compound in which a hydroxyl group is attached to the C(1) atom that is adjacent to a 2,3-fused epoxy ring. The findings are that the longer epoxide C-O bond (and hence the one expected to be more readily broken) is the one farther from the hydroxyl group [1.462(1) a versus 1.447(1) a] and that the optimal hydrogen bonding is to an adjacent molecule radier than within the molecule. The shortest C-C bond is that of the epoxide group; the bond adjacent to it (on the side farther from the hydroxyl group) is the next shortest.

The synthesis of a novel compound, 3-deoxy-3-fluoro-β-d-allopyranoside, is described. It involves blocking the 4- and 6-positions of allose to cause fluorination only at the 3-position. This six-step synthesis gave pure crystalline compound in a 5% overall yield. The crystal structure, determined by X-ray diffraction, confirmed the chemical formula and configuration of the product. It showed that the C-F bond isaxial, while the C-(OH) bonds areequatorial. The overall conformation of this fluoroallose is similar to that of allose (Acta Cryst.1984,C40, 1863) (with OH instead of F), but the packing in the two crystals is different in the region of C3, the site of chemical variation.

The molecular geometry of benzo[a]pyrene, its 4-methyl- structure of the monoclinic form was determined by Iball and and 3,11-dimethyl derivatives, benzo[e]pyrene, and two Young in 1956, based mainly on two-dimensional diffraction azabenzo[a]pyrenes are described. Results of these three- data so that the molecular dimensions were not very precise dimensional crystal structure determinations, together with (11). Later Iball refined the structure with new diffraction data, those from previous studies in this laboratory of 11- and obtained a more precise structure which included hydrogen methylbenzo[a]pyrene, indicate the extent to which non- atom positions (12). Since there have been extensive improvebonded interactions between hydrogen atoms contribute to ments in the art of small-molecule crystallography since 1976, molecular distortions, particularly in the bay-region. This and in order to provide structural data for comparison with strain is high if a bay-region methyl group is present. The those of analogues, the crystal structure determination of the major effect is an increase in the C‐C‐C angles in that monoclinic form of benzo[a]pyrene was repeated. Crystals area of the molecule, rather than torsion about bonds. were studied by us at low temperatures (120 K) so that atomic In addition, the effect of a nitrogen atom replacing one vibrations were decreased and, as a result, atomic positions of the C-H groups in the aromatic system is shown. could be better determined. This low temperature (120K 5 Molecules stack in planes ~3.5 A apart. In benzo[a]- ‐153°C) does not change the molecular geometry, although it pyrene, 5-azabenzo[a]pyrene and 3,11-dimethylbenzo[a]- might have a slight effect on intermolecular distances. As a pyrene crystals the stacking is similar to that in graphite. 4- result the molecular geometry is determined with higher Methylbenzo[a]pyrene molecules stack with less molecular precision than before, a situation similar to that of our lowoverlap. The packing in 4-aza-5-methylbenzo[a]pyrene con- temperature work on DMBA (13). The crystal structure of sists of modules of four stacked molecules, packed in BeP is also reported in a low-temperature study. This molecule, a ‘tile-like’ arrangement. Nonbonded C····H interactions unlike BaP, is not reported to be carcinogenic. between adjacent molecules lead to a herring-bone arrange- The overall aim in these studies was to determine the amount ment between these stacks. The types of C····H andp‐p of distortion due to steric overcrowding in these molecules. interactions involving PAHs in the crystalline state, Such distortions are much less evident in BaP and its analogues described here, can also be expected to be found when the than in DMBA (13). Finally the effect of a bay-region methyl PAHs bind to hydrophobic areas of biological macro- group in 3,11-dimethyl-BaP (which has carcinogenic activity) molecules such as proteins, nucleic acids and membranes. is assessed. Structural data have already been reported by us for 11-MeBaP (disordered) (14) and can now be analysed in detail. The numbering in each BaP analogue has been chosen

As part of our investigation of the role of 6,8-dioxabicyclo[5.1.0]octa-2,4-diene (6,8-dioxa BCOD; epoxyoxepin) as the precursor of muconaldehyde in the metabolic oxidation of benzene, we have carried out ab initio molecular orbital calculations on the fission of the three-membered (epoxide) ring in 6,8-dioxaBCOD and 8-oxaBCOD in which cyclic enol structures are formed. Electronic energies have been calculated at the MP 2 6–31 G ∗ (frozen core, valence orbitals active) level with full geometry optimization at the RHF 6–31 G ∗ level. With the inclusion of thermal energies derived from vibrational frequencies obtained at the RHF/6–31G∗//RHF/6–31G∗ level, reaction energies and activation energies that would correspond to gas phase data at 298 K have been evaluated. Syn and anti conformers of the enol structures have been identified. The syn conformer from 8-oxaBCOD is more stable than the anti by 2.0 kcal mol−1, in common with other enols, whereas the anti conformer from 6,8-dioxaBCOD is more stable than the syn by 1.9 kcal mol−1; a difference attributable to a hydrogen bonding interaction with O6 in the seven-membered ring. The ketone formed by the tautomeric shift is 8.4 kcal mol−1 lower in energy than the syn-enol from 8-oxaBCOD, whereas the lactone formed by the corresponding shift in the anti-enol from 6,8-dioxaBCOD is 27.4 kcal mol−1 lower in energy; an enhanced energy difference mainly attributable to the well-known stabilization in an acyl grouping. Transition states for the ring fission have been characterized and found to lead to the syn conformers of the enol structures. The activation energy for the fission in 6,8-dioxaBCOD is far larger than that for the cooperative fission of both rings; 32.7 compared with 16.5 kcal mol−1. Hence, competition with the formation of eZzZz-muconaldehyde in the latter reaction is negligible. The energy barriers for the two fission processes in 8-oxaBCOD, however, favor the former; 33.7 compared with 41.5 kcal mol−1. These results have established that the fission of the epoxide ring giving enol structures is an extremely unfavorable process, due apparently to an inherent difficulty in effecting the requisite 1,2 H-shift and the lack of any driving force that might originate in changes in the bonding in the seven-membered ring. In contradistinction, the fission of both rings, which in the case of 6,8-dioxaBCOD results in the formation of muconaldehyde, is characterized by a profound alteration in the bonding between the heavy atoms: all the bonds but one change from double to single, or vice versa, notably the bonding to the oxygen atoms.

Ab initio molecular orbital calculations have been used to investigate contributions of water molecules in the first and second coordination shells to the overall hydration energy of divalent beryllium and magnesium cations. Enthalpy and free energy changes at 298 K have been calculated at a variety of computational levels for the reactions M2+ + [H2O]p → M2+·nH2O·mH2O, where M = Be or Mg, [H2O]p (p = 2, 4, 6, 8; p = n + m) are water clusters, and M2+·nH2O·mH2O are ion−water complexes with n and m water molecules in the first and second coordination shells, respectively. These reactions involve the disruption of the water cluster and naturally include the competitive effects of ion−water and water−water interactions inherent in the hydration process. At the MP2(FULL)/6-311++G**//RHF/6-31G* computational level, the values of ΔG298 for the reactions which complete the first hydration shells, Be2+ + [H2O]4 → Be2+·4H2O and Mg2+ + [H2O]6 → Mg2+·6H2O, are −352.0 and −266.7 kcal/mol, accounting for 61.2% and 60....

The three-dimensional structure of 3-methyl-2H-anthra[1,2-b]pyran-2-one, an anticarcinogenic coumarin related to the carcinogen benz[a]anthracene, has been determined by X-ray diffraction techniques. The molecule, apart from hydrogen atoms in the methyl group, is flat, the maximum deviation from its least squares best plane being 0.13 angstroms. The carbonyl C=O bond length is normal [1.206(1) angstroms] and the bonding throughout the molecule indicates localization of double bonds within the coumarin ring, but some delocalization of electrons in the other rings. Molecules pack in planes parallel to each other, the coumarin ring oxygen atom lying between two aromatic rings of other coumarin molecules. The bulky methyl groups are not involved in such stacking, while the carbonyl groups attract C-H groups in neighboring molecules by way of C-H...O interactions. These are the types of interactions that such coumarins could make if they bound to hydrophobic areas in biological macromolecules.

The bidentate hydrogen-bonding patterns frequently formed by the side chains of the amino acids arginine, asparagine, and glutamine can be described, using graph-set notation, as (8) (ring pattern of eight atoms with two donor and two acceptor hydrogen bonds). It is shown that this hydrogen-bonding pattern is present in approximately 34% of the high-resolution crystal structures in the Cambridge Structural Database (CSD) that have the potential to form this particular pattern. Most of these crystal structures involve an interaction between two amide groups, but a significant number involve an interaction between an amidinium cation and a carboxylate anion. The mean H···O bond distances and the N−H···O bond angles found for these two types of interaction are nearly the same. Ab initio molecular orbital calculations are used to investigate the structure, charge distribution, and decomposition enthalpies of several gas phase hydrogen-bonded complexes which have these types of (8) interactions. Calculated H··...

The three-dimensional structure of the product of the reaction of a diol epoxide of the carcinogen 5-methylchrysene with methanol has been determined by an X-ray diffraction analysis. The diol epoxide used to obtain this compound contains a stereochemically hindered bay region because of the location of the 5-methyl group, and this might be expected to affect the type of chemical reaction that occurs. The crystal structure analysis of this adduct of a polycyclic aromatic hydrocarbon (PAH) showed that a methoxy group has been added at the carbon atom of the epoxy group that is nearest to the aromatic system. The bond that is formed is axial to the ring system so that the carbon and hydrogen atoms of the methoxy group are considerably displaced from the PAH ring plane. The bay-region methyl group at position 5 is displaced out of the ring plane in the opposite direction. The major steric distortion in this methanol adduct is shown, by a comparison with crystal structures of related non-methylated compounds, to be in the area of the 5-methyl group and not in the tetrol-bearing ring. The steric effects that caused the axial conformation of the newly formed bond would also be expected to pertain in the DNA adduct of a PAH with a bay-region methyl group. Since the presence of the bay-region methyl group in 5-methylchrysene has been shown to enhance the carcinogenicity of this PAH over the parent compound or compounds with methyl groups in other positions of the molecule, it might be anticipated that this axial bond is found in carcinogenic lesions in DNA, and that any factor that ensures this axial conformation may accentuate the carcinogenic potential of a PAH of the appropriate size.

The coordination geometry of divalent calcium ions has been investigated by analyses of the crystal structures of small molecules containing this cation that are found in the Cambridge Structural Database, protein crystal structures in the Protein Databank, and by ab initio molecular orbital calculations on hydrated structures of the form Ca[H2O]n2+·mH2O, in which there are n water molecules in the first coordination shell and m water molecules in the second coordination shell (hydrogen bonded to water molecules in the first shell). Calcium ions in crystal structures generally bind to oxygen atoms in ligands (rather than any other element), and their preferred coordination numbers range from 6 to 8. In protein crystal structures the tendency of calcium to bind water molecules is less than for magnesium (1.5 versus 2.2 water molecules on the average per metal ion site, respectively). The ratio of bidentate to monodentate binding of calcium ions to carboxylate groups is similar for small molecules and prote...

Estramustine is an antimicrotubule agent that is effective against prostate cancer when used in combination with other microtubule-binding drugs. It is a derivative of estradiol and has a nitrogen mustard group attached via an intervening carbamate group. The molecular dimensions published for estramustine from crystal structure analyses (Mol. Pharmacol. 41∶569, 1992) indicate that the carbamate group modifies the mustard group by giving considerable double-bond character to the C-N bond. As a result the mustard group cannot form an active aziridine ring and therefore does not show the expected alkylating function. The substitution at O(3) of the aromatic A ring of the steroid moiety has also modified its activity as a steroid. Geometric data are presented here on a compound in which the two chlorine atoms of the mustard group of estramustine are replaced by hydroxyl groups. The question was, why does the dihydroxy derivative not show biological activity when chlorine atoms do not appear to be activated in estramustine itself? A comparison of the molecular geometries of the two compounds shows that the dimensions of the carbamate group are similar in both compounds. Therefore it appears that it is the extensive hydrogen-bonding capability of the dihydroxy compound that destroys its estramustine-like activity. In crystals of both compounds there is a hydrogen bond between O(17) -H and O(19) of another molecule, but the dihydroxy compound can form two more hydrogen bonds. This may possibly prevent it from reaching the site of action of estramustine or, if it does reach that site, cause it to behave differently.

To investigate the extent to which individual bond angles around a tetrahedrally bonded carbon atom deviate from the regular tetrahedral angle of 109.47 , and the sum of the six angles from the maximum value of 656.83°, we have used results derived from neutron diffraction studies on molecules containing the X-CH 2 -Y grouping, and corresponding results for CH 3 -X, X-CH 2 -Y and H-CXYZ structures calculated using ab initio molecular orbital methods. In both sets of data the individual values vary between 105° and 117°. Yet, provided there is no steric constraint such as the bonding of the carbon in a four- or three-membered ring, the summation of the angles is less than the maximum by only a few tenths of a degree. An inherent tendency for the summation to attain this maximum value is further substantiated by the data for CCC and COC rings. Even though the CCC and CCO ring angles are about 60°, compensatory increases in the remaining five angles are sufficiently large to reduce the deficit in the summation to approximately 14°. The distorsion of the tetrahedra is discussed in terms of the interplay between bond angle relationships and the bond lengths. In the CH 3 X structures in which C--X is a trigonal axis of symmetry, the tetrahedra are elongated along this axis. In other CH 3 X structures, where two of the hydrogen atoms, H b and H c , are located symmetrically about the plane containing C, X, and the other hydrogen atom, H a , the tetrahedra are also elongated but tilted a little toward, or away from, the H b -H c side of the H a H b H c triangle at the base of the tetrahedron.

When a small biologically active molecule enters the body it has the possibility of interacting with one or many of the large variety of macromolecules that are present. This interaction involves a unique complementary fit between the two that depends not only on the shape, but also on the distribution of charges on the surfaces of both [Fischer (1894). Ber. Dtsch. Chem. Ges. 27, 2984-993]. This recognition between two molecules may elicit a biological response and such processes are the subject of biochemical investigations. The question asked here is: what geometrical information on distances and relative orientations of interacting non-bonded functional groups can be found from X-ray crystallographic investigations?

The crystal structure of the derivative of tetrahydronaphthalene with substituent epoxy, hydroxyl, and methyl groups in the more saturated ring (r-1-hydroxy-t-2-methyl-t,t-3,4-epoxy-1,2,3,4-tetrahydronaphthalene) has been determined. The hydroxyl and methyl groups are both found to beequatorial. The crystal structure is characterized by chains of molecules linked by O-H ⋯ O hydrogen bonds involving the hydroxyl groups; these hydrogen bonds lie approximately parallel to theb axis. The conformations of the epoxide-bearing rings in various hydroxy epoxides are compared and shown to be similar.

The crystal structure of the weak carcinogen 5-methylchrysene-7,8-dihydro-7,8-trans-(e,e)-diol is reported. This molecule contains a distorted bay region as a result of the presence of the 5-methyl group as found in 5-methylchrysene and 5,6- and 5, 12-dimethylchrysene. One torsion angle in this bay region is 20‡. The two hydroxyl groups of this molecule form hydrogen bonds throughout the crystal along theb direction. This is similar to the packing in other crystal structures of dihydrodiols of polycyclic aromatic hydrocarbons, each hydroxyl group both receiving and donating one hydrogen bond.

The modes of hydrogen bonding of arginine, asparagine, and glutamine side chains and of urea have been examined in small-molecule crystal structures in the Cambridge Structural Database and in crystal structures of protein-nucleic acid and protein-protein complexes. Analysis of the hydrogen bonding patterns of each by graph-set theory shows three patterns of rings (R) with one or two hydrogen bond acceptors and two donors and with eight, nine, or six atoms in the ring, designated R2(2)(8), R2(2)(9), and R1(2)(6). These three patterns are found for arginine-like groups and for urea, whereas only the first two patterns R2(2)(8) and R2(2)(9) are found for asparagine- and glutamine-like groups. In each case, the entire system is planar within 0.7 A or less. On the other hand, in macromolecular crystal structures, the hydrogen bonding patterns in protein-nucleic acid complexes between the nucleic acid base and the protein are all R2(2)(9), whereas hydrogen bonding between Watson-Crick-like pairs of nucleic acid bases is R2(2)(8). These two hydrogen bonding arrangements [R2(2)(9)] and R2(2)(8)] are predetermined by the nature of the groups available for hydrogen bonding. The third motif identified, R1(2)(6), involves hydrogen bonds that are less linear than in the other two motifs and is found in proteins.

Benzene exhibits a metabolic dichotomy in that it is ring-opened by bacteria, via dioxygenases, to yield Z,Z-muconic acid which eventually is metabolized in the tricarboxylic acid cycle, while mammals produce the E,E-isomer, via monooxygenases, as a relatively minor product relative to phenol and other monocyclic species. The dichotomy is further evidenced by the ability of bacteria to metabolically ring open PAH while mammals appear to retain the fully cyclic structures. This dichotomy is explicable in terms of the postulated formation of 2,3-epoxyoxepin via two successive monooxygenations of benzene and oxepin. The absence (or rarity) of natural oxepin metabolites of PAH explains the absence of ring-opening metabolism in species dependent upon monooxygenases.

To determine whether conformers of 2-formyl-2H-pyran (2F2HP) can serve as intermediates in the isomerization (Z,Z)-muconaldehyde-->(E,Z)-muconaldehyde--an essential step in the metabolic oxidation of benzene in which (E,E)-muconic acid is formed--we have carried out ab initio molecular orbital calculations at the MP2/6-31G* (frozen core, valence orbitals active) level with full geometry optimization at the RHF/6-31G* level. Taking account of the configuration about the carbon-carbon single bonds as well as that about the double bonds, the six conformers of (Z,Z)-muconaldehyde have been characterized, as well as the eight conformers of (E,Z)-muconaldehyde. Axial and equatorial conformers of 2F2HP have been identified, which exist in stable syn or anti forms depending on the relative position of the pyran and carbonyl O-atoms. Each step in the metabolic pathway is stereospecific. The initial ring opening in 2,3-epoxyoxepin gives (eZzZz)-muconaldehyde, which then undergoes ring closure to give anti-axial-2F2HP (step a). Inversion of the ring gives anti-equatorial-2F2HP, which upon ring opening gives (zEzZz)-muconaldehyde (step b). An alternative pathway links (zZzZz)-muconaldehyde with syn-axial-2F2HP (step a'), and syn-equatorial with (eEzZz)-muconaldehyde (step b'). Half-reaction times, taking into account the fractional representation of each reacting conformer in rapidly established equilibrium mixtures, suggest that the operative pathway is via step a, with little to choose between steps b and b'.

Studies of binding of substrates and inhibitors of the enzyme D-xylose isomerase show, from X-ray diffraction data at 1.6-1.9 A resolution, that there are a variety of binding modes. These vary in the manner in which the substrate or its analogue extend, on binding, across the carboxy end of the (betaalpha)(8)-barrel structure. These binding sites are His54 and the metal ion (magnesium or manganese) that is held in place by Glul81, Asp245, Glu217 and Asp287. Possible catalytic groups have been identified in proposed mechanisms and their role in the binding of ligands is illustrated.

The stereochemistry of binding of ligands by divalent metals and the propensity of these ligands to be water were investigated. Structural data of crystal structures in the Cambridge Structural Database (CSD) that contain divalent magnesium were examined with respect to the coordination of water molecules and other groups around a magnesium ion and any possible variability in the coordination number of magnesium. The analysis highlighted the stability of the hexaaquated magnesium ion, Mg [H 2 O] 6 2+ , which is found in the presence of various anions or chelating groups; this implies that the magnesium ion often prefers to bind directly to water rather than to anions