Geometrical Preferences Research Articles

Archetypical Modeling and Amphiphilic Behavior of Cobalt(II)-Containing Soft-Materials with Asymmetric Tridentate Ligands

The stabilization of a bivalent oxidation state in cobalt complexes of phenolate-based asymmetric tridentate ligands with iodo and bromo substituents is studied. The complexes [CoII(LIA)2].2CH3OH (1) and [CoII(LBrA)2].CH3OH (2) were characterized by means of several spectroscopic and spectrometric techniques. The molecular structure of 1 was determined by diffractometric analysis and reveals the cobalt(II) ion in a distorted-octahedral geometry. The centrosymmetric metal ion adopts a local D2h symmetry and is surrounded by facially coordinated ligands. Equivalent donor sets in both ligands are trans to each other, and DFT calculations suggest that the fac-trans configuration is favored by a small margin when compared to the fac-cis isomers. Both DFT calculations and EPR spectroscopy agree with a high-spin S=3/2 electronic configuration given by [ag1, b1g1, ag1, b2g2, b3g2]. This oxidation state was indirectly observed by the lack of a ppiphenolate-->dsigma*cobalt(III) charge-transfer band, which is found between 430 and 470 nm for similar cobalt(III) species. On the basis of the geometrical preferences and the oxidation state of archetypical 1 and 2, two metallosurfactants [CoII(LI-ODA)2] (3) and [CoII(LI-NOBA)2].CH2Cl2 (4) were obtained. The redox chemistry of 1-4 is marked by metal- and ligand-centered activity with several follow up processes and film formation on the electrode. Both metallosurfactants exhibit amphiphilic properties and organization, as shown by compression isotherms and Brewster angle microscopy but exhibit dissimilar collapse mechanisms; whereas 3 collapses at constant pressure, 4 exhibits a constant-area collapse. Langmuir-Blodgett films are readily obtained and were characterized by equilibrium contact angle and atomic force microscopy.

Synthesis, characterization and copper chemistry of a non-symmetric phenanthroline ligand: 2-Methyl-9-(3,5-dimethyl- N-pyrazolylmethyl)-1,10-phenanthroline

The synthesis of an unsymmetrical phenanthroline-based ligand, 2-methyl-9-(3,5-dimethylpyrazolylmethyl)-1,10-phenanthroline ( L), and its cupric [Cu(II)] ( 1) and cuprous [Cu(I)] ( 2) complexes, are reported. The X-ray structures of each of these Cu complexes show distinct changes in coordination environments consistent with the geometrical preferences of the two oxidation states. In the solid-state, the Cu(II) complex ( 1) adopts a geometry best described as trigonal bipyramidal, while the Cu(I) complex ( 2) consists of a single dicationic dimer in which the ligand bridges between two copper ions, separated by 4.26 Å. The two Cu(I) coordination sites differ in 2 with one copper center complexed in a trigonal planar geometry and the other copper in a distorted tetrahedral environment; the latter coordination results from an additional CH 3CN ligand. Complex 1 exhibits a reversible redox process at −0.34 V versus Fc/Fc + in CH 3CN, attributable to the Cu 2+/Cu + couple, while the dimeric Cu(I) complex ( 2) does not display this redox couple on the CV timescale. Over minutes however, complex 1 does oxidize in the presence of dioxygen to 2 in CH 3CN.

Model of Peptide Bond−Aromatic Ring Interaction: Correlated Ab Initio Quantum Chemical Study

Aromatic ring-peptide bond interactions (modeled as benzene and formamide, N-methylformamide and N-methylacetamide) are studied by means of advanced computational chemistry methods: second-order Möller-Plesset (MP2), coupled-cluster single and double excitation model [CCSD(T)], and density functional theory with dispersion (DFT-D). The geometrical preferences of these interactions as well as their interaction energy content, in both parallel and T-shaped arrangements, are investigated. The stabilization energy reaches a value of over 5 kcal/mol for the N-methylformamide-benzene complex at the CCSD(T)/complete basis set (CBS) level. Decomposition of interaction energy by the DFT-symmetry-adapted perturbation treatment (SAPT) technique shows that the parallel and T-shaped arrangements, although similar in their total interaction energies, differ significantly in the proportion of electrostatic and dispersion terms.

Multiple molecular dynamics simulations of human p450 monooxygenase CYP2C9: The molecular basis of substrate binding and regioselectivity toward warfarin

To examine the molecular basis of activity and regioselectivity of the clinically important human microsomal cytochrome P450 (CYP) monooxygenase 2C9 toward its substrate warfarin, 22 molecular dynamics simulations (3-5 ns each) were performed in the presence and absence of warfarin. The resulting trajectories revealed a stable protein core and mobile surface elements. This mobility leads to the formation of two surface channels in the region between F-G loop, B' helix/B-B' loop, beta(1)-sheet, and between helices F and I and the turn in the C-terminal antiparallel beta-sheet in the presence of warfarin. Besides the nonproductive state of the CYP2C9 warfarin complex captured in the crystal structure, three additional states were observed. These states differ in the shape of the substrate binding cavity and the position of the warfarin molecule relative to heme. In one of these states, the 7- and 6-positions of warfarin contact the heme with a marked geometrical preference for position 7 over position 6. This modeling result is consistent with experimentally determined regioselectivity (71 and 22% hydroxylation in positions 7 and 6, respectively). Access to the heme group is limited by the core amino acids Ala297, Leu362, Leu366, and Thr301, which therefore are expected to have a major impact on regioselectivity. In addition, modeling predicts that autoactivation of warfarin is sterically hindered. Our study demonstrates how the combination of mobile surface and rigid core leads to interesting properties: a broad substrate profile and simultaneously a high regioselectivity.

Minimization and Optimization of Designed β-Hairpin Folds

Minimized beta hairpins have provided additional data on the geometric preferences of Trp interactions in TW-loop-WT motifs. This motif imparts significant fold stability to peptides as short as 8 residues. High-resolution NMR structures of a 16- (KKWTWNPATGKWTWQE, DeltaG(U)(298) >or= +7 kJ/mol) and 12-residue (KTWNPATGKWTE, DeltaG(U)(298) = +5.05 kJ/mol) hairpin reveal a common turn geometry and edge-to-face (EtF) packing motif and a cation-pi interaction between Lys(1) and the Trp residue nearest the C-terminus. The magnitude of a CD exciton couplet (due to the two Trp residues) and the chemical shifts of a Trp Hepsilon3 site (shifted upfield by 2.4 ppm due to the EtF stacking geometry) provided near-identical measures of folding. CD melts of representative peptides with the -TW-loop-WT- motif provided the thermodynamic parameters for folding, which reflect enthalpically driven folding at laboratory temperatures with a small DeltaC(p) for unfolding (+420 J K(-)(1)/mol). In the case of Asx-Pro-Xaa-Thr-Gly-Xaa loops, mutations established that the two most important residues in this class of direction-reversing loops are Asx and Gly: mutation to alanine is destabilizing by about 6 and 2 kJ/mol, respectively. All indicators of structuring are retained in a minimized 8-residue construct (Ac-WNPATGKW-NH(2)) with the fold stability reduced to DeltaG(U)(278) = -0.7 kJ/mol. NMR and CD comparisons indicate that -TWXNGKWT- (X = S, I) sequences also form the same hairpin-stabilizing W/W interaction.

Comparison of Phosphatidylcholine Vesicle Properties Related to Geometrical Isomerism†

Glycerophosphatidylcholine containing trans-unsaturated fatty acid residues was prepared by reaction of the corresponding naturally occurring cis lipid with photochemically generated thiyl radicals. This modified lipid was chosen as the simplest model for gaining some insights of the complex scenario of membrane formation, in connection with the role of lipid geometry and the predominance of cis lipids in eukaryotic cells. The critical aggregation concentration for the spontaneous formation of vesicles was determined for cis and trans isomers with cis-parinaric acid used as a fluorescent probe and it was found to be similar for both lipids. Vesicle dimensions were investigated by light scattering and electron microscopy, and the type of fatty acid residues influenced the vesicle diameter, with a decrease along the series cis > trans > saturated. Fluorescence measurement of dye release from trans and cis vesicles showed also a different permeability. A picture emerged of the geometrical isomer preference in cells as a process driven by natural selection during the life evolution of different organisms, both in terms of compartment dimensions and membrane functionality.

A T-Shaped Three-Coordinate Nickel(I) Carbonyl Complex and the Geometric Preferences of Three-Coordinate d9 Complexes

A three-coordinate diketiminate-nickel(I) complex with a carbonyl ligand has been characterized using EPR and IR spectroscopies and X-ray crystallography. The T geometry (bending from the sterically favored C(2)(v)() structure) contrasts with that of isosteric d(9) copper(II) complexes. DFT calculations on a truncated model reproduce experimental geometries, implying that the geometric differences are electronic in nature. Analysis of the charge distribution in the complexes shows that the geometry of the three-coordinate d(9) complexes is affected by differential charge donation of the ligands to the metal center.

Comparison of aesthetic preferences among Roman and Arabic script readers

The systemic bias for aesthetic preferences demonstrated by prior research is thought to reflect neural organisation. Research on aesthetic preference and laterality has usually been conducted with participants who read a left-to-right Roman script, e.g., English. In order to determine if the aesthetic judgments were influenced by habitual scanning direction, we administered a geometric aesthetic preference test to 578 right-handed adults who represented a range of script experience, i.e., left-to-right Roman script readers (English); right-to-left Arabic script readers; bi-directional readers of Roman and Arabic scripts; and illiterates. We also administered an asymmetric chimeric faces test. Our findings showed that biases in aesthetic preference were influenced by script direction and pictorial dimensions. In a laterally balanced composition, participants preferred to begin their scan with the object representing Interest and terminate with the object representing Weight, the direction being determined by the script. In an unbalanced composition, participants tended to fixate on content, whether Interest or Weight, and move in a direction consistent with the script.

Theoretical studies of π-loading and structural diversity in Cp 3MX (M = Zr, Hf; X = H, CH 3, OR, NR 2) compounds

Density functional theory has been used to explore the bonding and geometric preferences of tris-Cp zirconium and hafnium compounds of the type Cp 3MX. In most cases, two primary isomers were found: a “ 3-5” isomer, which contains three η 5-Cp ligands, and a “ 2-5,1-1” isomer, which contains two η 5-Cp and one η 1-Cp ligands. The relative energies of these isomers are dependent upon the π-donor ability of the X ligand. For the tris-Cp methyl compounds, the “ 3-5” isomers are more stable by 1–4 kcal/mol. The “ 2-5,1-1” isomers of the tris-Cp alkoxide and amido compounds are more stable by 3–6 and 6–11 kcal/mol, respectively. Bonding analyses show these binding preferences can be understood in terms of π-competition between the tris-Cp ligand set and the lone pair of the X ligand. π-loading on the X ligand decreases the π-donor ability of the “ 3-5” tris-Cp ligand set, which increases the preference for the “ 2-5,1-1” ground state geometry in the complexes with strong π-donors. In addition, molecular orbital theory provides evidence for destabilization effects arising from filled–filled interactions between the “ 3-5” Cp 3M fragment and the X lone pair.

Square Planar vs Tetrahedral Geometry in Four Coordinate Iron(II) Complexes

The geometric preferences of a family of four coordinate, iron(II) d6 complexes of the general form L2FeX2 have been systematically evaluated. Treatment of Fe2(Mes)4 (Mes = 2,4,6-Me3C6H2) with monodentate phosphine and phosphite ligands furnished square planar trans-P2Fe(Mes)2 derivatives. Identification of the geometry has been accomplished by a combination of solution and solid-state magnetometry and, in two cases (P = PMe3, PEt2Ph), X-ray diffraction. In contrast, both tetrahedral and square planar coordination has been observed upon complexation of chelating phosphine ligands. A combination of crystallographic and magnetic susceptibility data for (depe)Fe(Mes)2 (depe = 1,2-bis(diethylphosphino)ethane) established a tetrahedral molecular geometry whereas SQUID magnetometry and Mössbauer spectroscopy on samples of (dppe)Fe(Mes)2 (dppe = 1,2-bis(diphenylphosphino)ethane) indicated a planar molecule. When dissolved in chlorinated solvents, the latter compound promotes chlorine atom abstraction, forming tetrahedral (dppe)Fe(Mes)Cl and (dppe)FeCl2. Ligand substitution reactions have been studied for both structural types and are rapid on the NMR time scale at ambient temperature.

Theoretical study of intramolecular interaction energies during dynamics simulations of oligopeptides by the fragment molecular orbital-Hamiltonian algorithm method

We analyzed the interaction energies between residues (fragments) in an oligopeptide occurring during dynamic simulations by using the fragment molecular orbital-Hamiltonian algorithm (FMO-HA) method, an ab initio MO-molecular dynamics technique. The FMO method enables not only calculation of large molecules based on ab initio MO but also easy evaluation of interfragment interaction energies. The glycine pentamer [(Gly)(5)] and decamer [(Gly)(10)] were divided into five and ten fragments, respectively. alpha-helix structures of (Gly)(5) and (Gly)(10) were stabilized by attractive interaction energies owing to intramolecular hydrogen bonds between fragments n and n+3 (and n+4), and beta-strand structures were characterized by repulsive interaction energies between fragments n and n+2. We analyzed interfragment interaction energies during dynamics simulations as the peptides' geometries changed from alpha helix to beta strand. Intramolecular hydrogen bonds between fragments 2-4 and 2-5 control the geometrical preference of (Gly)(5) for the beta-strand structure. The pitch of one turn of the alpha helix of (Gly)(10) elongated and thus weakened during dynamics due to a shifting of the intramolecular hydrogen bonds, and enabled the beta-strand structure to form. Changes in interaction energies due to the intramolecular hydrogen bonds controlled the tendency toward alpha-helix or beta-strand structure of (Gly)(5) and (Gly)(10). Evaluation of interfragment interaction energies during dynamics simulations thus enabled detailed analysis of the process of the geometrical changes occurring in oligopeptides.

Geometric preferences of crosslinked protein‐derived cofactors reveal a high propensity for near‐sequence pairs

Protein-derived cofactors that are composed of covalently crosslinked amino acid side chains are of increasing importance in protein science. These crosslinked protein-derived cofactors (CPDC) are formed either through direct oxidation by metal/O(2)-derived intermediates or through outer sphere oxidation by highly oxidizing cofactors. CPDCs that are formed by outer sphere oxidation do not require side-chain precursors to be coordinated by a metal center, and therefore are more difficult to identify than those formed by direct oxidation. To better understand the propensity for CPDC formation by outer sphere oxidation, the geometrical preferences of CPDCs were examined. The Dezymer algorithm has been used to identify all putative CPDC-forming mutations in 500 proteins. Geometrically, although chemically unrelated, these CPDCs were found to be similar to disulfide-bonded cysteine pairs. Additionally, the percentage of near-sequence pairs (i and i +1 to i and i + 5) increased as the average C(alpha)-C(alpha) distance between the amino acid pairs increased. This survey also examined the protein databank for proteins with pre-attack conformations for CPDCs, using non-bonded contacts reported by Procheck. A total of 323 unique proteins was identified, with 55 being near-sequence amino acid pairs. The high geometric propensity of near-sequence amino acid pairs for forming CPDCs is significant due to difficulties associated with detection by structural or mass spectrometric methods.

Theoretical study of H 3AXH 3 and H 3AYH 2 (A = B, Al, Ga; X = N, P, As and Y = O, S, and Se), electrostatic and hyperconjugative interactions roles

H 3AXH n (A = B, Al, and Ga; XH n = NH 3, PH 3, AsH 3, H 2O, SH 2 and SeH 2) donor–acceptor complexes are studied from conformational and coordination-mode points of view at B3LYP/6-311+G(3df,2p) and CCSD(T)/6-311+G(3df,2p) levels of theory. The metallic character of gallium atom is responsible of the irregular structural and coordination mode trends in free and complexed gallane (GaH 3). The intuitive staggered conformation is not adopted by all compounds because there is, in some cases, competition between H(donor)–H(acceptor) electrostatic interaction and hyperconjugative electronic delocalisation. All H 3AXH 3 (X = N, P, and As) complexes are staggered. In accordance with Pophristic–Goodman’s study (V. Pophristic, L. Goodman, Nature 411 (2001) 565), hyperconjugation is behind this geometrical preference. For the H 3AYH 2 series, the H 3BOH 2 staggered conformation is also favoured by this interaction. Nevertheless, H 3AlOH 2 and H 3GaOH 2 are curiously eclipsed and not favoured by the hyperconjugation. This paradox is clarified by both electrostatic and energetic delocalisation interactions analysis. The coordination mode is horizontally and vertically discussed in N and O groups of the periodic table within these complex sets.

Retrieval of Crystallographically-Derived Molecular Geometry Information

The crystallographically determined bond length, valence angle, and torsion angle information in the Cambridge Structural Database (CSD) has many uses. However, accessing it by means of conventional substructure searching requires nontrivial user intervention. In consequence, these valuable data have been underutilized and have not been directly accessible to client applications. The situation has been remedied by development of a new program (Mogul) for automated retrieval of molecular geometry data from the CSD. The program uses a system of keys to encode the chemical environments of fragments (bonds, valence angles, and acyclic torsions) from CSD structures. Fragments with identical keys are deemed to be chemically identical and are grouped together, and the distribution of the appropriate geometrical parameter (bond length, valence angle, or torsion angle) is computed and stored. Use of a search tree indexed on key values, together with a novel similarity calculation, then enables the distribution matching any given query fragment (or the distributions most closely matching, if an adequate exact match is unavailable) to be found easily and with no user intervention. Validation experiments indicate that, with rare exceptions, search results afford precise and unbiased estimates of molecular geometrical preferences. Such estimates may be used, for example, to validate the geometries of libraries of modeled molecules or of newly determined crystal structures or to assist structure solution from low-resolution (e.g. powder diffraction) X-ray data.

Progress Toward Understanding the Nature and Function of C-H...O Interactions

Recent studies confirm that C-H...O hydrogen bonds have many, if not all, of the spectroscopic and physical earmarks of “traditional” H-bonds. Only more recently have we come to understand that these contacts are operative not only in protein-protein recognition, but enzyme-substrate interactions (with implications for drug design), biological and nonbiological transition state stabilization and have, in some circumstances, a strength and geometric predictability to make them useful in the construction of materials and supramolecular assemblies. Forays into each of these areas have come largely due to advances in computational protocols and spectroscopic instrumentation. This review discusses the most recent findings related to the nature (i.e. strength, geometrical preferences, and spectroscopic features) and function (i.e. in supramolecular design and synthesis, conformational control, enantioselective synthesis, and biology) of C-H...O interactions in a variety of chemical and biological systems. An understanding of the key features of these interactions should promote their deployment in target areas like medicinal chemistry and materials science.

P-benzoquinone-benzene clusters as potential nanomechanical devices: a theoretical study.

The equilibrium structures and binding energies of the benzene complexes of p-benzoquinones (PBQ) and its negatively charged anionic species (PBQ- and PBQ2-) have been investigated theoretically using second-order Møller-Plesset calculations. While neutral p-benzoquinone-benzene clusters (PBQ-Bz) prefer to have a parallel displaced geometry (P-c), CH...pi interactions (T-shaped geometries) prevail in the di-anionic PBQ-benzene (PBQ2- -Bz) complexes (T-e2-). Studies on dianionic p-benzoquinone-benzene clusters showed that two nonbonded intermolecular interactions compete in the most stable conformation. One is H-bonding interaction (C-H...O type) between carbonyl oxygen of p-benzoquinone and one of the hydrogen atoms of benzene, and the other is a pi-H interaction between pi-electron cloud of PBQ2- and another hydrogen atom of benzene. Blueshifted H-bonds were observed in T-shaped clusters. The changes in the geometrical preference of PBQ-Bz complex upon addition of electrons would be useful in designing optimized molecular mechanical devices based on the edge-to-face and face-to-face aromatic interactions.

Reactions of the hexaaquarhodium(III) cation with bis(benzimidazol-2-ylmethyl)methylamine and PPh3: syntheses and properties of new hydrido- and carbonylrhodium complexes

Reactions of [Rh(H 2 O) 6 ] 3+ with bis(benzimidazol-2-ylmethyl)methylamine (L) and PPh 3 yielded novel hydrido- and carbonylrhodium compounds [Rh(H)L(PPh 3 ) 2 ](ClO 4 ) 2 ( 1 ) and [Rh(CO)L(PPh 3 ) 2 ](ClO 4 ) ( 2 ). The stdies revealed the formation of a metalloradical Rh(II) species as an intermediate and the ability of L to adopt its geometry to the electronic and geometric preferences of the metal centre. Hexaaquarhodium(III) perchlorate has been found to be an interesting starting material for the preparation of rhodium compounds. New mononuclear hydrido- and carbonylrhodium compounds with bis(benzimidazol-2-ylmethyl)methylamine (L) and PPh 3 of the type [Rh(H)L(PPh 3 ) 2 ](ClO 4 ) 2 ( 1 ) and [Rh(CO)L(PPh 3 ) 2 ](ClO 4 ) ( 2 ) have been synthesized. The monomeric Rh(II) compound was identified as an intermediate. Complexes 1 and 2 were characterized by elemental analysis, mass spectrometry and IR, and NMR spectroscopies. The fluxional behaviour of 2 was studied by variable-temperature 1 H and 31 P{H} NMR experiments.

Structure-activity studies on the cleavage of an RNA analogue by a potent dinuclear metal ion catalyst: effect of changing the metal ion.

Dinuclear Cd(II), Cu(II), and Zn(II) complexes of L2OH (L2OH = 1,3-bis(1,4,7-triazacyclonon-1-yl)-2-hydroxypropane) are compared as catalysts for cleavage of the RNA analogue HpPNP (HpPNP = 2-hydroxypropyl 4-nitrophenyl phosphate) at 25 degrees C, I = 0.10 M (NaNO(3)). Zn(II) and Cu(II) readily form dinuclear complexes at millimolar concentrations and a 2:1 ratio of metal ion to L2OH at neutral pH. The dinuclear Zn(2)(L2O) and Cu(2)(L2O) complexes have a bridging alkoxide group that brings together the two cations in close proximity to facilitate cooperative catalysis. Under similar conditions, the dinuclear complex of Cd(II) is a minor species in solution; only at high pH values (pH 10.4) does the Cd(2)(L2O) complex become the predominant species in solution. Analysis of the second-order rate constants for cleavage of HpPNP by Zn(2)(L2O) is straightforward because a linear dependence of pseudo-first-order rate constant on dinuclear complex is observed over a wide pH range. In contrast, plots of pseudo-first-order rate constants for cleavage of HpPNP by solutions containing a 2:1 ratio of Cd(II) to L2OH as a function of increasing L2OH are curved, and second-order rate constants are obtained by fitting the kinetic data to an equation for the formation of the dinuclear Cd(II) complex as a function of pH and [L2OH]. Second-order rate constants for cleavage of HpPNP by these dinuclear complexes at pH 9.3 and 25 degrees C vary by 3 orders of magnitude in the order Cd(2)(L2O) (2.8 M(-)(1) s(-)(1)) > Zn(2)(L2O) (0.68 M(-)(1) s(-)(1)) > Cu(2)(L2O) (0.0041 M(-1) s(-1)). The relative reactivity of these complexes is discussed in terms of the different geometric preferences and Lewis acidity of the dinuclear Zn(II), Cu(II), and Cd(II) complexes, giving insight into the importance of these catalyst properties in the cleavage of phosphate diesters resembling RNA.

Tertiary phosphine binding to pyridylazole chelated rhenium via substitution in phosphine oxide precursors: geometrical preference, twin isomerization and effects of diphosphine spacer length and metal oxidation state

The bimolecular reaction of [ReVL(O)Cl3] [L = 2-(2-pyridyl)benzoxazole (L1), 2-(2-pyridyl)benzthiazole (L2)], 1 with excess diphosphine [Ph2P(CH2)xPPh2 (x = 1–4)] has furnished [ReIIIL(OP(Ph)2(CH2)xP(Ph)2)Cl3], 2 which is spontaneously converted in solution to [ReIIIL(P(Ph)2(CH2)xP(O)(Ph)2)Cl3], 4. The reaction of [ReIIIL(OPMeyPh3 − y)Cl3], 3 with PMeyPh3 − y (y = 0–2) has afforded [ReIIIL(PMeyPh3 − y)Cl3], 5. Oxidation of 2 and 3 by dilute nitric acid has furnished nitrates of the rhenium(IV) species, 2+ and 3+. Structure determination vis-a-vis spectral and electrochemical comparisons have revealed a meridional geometry for 2, 3, 2+, and 3+ and a facial geometry for 4 and 5. The transformation 2 → 4 is a twin isomerization (linkage-cum-geometrical), the geometrical part of which recurs in the conversion 3 → 5. Rate studies have revealed that the reaction 2 → 4 is intramolecular in nature. It is initiated by nucleophilic attack of the metal by the dangling phosphine function. The process slows down nearly exponentially as the diphosphine spacer length (x) increases. The oxidised complex 2+ does not isomerize.

Kinase inhibitors and the case for CH...O hydrogen bonds in protein-ligand binding.

Although the hydrogen bond is known to be an important mediator of intermolecular interactions, there has yet to be an analysis of the role of CH...O hydrogen bonds in protein-ligand complexes. In this work, we present evidence for such nonstandard hydrogen bonds from a survey of aromatic ligands in 184 kinase crystal structures and 358 high-resolution structures from the Protein Data Bank. CH groups adjacent to the positively charged nitrogen of nicotinamide exhibit geometric preferences strongly suggestive of hydrogen bonding interactions, as do heterocyclic CH groups in kinase ligands, while other aromatic CH groups do not exhibit these characteristics. Ab initio calculations reveal a considerable range of CH...O hydrogen bonding potentials among different aromatic ring systems, with nicotinamide and heterocycles preferred in kinase inhibitors showing particularly favorable interactions. These results provide compelling evidence for the existence of CH...O hydrogen bonds in protein-ligand interactions, as well as information on the relative strength of various aromatic CH donors. Such knowledge will be of considerable value in protein modeling, ligand design, and structure-activity analysis.