Chemical Tools for Studying Phosphohistidine: Generation of Selective τ-Phosphohistidine and π-Phosphohistidine Antibodies.

Nonhydrolysable stable analogues of τ-phosphohistidine (τ-pHis) and π-pHis have been designed, aided by electrostatic surface potential calculations, and subsequently synthesized. The τ-pHis and π-pHis analogues (phosphopyrazole 8 and pyridyl amino amide 13, respectively) were used as haptens to generate pHis polyclonal antibodies. Both τ-pHis and π-pHis conjugates in the form of BSA-glutaraldehyde-τ-pHis and BSA-glutaraldehyde-π-pHis were synthesized and characterized by 31 P NMR spectroscopy. Commercially available τ-pHis (SC56-2) and π-pHis (SC1-1; SC50-3) monoclonal antibodies were used to show that the BSA-G-τ-pHis and BSA-G-π-pHis conjugates could be used to assess the selectivity of pHis antibodies in a competitive ELISA. Subsequently, the selectivity of the pHis antibodies generated by using phosphopyrazole 8 and pyridyl amino amide 13 as haptens was assessed by competitive ELISA against His, pSer, pThr, pTyr, τ-pHis and π-pHis. Antibodies generated by using phosphopyrazole 8 as a hapten were found to be selective for τ-pHis, and antibodies generated by using pyridyl amino amide 13 were found to be selective for π-pHis. Both τ- and π-pHis antibodies were shown to be effective in immunological experiments, including ELISA, western blot, and immunofluorescence. The τ-pHis antibody was also shown to be useful in the immunoprecipitation of proteins containing pHis.

Molecular graphs and molecular conduction: the d-omni-conductors.

Ernzerhof's source-and-sink-potential (SSP) model for ballistic conduction in conjugated π systems predicts transmission of electrons through a two-wire device in terms of characteristic polynomials of the molecular graph and subgraphs based on the pattern of connections. We present here a complete classification of conduction properties of all molecular graphs within the SSP model. An omni-conductor/omni-insulator is a molecular graph that conducts/insulates at the Fermi level (zero of energy) for all connection patterns. In the new scheme, we define d-omni-conduction/insulation in terms of Fermi-level conduction/insulation for all devices with graph distance d between connections. This gives a natural generalisation to all graphs of the concept of near-omni-conduction/insulation previously defined for bipartite graphs only. Every molecular graph can be assigned to a nullity class and a compact code defining conduction behaviour; each graph has 0, 1, >1 zero eigenvalues (non-bonding molecular orbitals), and three letters drawn from {C, I, X} indicate conducting, insulating or mixed behaviour within the sets of devices with connection vertices at odd, even and zero distances d. Examples of graphs (in 28 cases chemical) are given for 35 of the 81 possible combinations of nullity and letter codes, and proofs of non-existence are given for 42 others, leaving only four cases open.

A Correlated Source-Sink-Potential Model Consistent with the Meir-Wingreen Formula.

We model a molecular device as a molecule attached to a set of leads treated at the tight-binding level, with the central molecule described to any desired level of electronic structure theory. Within this model, in the absence of electron-phonon interactions, the Landauer-Büttiker part of the Meir-Wingreen formula is shown to be sufficient to describe the transmission factor of the correlated device. The key to this demonstration is to ensure that the correlation self-energy has the same functional form as the exact correlation self-energy. This form implies that nonsymmetric contributions to the Meir-Wingreen formula vanish, and hence, conservation of current is achieved without the need for Green's Function self-consistency. An extension of the Source-Sink-Potential (SSP) approach gives a computational route to the calculation and interpretation of electron transmission in correlated systems. In this picture, current passes through internal molecular channels via resonance states with complex-valued energies. Each resonance state arises from one of the states in the Lehmann expansion of the one-electron Green's function, hole conduction derived from ionized states, and particle conduction from attached states. In the correlated device, the dependence of transmission on electron energy is determined by four structural polynomials, as it was in the tight-binding (Hückel) version of the SSP method. Hence, there are active and inert conduction channels (in the correlated case, linked to Dyson orbitals) governed by a set of selection rules that map smoothly onto the simplest picture.

In search of Coulson's lost theorem.

In Hückel theory, the bond number is the sum of the orders of the π bonds incident on a given carbon center. From the work of Coulson and his school, it has been believed for over 70 years that the bond number has a maximum of 3 and that this bound is realized by exactly one conjugated framework, that of the trimethylenemethane radical. Search of published literature and archived correspondence failed to find any formal proof of these two statements. Here, we provide a new formula for bond number that leads to an easily checked proof of both. The bond number of graphene is 1.574 597… (90.9% of the mathematical limit), and this value appears to act as a separator for the classes of metallic and semiconducting single-walled nanotubes, as defined within Hückel theory.

Near omni-conductors and insulators: Alternant hydrocarbons in the SSP model of ballistic conduction.

Within the source-and-sink-potential model, a complete characterisation is obtained for the conduction behaviour of alternant π-conjugated hydrocarbons (conjugated hydrocarbons without odd cycles). In this model, an omni-conductor has a molecular graph that conducts at the Fermi level irrespective of the choice of connection vertices. Likewise, an omni-insulator is a molecular graph that fails to conduct for any choice of connections. We give a comprehensive classification of possible combinations of omni-conducting and omni-insulating behaviour for molecular graphs, ranked by nullity (number of non-bonding orbitals). Alternant hydrocarbons are those that have bipartite molecular graphs; they cannot be full omni-conductors or full omni-insulators but may conduct or insulate within well-defined subsets of vertices (unsaturated carbon centres). This leads to the definition of "near omni-conductors" and "near omni-insulators." Of 81 conceivable classes of conduction behaviour for alternants, only 14 are realisable. Of these, nine are realised by more than one chemical graph. For example, conduction of all Kekulean benzenoids (nanographenes) is described by just two classes. In particular, the catafused benzenoids (benzenoids in which no carbon atom belongs to three hexagons) conduct when connected to leads via one starred and one unstarred atom, and otherwise insulate, corresponding to conduction type CII in the near-omni classification scheme.

A Hückel source-sink-potential theory of Pauli spin blockade in molecular electronic devices.

This paper shows how to include Pauli (exclusion principle) effects within a treatment of ballistic molecular conduction that uses the tight-binding Hückel Hamiltonian and the source-sink-potential (SSP) method. We take into account the many-electron ground-state of the molecule and show that we can discuss ballistic conduction for a specific molecular device in terms of four structural polynomials. In the standard one-electron picture, these are characteristic polynomials of vertex-deleted graphs, with spectral representations in terms of molecular-orbital eigenvectors and eigenvalues. In a more realistic many-electron picture, the spectral representation of each polynomial is retained but projected into the manifold of unoccupied spin-orbitals. Crucially, this projection preserves interlacing properties. With this simple reformulation, selection rules for device transmission, expressions for overall transmission, and partition of transmission into bond currents can all be mapped onto the formalism previously developed. Inclusion of Pauli spin blockade, in the absence of external perturbations, has a generic effect (suppression of transmission at energies below the Fermi level) and specific effects at anti-bonding energies, which can be understood using our previous classification of inert and active shells. The theory predicts the intriguing phenomenon of Pauli perfect reflection whereby, once a critical electron count is reached, some electronic states of devices can give total reflection of electrons at all energies.

A new approach to the method of source-sink potentials for molecular conduction.

We re-derive the tight-binding source-sink potential (SSP) equations for ballistic conduction through conjugated molecular structures in a form that avoids singularities. This enables derivation of new results for families of molecular devices in terms of eigenvectors and eigenvalues of the adjacency matrix of the molecular graph. In particular, we define the transmission of electrons through individual molecular orbitals (MO) and through MO shells. We make explicit the behaviour of the total current and individual MO and shell currents at molecular eigenvalues. A rich variety of behaviour is found. A SSP device has specific insulation or conduction at an eigenvalue of the molecular graph (a root of the characteristic polynomial) according to the multiplicities of that value in the spectra of four defined device polynomials. Conduction near eigenvalues is dominated by the transmission curves of nearby shells. A shell may be inert or active. An inert shell does not conduct at any energy, not even at its own eigenvalue. Conduction may occur at the eigenvalue of an inert shell, but is then carried entirely by other shells. If a shell is active, it carries all conduction at its own eigenvalue. For bipartite molecular graphs (alternant molecules), orbital conduction properties are governed by a pairing theorem. Inertness of shells for families such as chains and rings is predicted by selection rules based on node counting and degeneracy.

Evidence for the role of tetramethylethylenediamine in aqueous Negishi cross-coupling: synthesis of nonproteinogenic phenylalanine derivatives on water.

The structure of the alkylzinc-tetramethylethyl-enediamine (TMEDA) cluster cation 3 has been determined in the gas phase by a combination of tandem mass spectrometry, infrared multiphoton dissociation (IRMPD) spectroscopy, and DFT calculations. Both sets of experimental results establish the existence of a strongly stabilizing interaction of TMEDA with the zinc cation. High-level DFT calculations on the alkylzinc-TMEDA cluster cation 3 allowed the identification of two low energy conformers, each featuring a four-coordinate zinc atom with a bidentate TMEDA ligand, and internal coordination from the carbonyl group of the Boc group to zinc. The experimental IRMPD spectrum is reproduced with an appropriately weighted combination of the IR spectra of the two conformers identified by theory. DFT calculations on the structure of the alkylzinc halide 2 with coordinated TMEDA using the PCM model of water solvent suggest that TMEDA can promote ionization of the zinc-iodine bond in organozinc iodides under aqueous conditions, providing a credible explanation for the role of TMEDA in stabilizing the carbon-zinc bond. Reaction of the serine-derived iodide 1 with aryl iodides "on water", promoted by nano zinc in the presence of PdCl(2)(Amphos)(2) (5 mol %) and TMEDA, leads to the formation of protected phenylalanine derivatives 4 in reasonable yields. In the case of ortho-substituted aryl iodides and aryl iodides that are solids at room temperature, conducting the reaction at 65 °C gives improved results. In all cases, the product 5 of reductive dimerization of the iodide 1 is also isolated.

Gas-phase study of new organozinc reagents by IRMPD-spectroscopy, computational modelling and tandem-MS.

An extensive set of organozinc iodides, useful for Negishi-type cross-coupling reactions, are investigated as respective cations after formal loss of iodide in the gas phase. Firstly, two new alkylzinc compounds derived from Tyrosine (Tyr) and Tryptophan (Trp) are closely examined. Secondly, the influence of specific protecting groups on the subtle balance between intra- and intermolecular coordination of zinc in these reagents is probed through trifluoroacetyl (TFA)-derivatized alkylzinc compounds. Finally, the influence of the strongly coordinating bidentate ligand N,N,N',N'-tetramethylethylenediamine (TMEDA) on the structure of alkylzinc cations is further explored in order to better understand the stability of the respective complexes towards water. A combination of electrospray (ESI)-MS/MS, accurate ion mass measurements, infrared multiple-photon dissociation (IRMPD) spectroscopy and computational modelling allowed the full characterisation of all dimethylformamide (DMF)-solvated and TMEDA-coordinated alkylzinc cations in the gas phase. The calculations indicate that the zinc cation in gas-phase alkylzinc-DMF or TMEDA-complex ions preferentially adopts a tetrahedral coordination sphere with four ligands. Additionally, conformers with only three binding partners bound to zinc but with effectively combined hydrogen-bond interactions are also found. Collision induced dissociation (CID) patterns demonstrate that the zinc-DMF interaction in tetrahedral four-coordinate mono-DMF-zinc complex ions as well as the interaction between TMEDA and zinc in the corresponding complex ions is even stronger than typical covalent bonds. In most cases, all major features of the IRMPD spectra are consistent with only a single major isomer, allowing secured identification and assignment.

Structure elucidation of dimethylformamide-solvated alkylzinc cations in the gas phase.

Organozinc iodides, useful for the synthesis of nonproteinogenic amino acids, are investigated in the gas phase by a combination of electrospray (ESI)-MS/MS, accurate ion mass measurements, and infrared multiphoton dissociation (IRMPD) spectroscopy employing a free electron laser. ESI allowed the full characterization of a set of dimethylformamide (DMF)-solvated alkylzinc cations formed by formal loss of I(-) in the gas phase. Gas phase ion structures of the organozinc cations were identified and optimized by computations at the B3LYP/6-311G** level of theory. The calculations indicate that the zinc cation in gas phase alkylzinc-DMF species preferentially adopts a tetrahedral coordination sphere with four ligands, namely the alkyl group, any internal coordinating group, and DMF (the number of which depends on the number of internal coordinating groups present). Besides the sequential loss of coordinated DMF, collision-induced dissociation (CID) patterns demonstrate that the zinc-DMF interaction in tetrahedral four-coordinate mono-DMF-zinc complex ions can be even stronger than covalent bonds. The IRMPD spectra of the alkylzinc-DMF species examined show a rich pattern of indicative bands in the range of 1000-1800 cm(-1). All major features of the recorded IRMPD spectra are consistent with the computed IR spectra of the respective gas phase ion structures predicted by theory, allowing identification and assignment.

Lingos, finite state machines, and fast similarity searching.

We apply a recently published method of text-based molecular similarity searching (LINGO) to standard data sets for the purpose of quantifying the accuracy of the approach. Our implementation is based on a pattern-matching finite state machine (FSM) which results in fast search times. The accuracy of LINGO is demonstrated to be comparable to that of a path-based fingerprint and offers a simple yet effective method for similarity searching.

Small molecule shape-fingerprints.

The optimal overlap between two molecular structures is a useful measure of shape similarity. However, it usually requires significant computation. This work describes the design of shape-fingerprints: binary bit strings that encode molecular shape. Standard measures of similarity between two shape-fingerprints are shown to be an excellent surrogate for similarity based on volume overlap but several orders of magnitude faster to compute. Consequently, shape-fingerprints can be used for clustering of large data sets, evaluating the diversity of compound libraries, as descriptors in SAR and as a prescreen for exact shape comparison against large virtual databases. Our results show that a small set of shapes can be used to build these fingerprints and that this set can be applied universally.