A quantum chemical approach to the mechanism of the biochemical action of nicotinamide

The reaction of protonated nicotinamide with hydride ion, which models the transfer of hydrogen from a substrate to the nicotinamideadeninedinucleotide (NAD⁺) molecule, i.e., the principal biological function of vitamin PP, was investigated by optimization of the geometry in terms of the self-consistent field (SCF) method with allowance for configuration interaction (CI) in the PM-3 approximation. It was shown that the initial event of the reaction is electron transfer, followed by the addition of a hydrogen atom to the NAD radical. The addition product is relatively stable and has a heat of formation of −68.25 kJ/mol. The geometric structure and the distribution of charges of the reagent and also the behavior of the singlet and triplet terms in the course of the reaction were analyzed. Translated from Teoreticheskaya i éksperimental'naya Khimiya, Vol. 35, No. 5, pp. 277–283, September–October, 1999.     

A chemical systems approach to evolution

A novel approach to the evolution of organisms is given. It asserts that biological evolution was consequential upon geochemical, environment, change and was inevitable not accidental.     

A new approach to the chemical synthesis of keto-proteins

To increase the versatility of protein-conjugation, an orthogonal protection strategy is described, which enables the efficient synthesis of keto-proteins bearing a reactive ketone functionality using Boc, Fmoc, and chemical ligation methodologies. A 1,3-dithiolane group was used to protect the ketone function of levulinate- and pyruvate-derivatized peptides during solid-phase synthesis, acidolytic cleavage, and purification. When required, the 1,3-dithiolane group could be cleanly removed using aqueous silver or mercuric solutions to regenerate the reactive keto-protein at ambient temperature. The liberated keto-protein was chemoselectively conjugated in situ to an aminooxy-derivatized monodisperse polymer.     

A convolution approach to the kinetics of chemical and photochemical reactions

A new method for writing kinetic equations directly in the integrated form is presented. This method applies to any species that is consumed solely through first order steps, regardless of the complexity of its formation pathways.     

A stepwise simulation approach to the chemical potential of fluids

A new approach to the computation of the chemical potential of fluids is presented. In this method the particle-insertion operation in the conventional test particle method is replaced by the growth of a specific particle. Application of the new technique to hard sphere and Lennard-Jones fluids shows that it is capable of providing reliable estimates of the chemical potential, even at high density where the conventional test particle methods are difficult to apply.     

A green chemical approach to the synthesis of tellurium nanowires

Starch, an economical and safe carbohydrate, has been found to be not only an effective reducing agent but also a new morphology-directing agent for the synthesis of tellurium nanowires using commercial H2TeO4 precursor. The obtained tellurium nanowires are of single-crystal in nature, with an average diameter of approximately 25 nm and length up to 10 microm. A possible synthetic mechanism involves the chain-shaped bioorganic molecule acting as a template for the one-dimensional growth of inorganic tellurium. The effects of different chain-shaped structures and concentrations of biomolecules on the nanowire morphology have been investigated and different one-dimensional structures, including thick rods, short nanowires, bunched nanowires, and assembled spikelet structures, have been fabricated. These experimental results have been found to be useful in substantiating the proposed synthetic mechanism.     

A 3D-QSAR-driven approach to binding mode and affinity prediction

A method for predicting the binding mode of a series of ligands is proposed. The procedure relies on three-dimensional quantitative structure-activity relationships (3D-QSAR) and does not require structural knowledge of the binding site. Candidate alignments are automatically built and ranked according to a consensus scoring function. 3D-QSAR analysis based on the selected binding mode enables affinity prediction of new drug candidates having less than 10 rotatable bonds.     

A new approach to the calorimetric investigation of physical and chemical transitions

The theoretical basis for Modulated DSC is described and the additional information in can give over conventional DSC illustrated for some polymers.     

A chemical approach to the pharmaceutical optimization of an anti-HIV protein

Chemical protein synthesis is important for dissecting the molecular basis of protein function. Here we advance its scope by demonstrating the significant improvement of the multifaceted pharmaceutical profile of small proteins exclusively via a chemical-based approach. The focus of this work centered on CCL-5 (RANTES) derivatives with potent anti-HIV activity. The overall chemical strategy involved a combination of coded and noncoded amino acid mutagenesis, peptide backbone engineering, and site-specific polymer attachment. The ability to alter specific protein residues, as well as precise control of the position and type of polymer attachment, allows for the exploration of specific molecular designs and resulted in novel CCL-5 analogues with significant differences in their respective biochemical and pharmaceutical properties. Using this approach, the complex-interplay of variables contributing to the noncovalent self-association (aggregation) state, CCR-5 specificity, in vivo elimination half-life, and anti-HIV activity of CCL-5-based protein analogues could be empirically evaluated via total chemical synthesis. This work has led to the identification of potent (sub-nanomolar) anti-HIV proteins with significantly improved pharmaceutical profiles, and illustrates the increasing value of protein chemical synthesis in contemporary therapeutic discovery. These antiviral molecules provide a novel mechanism of action for the development of a new generation of anti-HIV therapeutics which are still desperately needed.     

A new and simple approach to chemical complexity. Application to the synthesis of natural products

A new approach to describe the complexity of chemical structures is proposed. This index is simple and can be easily programmed. It derives from Whitlock's index and, despite its empirical character, provides results paralleling those obtained with the mathematical Bertz index. It has been applied to follow the strategic progress of some natural product syntheses.     

A chemical approach to the problem of slow initiation in living cationic polymerizations

The effect of slow initiation on initiation efficiency and MWD has been investigated, with regard to the living carbocationic polymerization of isobutylene. The initiating system trans−2,5-diacetoxy-2,5-dimethyl−3–hexene(DiOAcDiMeH₆)BCl₃ has been investigated at −35°C in CH₃Cl. Based on considerations valid also for anionic polymerizations, the following methods have been applied to increase the initiation efficiency: 1. Increasing [M_o]/[I_o] (batch, AMI) or [ΔM].j/[I_o] (IMA). The applicability of this method is limited by the solubility of the polymer. 2. Increasing k_i/k_p, by (i) increasing k_i, e.g., by introducing an electron withdrawing substituent into the initiator, (ii) decreasing k_p, e.g., by the addition of a strong electron donor (DMSO) to the system, (iii) using Cl-CH₂-CH₂-Cl.     

A biomimetic approach to the chemical inactivation of chrysotile fibres by lichen metabolites

Some lichens were recently reported to modify the surface state of asbestos. Here we report some new insight on the physico-chemical modifications induced by natural chelators (lichen metabolites) on two asbestos samples collected in two different locations. A biomimetic approach was followed by reproducing in the laboratory the weathering effect of lichen metabolites. Norstictic, pulvinic and oxalic acid (0.005, 0.5 and 50 mM) were put in contact with chrysotile fibres, either in pure form (A) or intergrown with balangeroite, an iron-rich asbestiform phase (B). Mg and Si removal, measured by inductively coupled plasma atomic emission spectrometry (ICP-AES) and scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDS), reveals an incongruent dissolution for pure chrysotile (A), with Mg removal always exceeding that of Si, while chrysotile-balangeroite (B) follows a congruent dissolution pattern in all cases except in the presence of 50 mM oxalic acid. A much larger removal of Mg than Si in the solutions of 0.5 and 50 mM oxalic acid with chrysotile (A) suggests a structural collapse, which in the case of chrysotile-balangeroite (B) only occurs with 50 mM oxalic acid; in these cases both samples are converted into amorphous silica (as detected by X-ray diffraction (XRD)). Subsequent to incubation, some new phases (Fe(2)O(3), CaMg(CO(3))(2), Ca(C(2)O(4)) x H(2)O and Mg(C(2)O(4))2 x H(2)O), similar to those observed in the field, were detected by XRD and micro-Raman spectroscopy. The leaching effect of lichen metabolites also modifies the Fenton activity, a process widely correlated with asbestos pathogenicity: pure chrysotile (A) activity is reduced by 50 mM oxalic acid, while all lichen metabolites reduce the activity of chrysotile-balangeroite (B). The selective removal of poorly coordinated, highly reactive iron ions, evidenced by NO adsorption, accounts for the loss in Fenton activity. Such fibres were chemically close to the ones observed in the field. Chrysotile-rich rocks, colonised by lichens, could be exposed to a natural bioattenuation and considered as a transient environmental hazard.     

A phenomenological approach to modeling chemical dynamics in nonlinear and two-dimensional spectroscopy

We present an approach for calculating nonlinear spectroscopic observables, which overcomes the approximations inherent to current phenomenological models without requiring the computational cost of performing molecular dynamics simulations. The trajectory mapping method uses the semi-classical approximation to linear and nonlinear response functions, and calculates spectra from trajectories of the system's transition frequencies and transition dipole moments. It rests on identifying dynamical variables important to the problem, treating the dynamics of these variables stochastically, and then generating correlated trajectories of spectroscopic quantities by mapping from the dynamical variables. This approach allows one to describe non-Gaussian dynamics, correlated dynamics between variables of the system, and nonlinear relationships between spectroscopic variables of the system and the bath such as non-Condon effects. We illustrate the approach by applying it to three examples that are often not adequately treated by existing analytical models--the non-Condon effect in the nonlinear infrared spectra of water, non-Gaussian dynamics inherent to strongly hydrogen bonded systems, and chemical exchange processes in barrier crossing reactions. The methods described are generally applicable to nonlinear spectroscopy throughout the optical, infrared and terahertz regions.     

Semilocalized approach to investigation of chemical reactivity

Application of the power series for the one‐electron density matrix 36 to the case of two interacting molecules is shown to yield a semilocalized approach to investigate chemical reactivity, which is characterized by the following distinctive features: (1) Electron density (ED) redistributions embracing orbitals of the reaction centers of both molecules and of their neighboring fragments are studied instead of the total intermolecular interaction energy; (2) the ED redistributions are expressed directly in the basis of fragmental orbitals (FOs) without passing to the basis of delocalized molecular orbitals (MOs) of initial molecules; (3) terms describing the ED redistributions due to an intermolecular contact arise as additive corrections to the purely monomolecular terms and thereby may be analyzed independently; (4) local ED redistributions only between orbitals of the reaction centers of both molecules are described by lower‐order terms of the power series, whereas those embracing both the reaction centers and their neighborhoods are represented by higher‐order terms. As opposed to the standard perturbative methods based on invoking the delocalized (canonical) MOs of isolated molecules, the results of the approach suggested are in‐line with the well‐known intuition‐based concepts of the classic chemistry concerning reactivity, namely, with the assumption about different roles of the reaction center and of its neighborhood in a chemical process, with the expectation about extinction of the indirect influence of a certain fragment (substituent) when its distance from the reaction center grows, etc. Such a parallelism yields quantum chemical analogs for the classic concepts and thereby gives an additional insight into their nature. The scope of validity of these concepts also is discussed. Applicability of the approach suggested to specific chemical problems is illustrated by a brief consideration of the S_N2 and Ad_E2 reactions. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem 94: 302–316, 2003     

A fully simultaneously optimizing genetic approach to the highly excited coupled-cluster factorization problem

In this article we report on the coupled-cluster factorization problem. We describe the first implementation that optimizes (i) the contraction order for each term, (ii) the identification of reusable intermediates, (iii) the selection and factoring out of common factors simultaneously, considering all projection levels in a single step. The optimization is achieved by means of a genetic algorithm. Taking a one-term-at-a-time strategy as reference our factorization yields speedups of up to 4 (for intermediate excitation levels, smaller basis sets). We derive a theoretical lower bound for the highest order scaling cost and show that it is met by our implementation. Additionally, we report on the performance of the resulting highly excited coupled-cluster algorithms and find significant improvements with respect to the implementation of Kállay and Surján [J. Chem. Phys. 115, 2945 (2001)] and comparable performance with respect to MOLPRO's handwritten and dedicated open shell coupled cluster with singles and doubles substitutions implementation [P. J. Knowles, C. Hampel, and H.-J. Werner, J. Chem. Phys. 99, 5219 (1993)].     

Multivalency and the mode of action of bacterial sialidases

Although complex modular proteins are encountered frequently in a variety of biological systems, their occurrence in biocatalysis has not been widely appreciated. Here, we describe that bacterial sialidases, which have both a catalytic and carbohydrate-binding domain, can hydrolyze polyvalent substrates with much greater catalytic efficiency than their monovalent counterparts. The enhancement of catalytic efficiency was due to a much smaller Michaelis constant and rationalized by a model in which the catalytic and lectin domains interact simultaneously with the polyvalent substrate, leading to an enhancement of affinity. Inhibition studies have shown that galactosides released by the action of the sialidase can act as the ligand for the lectin domain. This knowledge has been exploited in the design of a potent polyvalent inhibitor of the sialidase of Vibrio cholerae, which displayed exquisite selectivities for sialidases that have a lectin domain.