Recent advances in activity-based probes (ABPs) and affinity-based probes (AfBPs) for profiling of enzymes

Activity-based protein profiling (ABPP) is a technique that uses highly selective active-site targeted chemical probes to label and monitor the state of proteins. ABPP integrates the strengths of both chemical and biological disciplines. By utilizing chemically synthesized or modified bioactive molecules, ABPP is able to reveal complex physiological and pathological enzyme–substrate interactions at molecular and cellular levels. It is also able to provide critical information of the catalytic activity changes of enzymes, annotate new functions of enzymes, discover new substrates of enzymes, and allow real-time monitoring of the cellular location of enzymes. Based on the mechanism of probe-enzyme interaction, two types of probes that have been used in ABPP are activity-based probes (ABPs) and affinity-based probes (AfBPs). This review highlights the recent advances in the use of ABPs and AfBPs, and summarizes their design strategies (based on inhibitors and substrates) and detection approaches.

This review highlights the recent advances in the use of activity-based probes (ABPs) and affinity-based probes (AfBPs), and summarizes their design strategies (based on inhibitors and substrates) and detection approaches.     

Theoretical study of direct dissociative charge exchange at low energy (1–100 eV)

A theoretical investigation of the direct dissociative charge exchange process in ion—molecule collisions at low energy (1–100 eV) is presented. The process is described within the semiclassical impact parameter framework in terms of transitions between vibronic states. The initial vibrational state ν of the molecule undergoing dissociation decays owing to interaction with the vibrational continuum ϵ in which it is embedded. In view of the nearly resonant characteristics of the process, the ν−ϵ interaction h_ν(ϵ) is assumed to behave like a function of the relative ion—molecule coordinates R and γ of the form A(ϵ)f(γ)R exp(− λR. Both isotropic (f(γ) = 1) and anisotropic (f(γ) = cos γ or sin γ) interactions are investigated. The problem is first solved in closed analytical form for model cases in the weak and strong coupling limits. Computer simulations are then performed on various prototype cases in order to provide examples illustrating the role of both the discrete—continuum energy differences Δ_ν(ϵ, R) and the coupling strength, as well as to illustrate typical dependences of the direct dissociative charge exchange spectra on collision energy, impact parameter and orientation of the molecular axis with respect to the incident beam direction.     

Nonpair interactions in Na<Superscript>+</Superscript>(H<Subscript>2</Subscript>O)<Subscript><Emphasis Type="Italic">n</Emphasis></Subscript> clusters under thermal fluctuation conditions

The influence of many-particle interactions on the structure of Na⁺(H₂O) _n clusters at 298 K was studied by the Monte Carlo method. The interaction parameters were reproduced from the experimental data on the Gibbs energy of hydration in water vapor. The interaction of induced dipoles results in the displacement of part of molecules through large distances from the ion. Covalent interactions strengthen the bond with the first attached molecule and weaken bonds with the other molecules.     

Systematics of f-element crystal-field interaction

Systematic behaviors of free-ion and crystal-field interactions are elucidated as a function of N, the number of f electrons in a lanthanide or actinide ion. Experimentally determined values of the free-ion interaction parameters are compared with those calculated based on Hartree-Fock theory. Comparison is also made between the lanthanide series in 4f^N configurations and the actinide series in 5f^N configurations. Variation in intra-ionic electrostatic interaction, spin-orbit coupling, and ion-ligand interaction is analyzed in comparison between the iso-f-electron lanthanide and actinide ions. Based on an exchange-charge model of crystal-field theory, crystal-field parameters of the f-element ions in various crystals are summarized in terms of point charge contribution and covalence effect. A systematic correlation is found between the free-ion parameters and the crystal-field strength. Increase of the crystal-field interaction results in a reduction in the free-ion parameters.     

Lifetimes and oscillator strengths of singly ionized vanadium

Lifetimes of 12VII levels have been measured by using the technique of laser-excited fluorescence from sputtered metal vapour. The uncertainty is between 7–9%. For a determination of the individual transition probabilities the corresponding emission branching ratios have been measured on a high-current hollow-cathode in conjunction with a 1 m Fourier-transform spectrometer. Thef-values of 86 VII lines, which cover a spectral range 260–420 nm, have an uncertainty of about 12%. Comparison is made with literature data.     

Point Decoration of Silicon Nanowires: An Approach Toward Single‐Molecule Electrical Detection

Probing interactions of biological systems at the molecular level is of great importance to fundamental biology, diagnosis, and drug discovery. A rational bioassay design of lithographically integrating individual point scattering sites into electrical circuits is capable of realizing real‐time, label‐free biodetection of influenza H1N1 viruses with single‐molecule sensitivity and high selectivity by using silicon nanowires as local reporters in combination with microfluidics. This nanocircuit‐based architecture is complementary to more conventional optical techniques, but has the advantages of no bleaching problems and no fluorescent labeling. These advantages offer a promising platform for exploring dynamics of stochastic processes in biological systems and gaining information from genomics to proteomics to improve accurate molecular and even point‐of‐care clinical diagnosis.     

Detecting “bad” regression models: multicriteria fitness functions in regression analysis

Regression models with good fitting but no predictive ability are sometimes chance correlations and often show some pathological features such as multicollinearity, overfitting, and inclusion of noisy/spurious variables. This problem is well known and of the utmost importance. The present paper proposes some criteria that are to be fulfilled as conditions for model acceptability, the aim being to recognize linear regression models with pathology. These criteria have been thought of in order to face the following problems:

•

model instability due to outliers and influential objects;

•

predictor multicollinearity;

•

redundancy in explanatory variables;

•

overfitting due to chance factors.

A multicriteria fitness function based on the maximization of the Q² statistics under a set of tests is proposed here. This new fitness function can also be used in model searching by variable selection approaches in order to obtain a final optimal population of models. Computations on the Selwood data set are reported to illustrate the use of this multicriteria fitness function in model searching.     

Platinum state in highly active Pt/CeO<Subscript>2</Subscript> catalysts from the X-ray photoelectron spectroscopy data

The states of components of highly efficient Pt/CeO₂ catalysts for low-temperature oxidation of carbon monoxide are studied in detail by X-ray photoelectron spectroscopy (XPS). Using the precise calibration of the spectra relative to the internal standard and the fitting of Ce3d and Pt4f spectra by elementary doublets, we found the features of the platinum interaction with the ceria lattice. It is shown that when the codeposition technique is used, depending on the quality of stock solutions, it is possible to obtain both homogeneous solid solutions of platinum in the ceria lattice and solutions containing polyatomic platinum associates of the (PtO) _m type. It is found that when homogeneous PtCeO _x solid solutions are stored in air at room temperature, the homogeneous solutions slowly pass into the state of solutions with platinum associates. Mechanical mixtures of metallic platinum and ceria nanoparticles, synthesized by laser ablation, were also investigated in the course of their annealing in the air. The results obtained from the Pt4f spectra completely confirm the specific features of the interaction of platinum with ceria.     

Thermal analysis techniques for characterization of polymer materials

Routine DSC and TGA techniques, used to characterise polymer thermal stability, have been further used for assessment of comparative thermal stability of various polymer materials and for prediction of material lifetimes. The following materials were investigated: (1) commercial and experimental polymer materials - results for poly(vinyl chloride) (PVC) and bisphenol A polycarbonate (PC) are presented; (2) a polydimethylsiloxane-polytetrafluoroethylene (SIL-PTFE) coating system; and (3) commercially available linear low density polyethylene (PE-LLD), unmodified and modified chemically and physically. The plot of reciprocal temperature of initial decomposition 1/T_di vs log heating rate β has been recommended for assessment of comparative thermal stability. The lifetime of polymer materials was calculated from the plots of log time-to-failure, log t_f, vs reciprocal temperature 1/T, where t_f values were obtained using T_di from TGA measurements or directly from the oxidation induction time (OIT) data as criteria for initial deterioration of polymer thermal stability. The following sequences of increasing thermal stability were found for investigated materials:

(1)

PVC ? PC;

(2)

SIL < SIL-PTFE 20% < SIL-PTFE 50% ? PTFE;

(3)

(B) PE-LLD, grafted < (A) PE-LLD, unmodified < (C) PE-LLD, filled.

The lifetime of polymer materials predicted from the plots of log t_f vs 1/T are in reasonable agreement with experimental data and users' observations, e.g. approximately 1 year for PC and unmodified PE-LLD both at 373 K (100 °C) and for PVC at temperature of outdoor conditions about 298 K (25 °C).     

Cellular and metabolic engineering

Metabolic engineering is defined as the purposeful modification of intermediary metabolism using recombinant DNA techniques. Cellular engineering, a more inclusive term, is defined as the purposeful modification of cell properties using the same techniques. Examples of cellular and metabolic engineering are divided into five categories:

1. Improved production of chemicals already produced by the host organism;
2. Extended substrate range for growth and product formation;
3. Addition of new catabolic activities for degradation of toxic chemicals;
4. Production of chemicals new to the host organism; and
5. Modification of cell properties.

Over 100 examples of cellular and metabolic engineering are summarized. Several molecular biological, analytical chemistry, and mathematical and computational tools of relevance to cellular and metabolic engineering are reviewed. The importance of host selection and gene selection is emphasized. Finally, some future directions and emerging areas are presented.     

Reactions of cyclohexene-annulated 3а,6а-diaza-1,4-diphosphapentalene with sulfur,selenium, and CS<Subscript>2</Subscript>: structural features of zwitterionic products

The reactions of b- and f-face cyclohexene-annulated 3a,6a-diaza-1,4-diphosphapentalene (CADDP) with elemental sulfur and selenium result in the addition of two chalcogen atoms to one phosphorus atom of CADDP. A specific feature of these structures is that the diazadiphosphapentalene skeleton retains planar geometry, with a significant elongation of the N—P bond. These compounds are zwitterions, as evidenced by their electronic structures, with considerable delocalization of the negative charge in the PS₂ (PSe₂) moieties and of the positive charge in the diazaphosphole ring. The reaction of CADDP with carbon disulfide is a more complicated process accompanied by the decomposition of the CS₂ molecule to form a molecule containing three structurally different CADDP moieties, one of which is a stabilized carbene complex.     

Multi-instance multi-label distance metric learning for genome-wide protein function prediction

Multi-instance multi-label (MIML) learning has been proven to be effective for the genome-wide protein function prediction problems where each training example is associated with not only multiple instances but also multiple class labels. To find an appropriate MIML learning method for genome-wide protein function prediction, many studies in the literature attempted to optimize objective functions in which dissimilarity between instances is measured using the Euclidean distance. But in many real applications, Euclidean distance may be unable to capture the intrinsic similarity/dissimilarity in feature space and label space. Unlike other previous approaches, in this paper, we propose to learn a multi-instance multi-label distance metric learning framework (MIMLDML) for genome-wide protein function prediction. Specifically, we learn a Mahalanobis distance to preserve and utilize the intrinsic geometric information of both feature space and label space for MIML learning. In addition, we try to deal with the sparsely labeled data by giving weight to the labeled data. Extensive experiments on seven real-world organisms covering the biological three-domain system (i.e., archaea, bacteria, and eukaryote; Woese et al., 1990) show that the MIMLDML algorithm is superior to most state-of-the-art MIML learning algorithms.     

The interaction of polar aromatic molecules with neutral (polar) polymers and polyanions in aqueous solution

The interaction of aniline, pyridine and its homologues, phenol and benzamide with a series of neutral polar polymers and polyanions in aqueous solution has been studied by the equilibrium dialysis method. The interaction isotherms were generally sigmoidal. Significant association between polymer and organic molecule was only observed beyond some specific free organic molecule-polymer concentration ratio; i. e., after inter-chain attractive forces and solvation have been partially weakened by preliminary absorption of a surface layer of organic molecules. Benzamide, in fact, shows practically no interaction with neutral ‘coiled’ polymers. Maximum interaction is reached at up to thirty percent utilisation of ‘polar’ sites on the polymer chain. Klotz's method was modified to correct for these weak interactions at low organic molecule concentration. Equilibrium constants and free energies for the main association were then determined. Equilibrium constants are low;K=5–50 (g. moles per l.)^?1 for interaction with neutral polymers andK=20–120 (g. moles per l.)^?1 for interaction with polyions. The free energies are (?δG)=1–3RT and 3–5RT calories per g. mole respectively. Complexing is due to dipole-dipole and/or ion-dipole type interaction and is greatest for aniline, pyridine and phenol with fully extended polyion chains. Van der Waals' interaction between the aromatic ring and the organic section of the polymer backbone augments the dipole-dipole or ion-dipole binding with pyridine homologues, especially with acridine.     

First-Principles Calculations of Magnetism in Nanoscale Carbon Materials Confining Metal with <Emphasis Type="Italic">f</Emphasis> Valence Electrons

The f electrons in the unfilled shell of actinide and lanthanide display complex bonding behavior and the hybridized sp electrons in carbon could show spin polarization in finite nanostructures. Correspondingly, materials combining these two features exhibit abundant magnetic properties. In this paper, we outline our first-principles calculations on various nanoscale carbon materials confining U and Gd which are representative actinide and lanthanide, respectively. The complex interaction between f electrons and sp electrons make the induced magnetic property sensitive to metal specie and carbon confinement. Specially, (1) The magnetism could be suppressed by stronger adsorption with vacancy sites on graphene and adjusted by varying the valence state of some endohedral metallofullerenes (EMFs). (2) The magnetic coupling between metal and carbon structures could be promoted by large curvature when confinement site is carbon nanotubes and altered by the adatom defect on fullerene cages. (3) Untrivial magnetic property with large net spin and asymmetric spin distribution is obtained by confining U atom and Gd atom in one fullerene as a heteronuclear EMF. These results contribute to a systematic understanding of the magnetism in nanoscale carbon materials confining metal with f valence electrons.     

The Effect of Deoxyfluorination on Intermolecular Interactions in the Crystal Structures of 1,6-Anhydro-2,3-epimino-hexopyranoses

The effect of substitution on intermolecular interactions was investigated in a series of 1,6-anhydro-2,3-epimino-hexopyranoses. The study focused on the qualitative evaluation of intermolecular interactions using DFT calculations and the comparison of molecular arrangements in the crystal lattice. Altogether, ten crystal structures were compared, including two structures of C4-deoxygenated, four C4-deoxyfluorinated and four parent epimino pyranoses. It was found that the substitution of the original hydroxy group by hydrogen or fluorine leads to a weakening of the intermolecular interaction by approximately 4 kcal/mol. The strength of the intermolecular interactions was found to be in the following descending order: hydrogen bonding of hydroxy groups, hydrogen bonding of the amino group, interactions with fluorine and weak electrostatic interactions. The intermolecular interactions that involved fluorine atom were rather weak; however, they were often supported by other weak interactions. The fluorine atom was not able to substitute the role of the hydroxy group in molecular packing and the fluorine atoms interacted only weakly with the hydrogen atoms located at electropositive regions of the carbohydrate molecules. However, the fluorine interaction was not restricted to a single molecule but was spread over at least three other molecules. This feature is a base for similar molecule arrangements in the structures of related compounds, as we found for the C4-F_ax and C4-F_eq epimines presented here.     

Progress in the understanding of drug-receptor interactions, part 2: experimental and theoretical electrostatic moments and interaction energies of an angiotensin II receptor antagonist (C30H30N6(O)3S)

A combined experimental and theoretical charge density study of an angiotensin II receptor antagonist (1) is presented focusing on electrostatic properties such as atomic charges, molecular electric moments up to the fourth rank and energies of the intermolecular interactions, to gain an insight into the physical nature of the drug-receptor interaction. Electrostatic properties were derived from both the experimental electron density (multipole refinement of X-ray data collected at T=17 K) and the ab initio wavefunction (single molecule and fully periodic calculations at the DFT level). The relevance of SO and SN intramolecular interactions on the activity of 1 is highlighted by using both the crystal and gas-phase geometries and their electrostatic nature is documented by means of QTAIM atomic charges. The derived electrostatic properties are consistent with a nearly spherical electron density distribution, characterised by an intermingling of electropositive and -negative zones rather than by a unique electrophilic region opposed to a nucleophilic area. This makes the first molecular moment scarcely significant and ill-determined, whereas the second moment is large, significant and highly reliable. A comparison between experimental and theoretical components of the third electric moment shows a few discrepancies, whereas the agreement for the fourth electric moment is excellent. The most favourable intermolecular bond is show to be an NHN hydrogen bond with an energy of about 50 kJ mol(-1). Key pharmacophoric features responsible for attractive electrostatic interactions include CHX hydrogen bonds. It is shown that methyl and methylene groups, known to be essential for the biological activity of the drug, provide a significant energetic contribution to the total binding energy. Dispersive interactions are important at the thiophene and at both the phenyl fragments. The experimental estimates of the electrostatic contribution to the intermolecular interaction energies of six molecular pairs, obtained by a new model proposed by Spackman, predict the correct relative electrostatic energies with no exceptions.     

Synthesis and study of novel fulleropyrrolidines bearing biologically active 1,4-dihydropyridines

New fulleropyrrolidines endowed with chlorine-containing biological active 1,4-dihydropyridines (1,4-DHPs) have been synthesised from the respective formyl substituted 1,4-DHPs by following Prato's procedure. The presence of the chlorine atom on C2 of the 1,4-DHP ring brings about important spectroscopical and structural differences in compounds 10a-f related to the parent hydrogen-containing 11a. The mass spectroscopy study reveals different fragmentation patterns for fulleropyrrolidines 10a-f and their precursors 1,4-DHPs, as well as with 11a. Semiempirical calculations (AM1 and PM3) predict a most stable stereoisomer in all cases (RS for 10a-f) and the same RR for 11a. The presence of chlorine atom in 10a-f is responsible for the higher calculated conformational energy barriers in comparison with 11a. The geometry of the 1,4-DHP shows that the presence of fullerene unit does not significantly alter the required conformation for biological activity.     

Backbonding contributions to small molecule chemisorption in a metal–organic framework with open copper(i) centers

Metal–organic frameworks are promising materials for applications such as gas capture, separation, and storage, due to their ability to selectively adsorb small molecules. The metal–organic framework Cu^I-MFU-4l, which contains coordinatively unsaturated copper(i) centers, can engage in backbonding interactions with various small molecule guests, motivating the design of frameworks that engage in backbonding and other electronic interactions for highly efficient and selective adsorption. Here, we examine several gases expected to bind to the open copper(i) sites in Cu^I-MFU-4l via different electronic interactions, including σ-donation, π-backbonding, and formal electron transfer. We show that in situ Cu L-edge near edge X-ray absorption fine structure (NEXAFS) spectroscopy can elucidate π-backbonding by directly probing excitations to unoccupied backbonding orbitals with Cu d-character, even for gases that participate in other dominant interactions, such as ligand-to-metal σ-donation. First-principles calculations based on density functional theory and time-dependent density functional theory additionally reveal the backbonding molecular orbitals associated with these spectroscopic transitions. The energies of the transitions correlate with the energy levels of the isolated small molecule adsorbates, and the transition intensities are proportional to the binding energies of the guest molecules within Cu^I-MFU-4l. By elucidating the molecular and electronic structure origins of backbonding interactions between electron rich metal centers in metal–organic frameworks and small molecule guests, it is possible to develop guidelines for further molecular-level design of solid-state adsorbents for energy-efficient separations of relevance to industry.

In situ near edge X-ray absorption fine structure spectroscopy directly probes unoccupied states associated with backbonding interactions between the open metal site in a metal–organic framework and various small molecule guests.     

The X<Superscript>−</Superscript>···benzohydrazide complexes: the interplay between anion-π and H-bond interactions

The compounds containing the benzohydrazide (BH) nucleus have a variety of biological activities because of various noncovalent intermolecular interactions. The interplay between anion-π and H-bond interactions, which can affect the activity of compounds, has been investigated in ten substituted BH exposed to the chloride ion using the quantum mechanical calculations. The total interaction energy is separated into the anion-π (ΔE _Aπ) and H-bond (ΔE _HB) contributions where both interactions are presented in the complexes. The electron-withdrawing substituents (EWSs) increase |ΔE _Aπ| and decrease |ΔE _HB|, while reversed changes are observed with the electron-donating substituents (EDSs). In addition, the total binding energy (ΔE) becomes more/less negative in the presence of EWSs/EDSs. The synergetic effects of mentioned interactions and substituent effects have also been investigated using the atoms in molecules (AIM), natural bond orbital (NBO) and molecular electrostatic potential (MEP) analyses. A good correlation is found between the energy data and the Hammett constants, the minimum of electrostatic potential (V _min) and the results of population analyses.     

Molecular interactions in binary mixtures of methyl formate with 1-butanol, 1-pentanol,and 1-hexanol by using ultrasonic data at 303 K

Density (ρ), viscosity (η), and ultrasonic velocity (U) have been measured for binary mixtures of methyl formate with 1-butanol, 1-pentanol and 1-hexanol at 303 K. From the experimental results, adiabatic compressibility (β), acoustic impedance (Z), viscous relaxation time (τ), free length (L_f), free volume (V_f), internal pressure (π_i), and Gibbs free energy (ΔG) have been determined. Excess values of various parameters have also been calculated and interoperated in terms of molecular interactions. The deviations in the parameters show that strength of intermolecular interactions between methyl formate with selected 1-alcohols have been observed in the order of 1-butanol < 1-pentanol < 1-hexanol.