Examining ligand-protein interactions with binding-energy landscapes

Binding-energy landscapes are used to investigate the thermodynamics of molecular recognition for the pteridine ring, a recognition anchor in binding with dihydrofolate reductase, and two molecules with the same shape but different heteroatom substitutions. The relative importance of hydrogen bonding and hydrophobic interactions in this system is analyzed by comparing these three different decorations of the pteridine scaffold. Received: 5 May 1998 / Accepted: 3 September 1998 / Published online: 17 December 1998     

Development of new isothiocyanate-based chiral derivatizing agent for amino acids

Summary (1S,2S)-1,3-Diacetoxy-1-(4-nitrophenyl)-2-propylisothiocyanate [(S,S)-DANI] has been developed as a new chiral derivatizing agent for resolution of compounds containing an amino group. The reagent is readily available in both enantiomeric forms. Its applicability was demonstrated by the resolution of representative α-amino acids. The diastereomeric thiourea derivatives produced were separated by reversed-phase (C₁₈) high-performance liquid chromatography, with mixtures of 0.1% aqueous trifluoroacetic acid (pH∼2) and methanol as eluents.     

Additional symmetry for the electronic shell in its ground state and many-electron effects

The additional symmetry for the properties related to the ground state of the atom is considered taking into account many-electron effects. Calculations of the I _4f, I _3d,I _2p,I _3p binding energies, 4f ^N-15d - 4f^N system differences and 2p, 3p electron affinities in the second order of perturbation theory and in the configuration interaction approximation have been performed for the ground configurations with one open shell. The analysis of separate many-electron corrections for these quantities and their variation along the sequences of atoms and ions shows that the main corrections maintain the considered symmetry. Received 18 January 1999 and Received in final form 17 July 1999     

Average Nuclear Binding Energies in a Lee-Wick Type Model

We find: (i) The Lee-Wick type relativistic mean-field theory with finite nucleon size effect can reproduce the binding energies for all nuclei over the nuclide table quite well. For 1654 nuclei, whose mass numbers range from 16 to 263 and charge numbers range from 8 to 106, the calculated binding energies are near to the corresponding experimental values with a systematical deviation of about 5.74%. (ii) The lowering of the calculated nuclear masses, by including Coulomb energy into the variational calculations, is very small.     

Effect of ligand volume correction on PMF scoring

Recently, a knowledge‐based scoring function has been introduced that estimates the protein‐binding affinity based on the 3D structure of a protein–ligand complex (J Med Chem 1999, 42, 791). A ligand volume correction factor has been proposed and applied to filter out intraligand interactions in this simplified potential approach. Here we evaluate the effect of the ligand volume correction on the predictive power of the PMF scoring function. It is found that the effect of the ligand volume correction is significant on the derived potentials and large on the overall score. However, the effect of the ligand correction on the predictive power of the scoring function appears to be smaller. For a test set containing serine proteases the predictive power of the PMF scoring function does not change with the introduction of the volume correction. For a test set of metalloprotease complexes, the predictive power of the PMF scoring function improves only slightly when the volume correction is applied. For five test sets comprising a total of 225 diverse protein ligand complexes taken from the Brookhaven Protein Data Bank it is found, however, that the introduction of the ligand volume correction consistently improves the correlation between the PMF scores and the measured binding affinities. The effect of the correction factor on docking/scoring experiments is also analyzed using a test set of 61 biphenyl inhibitor‐stromelysin complexes. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 418–425, 2001     

Characteristics and function of human hemoglobin vesicles as an oxygen carrier

A liposome‐encapsulated human hemoglobin (Neo Red Cell, (NRC) has been developed and evaluated as an artificial oxygen carrier. The NRC is a liposome‐encapsulated highly concentrated (>45%) stroma‐free human hemoglobin with inositol hexaphosphate (IHP as an allosteric effector), a coenzyme and substrates for reducing methemoglobin (metHb). The NRC's surface was coated with polyethylene glycol to prevent aggregation in plasma and to prolong their retention time in the blood stream. The oxygen binding behavior of the NRC in vitro was investigated and it was found that it effectively transports oxygen in vivo as an oxygen carrier. The oxygen binding behavior and kinetics were studied by the stopped‐flow method and the oxygen binding curve of the NRC was determined. The oxygen binding speed and binding coefficient (K_on) of NRC, washed human red blood cells (WRBC) and stroma‐free human hemoglobin (SFHb) were measured by stopped‐flow method. The oxygen binding speed of SFHb was the highest, while that of RBC was the lowest and that of NRC was intermediate. The oxygen binding of NRC ended within 60 msec when deoxy‐NRC was mixed with oxygen. The K_on of NRC was 2.9 × 10⁵, 10 times faster than that of RBC. The oxygen binding curve and P₅₀O₂ of NRC that contained various IHP concentrations were measured. The oxygen‐binding curve of the NRC sequentially shifted to the right as the IHP content was increased. Exchange transfusion of 70% was carried out for rats with NRC containing various concentrations of IHP and of Hb, and investigated the optimum concentration of NRC in vivo. The lactate value after exchange transfusion was three times higher than before exchange transfusion, when rats were subjected to exchange transfused with NRC that did not contain IHP. But the increase of lactate was suppressed when rats were transfused with NRC that contained IHP. When the Hb concentration of NRC was 5 and 6%, exchange transfused rats recovered to normality just like rats transfused with RBC. Copyright © 2000 John Wiley & Sons, Ltd.     

Study of chemical bonding in H2 and HF molecules: Wave function and density functional theory (DFT) parameters approach

Balint Kurti's Fourier grid Hamiltonian method is employed to obtain the molecular wave function and equilibrium bond length for H₂ and HF molecules. The density functional theory parameter, namely, the chemical hardness (η) value, was determined for some diatomic hydride molecules using this wave function and the results are found to be in good agreement with the values obtained from the ab initio HF–SCF method. A new formula for chemical hardness (η=1/2Dr, where D is the proportionality constant and r is the internuclear distance) is introduced in binding energy and change of hardness equations to determine the chemical hardness and chemical potential values for different bond lengths. The binding energy and change of hardness values are calculated for H₂, H, H, HF, HF⁺, and HF⁻ molecules and the bond stability is discussed. Finally, the concept of an atom in a molecule is examined in the context of DFT parameters and comparison is made between an atom in a molecule and the isolated atom. © 2000 John Wiley & Sons, Inc. Int J Quant Chem 76: 662–669, 2000     

Insights into Modeling Approaches in Chemistry: Assessing Ligand-Protein Binding Thermodynamics Based on Rigid-Flexible Model Molecules

In the field of chemistry, model compounds find extensive use for investigating complex objects. One prime example of such object is the protein-ligand supramolecular interaction. Prediction the enthalpic and entropic contribution to the free energy associated with this process, as well as the structural and dynamic characteristics of protein-ligand complexes poses considerable challenges. This review exemplifies modeling approaches used to study protein-ligand binding (PLB) thermodynamics by employing pairs of conformationally constrained/flexible model molecules. Strategically designing the model molecules can reduce the number of variables that influence thermodynamic parameters. This enables scientists to gain deeper insights into the enthalpy and entropy of PLB, which is relevant for medicinal chemistry and drug design. The model studies reviewed here demonstrate that rigidifying ligands may induce compensating changes in the enthalpy and entropy of binding. Some “rules of thumb” have started to emerge on how to minimize entropy-enthalpy compensation and design efficient rigidified or flexible ligands.     

Ionic absorption of polypropylene functionalized by surface grafting and reactions

Plasma-induced surface graft copolymerization of acrylic acid on polypropylene fibers and the subsequent reactions of the grafted carboxylic groups are reported. The extents of grafting was controlled by the plasma conditions. Reactions of the carboxylic acid with selected amines resulted in ion-exchanging and chelating functionalities. In general, ion adsorption is enhanced by higher levels of grafting and by raising temperature during adsorption. The adsorption level and preferences among ions of these functionalized fibers depend on the structure of the functional groups, i.e., the structure of the spacer and terminal groups. The carboxylic acid groups of the PP-g-AA fibers which behave like weakly acidic ion-exchangers are attributed to the low metal ion adsorption and the lack of ion preference. The F1 fibers with flexible  CH₂CH₂ spacer and small terminal  OH in the functional group exhibits highest ion adsorption among all functionalized fibers studied here. With benzene spacers, metal adsorption can be enchanced by the electron-donating nature of the terminal group. With the same ester end group in the functional structure, F3 fibers which contain benzene ring spacers show higher ion adsorption than F4 and F5 which have CH₂ and NH spacers, respectively. The ion preference and adsorption ability of the functionalized fibers, i.e., equilibrium binding constants (K_b) and saturation constants (K_s) derived from adsorption isotherms, also depend on the functional group structures. K_b increases with increasing grafting yield, increasing the electron donor atom in either terminal bonds or spacer, and reducing the steric hindrance of spacer. The K_s values are affected by the accessibility of functional groups, the size of spacer, and the terminal group structure. © 1997 John Wiley & Sons, Inc.