Can the electronegativity equalization method predict spectroscopic properties?

The electronegativity equalization method is classically used as a method allowing the fast generation of atomic charges using a set of calibrated parameters and provided knowledge of the molecular structure. Recently, it has started being used for the calculation of other reactivity descriptors and for the development of polarizable and reactive force fields. For such applications, it is of interest to know whether the method, through the inclusion of the molecular geometry in the Taylor expansion of the energy, would also allow sufficiently accurate predictions of spectroscopic data. In this work, relevant quantities for IR spectroscopy are considered, namely the dipole derivatives and the Cartesian Hessian. Despite careful calibration of parameters for this specific task, it is shown that the current models yield insufficiently accurate results.

Molecular dynamics and umbrella sampling study of stabilizing factors in cyclic peptide-based nanotubes.

In this study, the dissociation mechanism of self-assembled cyclic peptides (CPs) has been investigated using classical/steered molecular dynamics simulations combined with umbrella sampling techniques in a polar and a nonpolar solvent. The stability of cyclic peptide nanotubes (CPNTs) with different surface polarity, {cyclo-[(D-Trp-L-Leu)(4)]}(8) and {cyclo-[(L-Gln-D-Ala-L-Glu-D-Ala)(2)]}(8), are explored in detail. It is observed from the results that the CPNTs are less dynamic in the nonpolar solvent than in the polar solvent. The dissociation of CPs from a lower oligomeric form is achieved by gradual breaking of interactions, requiring relatively little force. In higher oligomeric CPNTs, the dissociation takes place by collective breaking of interactions with significantly higher force. During the dissociation process, the tendency for collective breaking of various intermolecular interactions increases from the terminal to the core of the CPNT. The breaking of backbone-backbone hydrogen bonding is the critical point in the dissociation of CPs which is followed by the annihilation of various side chain-side chain interactions. The polarity of the solvent plays a decisive role in the dissociation mechanism of self-assembled CPs. It is evident from the calculated free energy of binding values that the overall stability of CPNT is higher in the nonpolar solvent than in the polar solvent.

The Significance of Parameters in Charge Equilibration Models.

Charge equilibration models such as the electronegativity equalization method (EEM) and the split charge equilibration (SQE) are extensively used in the literature for the efficient computation of accurate atomic charges in molecules. However, there is no consensus on a generic set of optimal parameters, even when one only considers parameters calibrated against atomic charges in organic molecules. In this work, the origin of the disagreement in the parameters is investigated by comparing and analyzing six sets of parameters based on two sets of molecules and three calibration procedures. The resulting statistical analysis clearly indicates that the conventional least-squares cost function based solely on atomic charges is in general ill-conditioned and not capable of fixing all parameters in a charge-equilibration model. Methodological guidelines are formulated to improve the stability of the parameters. Although in this case a simple interpretation of individual parameters is not possible, charge equilibration models remain of great practical use for the computation of atomic charges.

QSAR analysis of salicylamide isosteres with the use of quantum chemical molecular descriptors.

Quantitative relationships between the molecular structure and the biological activity of 49 isosteric salicylamide derivatives as potential antituberculotics with a new mechanism of action against three Mycobacterial strains were investigated. The molecular structures were represented by quantum chemical B3LYP/6-31G( *) based molecular descriptors. A resulting set of 220 molecular descriptors, including especially electronic properties, was statistically analyzed using multiple linear regression, resulting in acceptable and robust QSAR models. The best QSAR model was found for Mycobacterium tuberculosis (r(2)=0.92; q(2)=0.89), and somewhat less good QSAR models were found for Mycobacterium avium (r(2)=0.84; q(2)=0.78) and Mycobacterium kansasii (r(2)=0.80; q(2)=0.56). All QSAR models were cross-validated using the leave-10-out procedure.

An atom counting strategy towards analyzing the biological activity of sex hormones.

A simple and effective molecular descriptor, viz., the number of atoms in a molecule (N(A)) is made use of in the development of the quantitative structure-activity relationship (QSAR). A series of testosterone derivatives with various biological activities and estrogen derivatives with the activities in terms of relative binding affinity (RBA) are considered to find out the potential of N(A) in predicting the activities of those molecules. It is heartening to note that N(A) along with the electrophilicity index (omega) is capable of explaining the biological activities of the male and female hormones.

Toward an alternative hardness kernel matrix structure in the Electronegativity Equalization Method (EEM).

This study presents an alternative of the Electronegativity Equalization Method (EEM), where the usual Coulomb kernel has been transformed into a smooth function. The new framework, as the classical EEM, permits fast calculations of atomic charges in a given molecule for a small computational cost. The original EEM procedure needs to previously calibrate the different implied atomic hardness and electronegativity, using a chosen set of molecules. In the new EEM algorithm half the number of parameters needs to be calibrated, since a relationship between electronegativities and hardnesses has been found.

Analyzing toxicity through electrophilicity.

The toxicological structure-activity relationships are investigated using conceptual DFT based descriptors like global and local electrophilicities. In the present work the usefulness of electrophilicity in predicting toxicity of several polyaromatic hydrocarbons (PAH) is assessed. The toxicity is expressed through biological activity data (pIC50) defined as molar concentration of those chemicals necessary to displace 50% of radiolabeled tetrachlorodibenzo-p-dioxin (TCDD) from the arylhydrocarbon (Ah) receptor. The experimental toxicity values (pIC50) for the electron acceptor toxin like polychlorinated dibenzofurans (PCDF) are taken as dependent variables and the DFT based global descriptor electrophilicity index (omega) is taken as independent variable in the training set. The same model is then tested on a test set of polychlorinated biphenyls (PCB). A good correlation is obtained which vindicates the importance of these descriptors in the QSAR studies on toxins. These toxins act as electron acceptors in the presence of biomolecules whereas aliphatic amines behave as electron donors some of which are also taken into account for the present work. The toxicity values of the aliphatic amines in terms of the 50% inhibitory growth concentration (IGC50) towards ciliate fresh-water protozoa Tetrahymena pyriformis are considered. Since there is no global nucleophilicity we apply local nucleophilicity (omegamax+) as the descriptor in this case of training set. The same regression model is then applied to a test set of amino alcohols. Although the correlation is very good the statistical analysis reflects some cross validation problem. As a further check the amines and amino alcohols are used together to form both the training and the test sets to provide good correlation. It is demonstrated that the toxicity of several toxins (both electron donors and acceptors) in the gas and solution phases can be adequately explained in terms of global and local electrophilicities. Amount of charge transfer between the toxin and the biosystem, simulated as nucleic acid bases and DNA base pairs, indicates the importance of charge transfer in the observed toxicity. The major strength of the present analysis vis-à-vis the existing ones rests on the fact that it requires only one descriptor having a direct relationship with toxicity to provide a better correlation. Importance of using the information from both the toxin and the biosystem is also analyzed.

Determination of the absolute configuration of three as-hydrindacene compounds by vibrational circular dichroism.

[Structure: see text]. The absolute configurations of three compounds with a rigid 1,8-disubstituted as-hydrindacene skeleton have been determined using vibrational circular dichroism spectroscopy and quantum chemical calculations. Experimental spectra were compared to B3LYP/6-31G and B3LYP/cc-pVTZ level predicted spectra. Based on the agreement between the predicted and experimental spectra, the stereochemistry could be assigned with high confidence. The results were found to be in agreement with ECD determinations and/or predictions based on the applied asymmetric methods in the synthetic route.