Multipole electrostatic potential derived atomic charges in NDDO-methods with <Emphasis Type="Italic">spd</Emphasis>-basis sets

The recently introduced multipole approach for computing the molecular electrostatic potential (MEP) within the semiempirical neglect of diatomic differential overlap (NDDO) framework [Horn AHC, Lin Jr-H., Clark T (2005) Theor Chem Acc 114:159–168] has been used to obtain atomic charges of nearly ab initio quality by scaling the semiempirical MEP. The parameterization set comprised a total of 797 compounds and included not only the newly parameterized AM1* elements Al, Si, P, S, Cl, Ti, Zr, and Mo but also the standard AM1 elements H, C, N, O and F. For comparison, the ZDO-approximated MEP was also calculated analytically in the spd-basis. For the AM1*-optimized structures, single-point calculations at the B3LYP, HF and MP2 levels with the 6-31G(d) and LanL2DZP basis sets were performed to obtain the MEP. The regression analysis of all 12 combinations of semiempirical and ab initio MEP data yielded correlation coefficients of at least 0.99 in all cases. Scaling the analytical and multipole-derived semiempirical MEP by the regression coefficients yielded mean unsigned errors below 2.6 and 1.9 kcal mol⁻¹, respectively. Subsequently, for 22 drug molecules from the World Drug Index, atomic charges were computed according to the RESP procedure using XX/6-31G(d) (XX=B3LYP, HF, MP2) and scaled AM1* multipole MEP; the correlation coefficients obtained are 0.83, 0.85 and 0.83, respectively. Figure: Schematic representation of the atomic charge generation: The molecular electrostatic potential (MEP) is calculated using the AM1* Hamiltonian; then the semiempirical MEP is scaled to DFT or ab initio level, and atomic charges are generated subsequently by the restraint electrostatic potential (RESP) fit method. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible to authorized users. Proceedings of “Modeling Interactions in Biomolecules II”, Prague, September 5th–9th, 2005.     

Intrinsic Amyloidogenic Behavior of Terminally Protected Alzheimer’s Aβ<Superscript>17–21</Superscript> Peptide: Self-Aggregation and Amyloid-Like Fibril Formation

The terminally protected peptide Boc-Leu-Val-Phe-Phe-Ala-OMe bearing sequence similarity with the central hydrophobic cluster (CHC) of Alzheimer’s Aβ^17–21 peptide self-assembles to produce amyloid-like straight unbranched fibrils from organic solvents. The fibrils readily bind with a physiological dye Congo red (CR) and exhibits green gold birefringence under polarized light, a characteristic feature of amyloid plaque obtained from many neurodegenerative diseases. FTIR spectroscopy and in silico energy minimization study shed some light on the antiparallel supramolecular β-sheet aggregation of the peptide.     

Allozyme diversity in pheasants (<Emphasis Type="Italic">Phasianus</Emphasis> spp.) from breeding stations in Serbia

The pheasant breeds are widely used for restocking of natural populations depleted by hunting. The pheasant population number decline was detected during the 1970s in many hunting areas of Europe. One of its possible reasons might be the loss of adaptability in populations originating from breeding stations, which was caused by inbreeding depression. The aim of this paper was the analysis of genetic variability in pheasant populations from three breeding stations in Vojvodina province (Serbia) by means of allozyme diversity detection. The allozyme variability analysis of pheasants from all three breeding stations revealed polymorphisms at nine loci: Ldh-1, Mor-1, Mor-2, Es-1, Mod-2, Pgd, Gpi-2, Odh, and Sod. The analysis of individuals from three different breeding stations showed mean values of observed heterozygosity of H _o=0.137, polymorphism P _95%=30%, and H/P ratio H/P=0.430, which indicate a normal level of genetic variability for bird populations. Comparative analysis of three pheasant populations showed a high level of interpopulation differentiation.     

Distribution of haplotypes and microsatellite alleles among Asian elephants (<Emphasis Type="Italic">Elephas maximus</Emphasis>) in Thailand

Habitat fragmentation often promotes increased inbreeding depression due to interrupted gene flow between populations. In this study, we demonstrate that Asian elephants most likely also suffer from outbreeding depression due to cryptic speciation. We analysed mitochondrial and nuclear DNA loci from 78 Asian elephants. Haplotype genealogy and analysis of molecular variance revealed two matrilinear clades (α _h, β _h). Microsatellite analyses of individuals grouped according to their haplotype clade (corresponding group of nuclear genotypes called α _nuc and β _nuc) revealed significant genotypic differentiation between α _nuc and β _nuc. Such genealogically differentiated forms in a morphologically uniform species are considered indicative of cryptic speciation. The differentiation was caused by bulls, whereas considering cows only resulted in no differentiation. Such result is best explained by Haldane’s rule whereby hybrid formation between genealogical forms causes lower viability and fertility of heterogametic hybrids. Although the lack of hybrid-specific morphological characteristics renders direct testing of reduced hybrid fitness under natural conditions unfeasible, the effects of Haldane’s rule are demonstrated by reduced male-mediated gene flow between genealogical forms under sympatric conditions, as was indeed suggested by the data found in Asian elephants: male-mediated gene flow between groups α _nuc and β _nuc was much lower than female-mediated gene flow. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.

Homology modeling and examination of the effect of the D92E mutation on the H5N1 nonstructural protein NS1 effector domain

Virulent H5N1 strains of influenza virus often harbor a D92E point mutation in the nonstructural protein NS1. This crucial mutation has been correlated with increased virulence and/or cytokine resistance, but the structural implications of such a change are still unclear. Furthermore, NS1 protein could also be a potential target for the development of novel antiviral agents against H5N1 strains. Therefore, a reasonable 3D model of H5N1 NS1 is important for the understanding of the molecular basis of increased virulence and the design of novel antiviral agents. Based on the crystal structure of a non-H5N1 NS1 protein, a model of H5N1 NS1 was developed by homology modeling, molecular mechanics and molecular dynamics simulations. It was found that the D92E mutation could result in weakened interactions of the carboxylate side chain with other phosphorylated residues, thereby activating phosphorylation of NS1. Figure Superposition of snapshots picked from the two molecular dynamic (MD) trajectories: a H5N1 NS1 homology model and b non-H5N1 NS1 crystal structure after 0 (green ribbon), 5 (blue ribbon) and 10 ns (pink ribbon) MD simulation     

Computational study of enantioselective interaction between C<Subscript>60</Subscript> fullerene and its derivatives with L-histidine

The mechanism of the enantioselective binding of L-histidine with C₆₀ fullerene and its derivatives, (1,2-methanofullerene C₆₀)-61-carboxylic acid, diethyl (1,2-methanofullerene C₆₀)-61-61-dicarboxylate and tert-butyl (1,2-methanofullerene C₆₀)-61-carboxylate based chiral selectors was studied by quantum chemical calculations. All the molecules were fully optimized at RHF/6-31G* basis set. Relative energies between the different complexes were subsequently estimated with single-point electronic energies computed using Møller-Plesset perturbation theory (MP2). Stability and feasibility of all the generated structures were supported by their respective energy minima and fundamental frequencies. It was observed that interaction of fullerene derivatives with L-histidine is due to the existence of hydrogen bonding forces during the complex formation. The intermolecular forces, flow of atomic charges, binding energy, hardness, dipole moment and localization of electrostatic potential are in agreement with enantioselective interaction of L-histidine with C₆₀ fullerene and its derivatives. It is found that theoretical evaluation to be consistent with the experimental data.     

Optimization of parameters for semiempirical methods V: Modification of NDDO approximations and application to 70 elements

Several modifications that have been made to the NDDO core-core interaction term and to the method of parameter optimization are described. These changes have resulted in a more complete parameter optimization, called PM6, which has, in turn, allowed 70 elements to be parameterized. The average unsigned error (AUE) between calculated and reference heats of formation for 4,492 species was 8.0 kcal mol⁻¹. For the subset of 1,373 compounds involving only the elements H, C, N, O, F, P, S, Cl, and Br, the PM6 AUE was 4.4 kcal mol⁻¹. The equivalent AUE for other methods were: RM1: 5.0, B3LYP 6–31G*: 5.2, PM5: 5.7, PM3: 6.3, HF 6–31G*: 7.4, and AM1: 10.0 kcal mol⁻¹. Several long-standing faults in AM1 and PM3 have been corrected and significant improvements have been made in the prediction of geometries. Figure Calculated structure of the complex ion [Ta₆Cl₁₂]²⁺ (footnote): Reference value in parenthesis Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Modeling the interaction of fipronil-related non-competitive antagonists with the GABA β3-receptor

A three-dimensional model of the beta3-homopentamer of the gamma-aminobutyric acid (GABA) receptor/chloride ionophore complex was developed by homology modeling using the cyro-electron microscopy structure of nicotinic acetylcholine as a template. Interactions between the beta3-homopentamer and two classes of fipronil-related non-competitive antagonists were investigated using docking studies. The phenyl groups of these compounds were stabilized by strong hydrophobic and hydrophilic interactions with the rings formed by Thr256 and Ala252. Leu253 and Ile255 were involved mainly in hydrophobic contact with the pyrazole moiety. Different substitution at positions 15, 16 and 17 of the pyrazole ring of fipronil resulted in weakening of the hydrogen bonds and hydrophobic interactions between the beta3-receptor and fipronil-related heterocyclic compounds, which maybe the principal cause of the decreased affinities reported in vitro. Moreover, a good correlation between total binding energies calculated by AutoDock and experimentally determined IC(50) values proved our models to be reasonable in predicting the interaction mode of the antagonist with the GABA beta3-receptor.     

Analysis of trophic structure of two carnivore assemblages by means of guild identification

We evaluated the existence of trophic guild structure, considering seasonal and annual variation, in two terrestrial carnivore assemblages: one from Santa Cruz province (Argentinean Patagonia, composed by six carnivore species), and the other from Doñana National Park (SW Spain, composed by five carnivore species). To identify trophic guilds, we first studied seasonal and annual diets of predators, calculated trophic overlap among species pairs, and then constructed overlap matrices (similarity matrices). We determined guild membership objectively by entering the similarity matrices into the clustering technique unweighted pair-group method with arithmetic averaging. Carnivores from both assemblages were grouped, respectively, into four feeding guilds. Lagomorphs and rodents promoted the formation of two feeding guilds in both study sites, although the taxonomic composition of predator species that composed them was different. The ungulates-edentates feeding guild was only present at Santa Cruz, whereas the birds and reptiles feeding guild was only present at Doñana. Invertebrates and fruits were the base for the formation of a guild composed by species of the same taxonomic origin both in Santa Cruz and Doñana. Guild structure of Santa Cruz and Doñana assemblages did not exhibit seasonal or annual variation, although the specific guild composition changed over the two studied periods for both assemblages. This structure probably responded to discontinuities in resource spectra in Santa Cruz and fluctuations in rabbit abundance in Doñana. Our results support the hypothesis that establishes that guilds are originated by opportunistic convergence of species on abundant and energetically rewarding resources.     

Effects of antler breakage on mating behavior in male tule elk (<Emphasis Type="Italic">Cervus elaphus nannodes</Emphasis>)

Although antler size has been identified as a primary determinant of dominance, fighting success, and reproductive success in male cervids, >80% of the male tule elk (Cervus elaphus nannodes) in the Owens Valley, California, experience antler breakage. To determine the effect of antler breakage on male mating success, we recorded antler morphology, body size, and mating behavior of male elk throughout the rut. Antler breakage, regardless of severity, had no effect on male–male assessment, fighting success, or harem-holding status. The factor consistently associated with our indices of male mating success was not antler size but body size. Although antler size is frequently emphasized as a key factor in male dominance and social rank, this association may reflect the correlation between antler size and body size. In the Owens Valley, it appears that male elk are not assessing competitors based on antler morphology but on other characteristics. An erratum to this article can be found at