Comparison of end-point continuum-solvation methods for the calculation of protein-ligand binding free energies

We have compared the predictions of ligand‐binding affinities from several methods based on end‐point molecular dynamics simulations and continuum solvation, that is, methods related to MM/PBSA (molecular mechanics combined with Poisson–Boltzmann and surface area solvation). Two continuum‐solvation models were considered, viz., the Poisson–Boltzmann (PB) and generalised Born (GB) approaches. The nonelectrostatic energies were also obtained in two different ways, viz., either from the sum of the bonded, van der Waals, nonpolar solvation energies, and entropy terms (as in MM/PBSA), or from the scaled protein–ligand van der Waals interaction energy (as in the linear interaction energy approach, LIE). Three different approaches to calculate electrostatic energies were tested, viz., the sum of electrostatic interaction energies and polar solvation energies, obtained either from a single simulation of the complex or from three independent simulations of the complex, the free protein, and the free ligand, or the linear‐response approximation (LRA). Moreover, we investigated the effect of scaling the electrostatic interactions by an effective internal dielectric constant of the protein (?_int). All these methods were tested on the binding of seven biotin analogues to avidin and nine 3‐amidinobenzyl‐1H‐indole‐2‐carboxamide inhibitors to factor Xa. For avidin, the best results were obtained with a combination of the LIE nonelectrostatic energies with the MM+GB electrostatic energies from a single simulation, using ?_int = 4. For fXa, standard MM/GBSA, based on one simulation and using ?_int = 4–10 gave the best result. The optimum internal dielectric constant seems to be slightly higher with PB than with GB solvation. © Proteins 2012; © 2012 Wiley Periodicals, Inc.     

Amphipod crustaceans from anchihaline cave waters of the Galapagos Islands

Three species of blind Amphipoda are recorded from anchihaline cave waters in the Galapagos Islands. One of these, Galapsiellus leleuporum (Monod, 1970) was previously know from the islands; the male is described for the first time. The other two belong to families with predominantly (though not exclusively) deep-sea members: Valettietta cavernicola sp. nov. (family Lysianassidae; and Antronicippe serrata gen. et sp. nov. (family Pardaliscidae). The genus Valettietta was not previously recorded from caves; it contained two abyssal species in the Atlantic, while a third species was recorded from the Pacific in a vertical haul between 0 and 5300 m. Antronicippe is closely related to Spelaeonicippe, a genus with two species known from anchihaline caves in the Canary Islands and the West Indies.     

Horse‐mounted invaders from the Russo‐Kazakh steppe or agricultural colonists from western Central Asia? A craniometric investigation of the Bronze Age settlement of Xinjiang

Numerous Bronze Age cemeteries in the oases surrounding the T?klamakan Desert of the Tarim Basin in the Xinjiang Uyghur Autonomous Region, western China, have yielded both mummified and skeletal human remains. A dearth of local antecedents, coupled with woolen textiles and the apparent Western physical appearance of the population, raised questions as to where these people came from. Two hypotheses have been offered by archaeologists to account for the origins of Bronze Age populations of the Tarim Basin. These are the "steppe hypothesis" and the "Bactrian oasis hypothesis." Eight craniometric variables from 25 Aeneolithic and Bronze Age samples, comprising 1,353 adults from the Tarim Basin, the Russo-Kazakh steppe, southern China, Central Asia, Iran, and the Indus Valley, are compared to test which, if either, of these hypotheses are supported by the pattern of phenetic affinities possessed by Bronze Age inhabitants of the Tarim Basin. Craniometric differences between samples are compared with Mahalanobis generalized distance (d2), and patterns of phenetic affinity are assessed with two types of cluster analysis (the weighted pair average linkage method and the neighbor-joining method), multidimensional scaling, and principal coordinates analysis. Results obtained by this analysis provide little support for either the steppe hypothesis or the Bactrian oasis hypothesis. Rather, the pattern of phenetic affinities manifested by Bronze Age inhabitants of the Tarim Basin suggests the presence of a population of unknown origin within the Tarim Basin during the early Bronze Age. After 1200 B.C., this population experienced significant gene flow from highland populations of the Pamirs and Ferghana Valley. These highland populations may include those who later became known as the Saka and who may have served as "middlemen" facilitating contacts between East (Tarim Basin, China) and West (Bactria, Uzbekistan) along what later became known as the Great Silk Road.     

The embryology ofStegnospermataceae,with a discussion on its status,affinities and systematic position

The embryology ofStegnosperma halimifolium andS. watsonii has been studied in detail. The tapetum is of the secretory type and its cells become multinucleate. Simultaneous cytokinesis in the pollen mother cells follows meiosis. The ripe pollen grains are 3-celled. The ovule is crassinucellate, bitegmic and amphitropous, with the micropyle formed by the inner integument alone. The female archesporium is one celled, and the parietal tissue 3–5 layered. The embryo sac development conforms to thePolygonum type. A central strand, 6 or 7 cells thick, differentiates inside the nucellus and extends from the base of the embryo sac to the chalazal region. The endosperm is nuclear. The embryogeny conforms to the Caryophyllad type. The seed coat is formed by the outer epidermis of the outer integument and the inner epidermis of the inner integument. Based on this evidence and other data, the status of the genus as an independent family,Stegnospermataceae (Stegnospermaceae) is confirmed. Apparently, it forms a connecting link betweenPhytolaccaceae andCaryophyllaceae.     

Dermatoglyphic distances and different linguistic groups in Sardinia

By means of Penrose's C _H ² , a matrix of dermatoglyphic distances was calculated from several palmar characteristics of 1831 males belonging to different Sardinian linguistic groups. Then, by means of cluster analysis, a dendrogram was constructed and compared with a diagram of the affinities among the linguistic groups. This comparison shows a good congruency between the dendrogram structure and the diagram of linguistic affinities. Supported by M.P.I. 60%, 1983.     

Collagen in the pterobranch coenecium and the problem of graptolite affinities

Amino-acid analysis of the extracellular skeleton (coenecium) of two pterobranchs (Hemichordata) Rhabdopleura normani and Cephalodiscus (C.) hodgsoni shows that both contain considerable quantities of collagenous material with relatively high hydroxyproline and low hydroxylysine levels. The appearance of the fibrous material in the skeleton of pterobranchs, although collagenous, differs from standard EM characteristics of collagen. The identification of the collagenous nature of the pterobranch skeleton with the presumed presence of collagen-like material in the periderm of fossil graptolites, taken in conjunction with other data, supports the hypothesis that both groups may be closely related phylogenetically.     

Growth characteristics of an obligately psychrophilic Vibrio sp.

The growth characteristics of an obligately psychrophilic Vibrio sp. have been studied in a chemostat with glucose or lactose as the limiting substrate over a temperature range 0–23°C. Vibrio AF-1 has an optimum growth temperature of 15°C and maximum growth temperature which is dependent upon the carbon source. On glucose growth ceases at 20°C whereas on lactose growth continues to 23°C. Growth rate is also a function of the carbon source provided. When grown on glucose, fructose, sucrose, maltose and galactose _max values of 0.046 h^-1 at 15°C were recorded whereas on lactose, mannose, ribose and xylose _max values of 0.020 h^-1 were obtained. Substrate affinities (K _s ) for the 9 sugars also fall into 2 divisions as for _max and are temperature dependent. Those sugars which support a high growth rate have highest K _s values at 0°C whereas these which give a low growth rate show maximum affinities at 15°C. Vibrio AF-1 produces the maximum cell yield (0.6 g/g sugar consumed) at temperature <8°C irrespective of the carbon source utilised and correlated with maximum rates of sugar uptake and minimum O₂ consumption. Maintenance energy determination on glucose grown cells show that at 2° C 2% of the carbon input is used for maintenance whereas at 20°C the requirement increases to 10% of the carbon input.     

Zur Kenntnis vonTetrasporopsis fuscescens

The macroscopic colonies ofTetrasporopsis fuscescens consist of a tegument of irregularly folded bag-like mucilage. It contains isolated ellipsoidal cells arranged in a regular peripheral stratum and rather sparsely and irregularly beneath. They show polarity, 4 parietal chromatophors when fully developed, have a wall containing cellulose, and no contractile vacuoles. Naked protoplasts are released from them through circular openings oriented towards the surface. Flagellated cells and cysts were not observed.T. reticulata may be closely related toT. fuscescens, but probably no other species is allied.

Herrn Univ.-Prof. Dr.Walter Leinfellner zum 70. Geburtstag gewidmet.     

A QM protein–ligand investigation of antipsychotic drugs with the dopamine D2 Receptor (D2R)

The dopamine D2 Receptor (D2R) is a member of the G-Protein-Coupled Receptor family and plays a critical role in neurotransmission activities in the human brain. Dysfunction in dopamine receptor signaling may lead to mental health illnesses such as schizophrenia and Parkinson’s disease. D2R is the target protein of the commonly used antipsychotic drugs such as risperidone, clozapine, aripiprazole, olanzapine, ziprasidone, and quetiapine. Due to their significant side effects and non-selective profiles, the discovery of novel drugs has become a challenge for researchers working in this field. Recently, our group has focused on the interactions of these drug molecules in the active site of the D2R using different in silico approaches. We here compare the performances of different approaches in estimating the drug binding affinities using quantum chemical approaches. Conformations of drug molecules (ligands) at the binding site of the D2R taken from the preliminary docking studies and molecular dynamics simulations were used to generate protein–ligand interaction models. In a first approach, the BSSE-corrected interaction energies of the ligands with the most critical amino acid Asp114 and with the other amino acids closest to ligands in the binding cavity were calculated separately by density functional theory method in implicit water environment at the M06-2X/6-31 g(d,p) level of the theory. In a second approach, ligand binding affinities were calculated by taking into consideration not only the interaction energies but also deformation and desolvation energies of ligands with surrounding amino acid residues, in a radius of 5 Å of the protein-bound ligand. The quantum mechanically obtained results were compared with the experimentally obtained binding affinity values. We concluded that although H-bond interactions of ligands with Asp114 are the most dominant interaction in the binding site, if van der Waals and steric interactions of ligands which have cumulative effect on the ligand binding are not included in the calculations, the interaction energies are overestimated.