Binding Sites of the Polyamines Putrescine,Cadaverine, Spermidine and Spermine on A- and B-DNA Located by Simulated Annealing

Abstract

Molecular dynamics simulations with simulated annealing are performed on polyamine-DNA systems in order to determine the binding sites of putrescine, cadaverine, spermidine and spermine on A- and B-DNA. The simulations either contain no additional counterions or sufficient Na⁺ ions, together with the charge on the polyamine, to provide 73% neutralisation of the charges on the DNA phosphates. The stabilisation energies of the complexes indicate that all four polyamines should stabilise A-DNA in preference to B-DNA, which is in agreement with experiment in the case of spermine and spermidine, but not in the case of putrescine or cadaverine. The major groove is the preferred binding site on A-DNA of all the polyamines. Putrescine and cadaverine tend to bind to the sugar-phosphate backbone of B-DNA, whereas spermidine and spermine occupy more varied sites, including binding along the backbone and bridging both the major and minor grooves.     

3D-QSAR,molecular docking and molecular dynamics studies of a series of RORγt inhibitors

The discovery of clinically relevant inhibitors of retinoic acid receptor-related orphan receptor-gamma-t (RORγt) for autoimmune diseases therapy has proven to be a challenging task. In the present work, to find out the structural features required for the inhibitory activity, we show for the first time a three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations for a series of novel thiazole/thiophene ketone amides with inhibitory activity at the RORγt receptor. The optimum CoMFA and CoMSIA models, derived from ligand-based superimposition I, exhibit leave-one-out cross-validated correlation coefficient (R²_cv) of .859 and .805, respectively. Furthermore, the external predictive abilities of the models were evaluated by a test set, producing the predicted correlation coefficient (R²_pred) of .7317 and .7097, respectively. In addition, molecular docking analysis was applied to explore the binding modes between the inhibitors and the receptor. MD simulation and MM/PBSA method were also employed to study the stability and rationality of the derived conformations, and the binding free energies in detail. The QSAR models and the results of molecular docking, MD simulation, binding free energies corroborate well with each other and further provide insights regarding the development of novel RORγt inhibitors with better activity.     

Full Length Vpu from HIV-1: Combining Molecular Dynamics Simulations with NMR Spectroscopy

Abstract

Based on structures made available by solution NMR, molecular models of the protein Vpu from HIV-1 were built and refined by 6 ns MD simulations in a fully hydrated lipid bilayer. Vpu is an 81 amino acid type I integral membrane protein encoded by the human immunodeficiency virus type-1 (HIV-1) and closely related simian immunodeficiency viruses (SIVs). Its role is to amplify viral release. Upon phosphorylation, the cytoplasmic domain adopts a more compact shape with helices 2 and 3 becoming almost parallel to each other. A loss of helicity for several residues belonging to the helices adjacent to both ends of the loop region containing serines 53 and 57 is observed. A fourth helix, present in one of the NMR-based structures of the cytoplasmic domain and located near the C-terminus, is lost upon phosphorylation.     

Preventing the return of smallpox: molecular modeling studies on thymidylate kinase from Variola virus

Smallpox was one of the most devastating diseases in the human history and still represents a serious menace today due to its potential use by bioterrorists. Considering this threat and the non-existence of effective chemotherapy, we propose the enzyme thymidylate kinase from Variola virus (VarTMPK) as a potential target to the drug design against smallpox. We first built a homology model for VarTMPK and performed molecular docking studies on it in order to investigate the interactions with inhibitors of Vaccinia virus TMPK (VacTMPK). Subsequently, molecular dynamics (MD) simulations of these compounds inside VarTMPK and human TMPK (HssTMPK) were carried out in order to select the most promising and selective compounds as leads for the design of potential VarTMPK inhibitors. Results of the docking and MD simulations corroborated to each other, suggesting selectivity towards VarTMPK and, also, a good correlation with the experimental data.     

Memory enhancement by traditional Chinese medicine?

Abstract

Cognitive repair by insulin-like growth factor-I (IGF-I) through activation of insulin-like growth factor-I receptor (IGF-IR) is well established, but not used for clinical therapy due to its link to cancer. We hypothesize that IGF-IR activation rather than IGF-I per se may be essential for cognitive repair and attempted to identify ligands from traditional Chinese medicine (TCM) with drug-like potential towards IGF-IR. TCM ligands, 3-(2-carboxyphenyl)-4(3H)-quinazolinone from Isatisin digotica, (+)-N-methyllaurotetanine from Lindera aggregate, and (+)-1(R)-Coclaurine from Nelumbonucifera Gaertn, exhibited high binding affinities and good blood brain barrier (BBB) penetration crucial for accessing IGF-IR. Stable complex formation of the candidates was observed during molecular dynamics (MD) simulation. Interactions with Leu975 and Gly1055 or Asp1056 were important for ligand binding. Amino acid distance analysis revealed residues 974/975, 984–986, 996–1006, 1040–1056, and 1122–1135 as “hotspots” for ligand binding in IGF-IR. Versatile entry pathways for the TCM candidates suggest high accessibility to the binding site. Blockage of the binding site opening by the TCM candidates limits binding site access by other compounds. Multiple linear regression (R²?=?0.9715), support vector machine (R²?=?0.9084), Bayesian network (R²?=?0.8233) comparative molecular field analysis (CoMFA, R²?=?0.9941), and comparative molecular similarity indices analysis (CoMSIA, R²?=?0.9877) models consistently suggest that the TCM candidates might exert bioactivity on IGF-IR. Contour of representative MD conformations to CoMFA and CoMSIA maps exhibits similar results. Properties including BBB passage, evidence of ability to form stable complexes with IGF-IR by MD simulation, and predicted bioactivity suggest that the TCM candidates have drug-like properties and might have potential as cognitive-enhancing drugs.

An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:38     

Characterisation of a thermo-alkali-stable lipase from oil-contaminated soil using a metagenomic approach

Lipases are widely used for a variety of biotechnological applications. Screening these industrial enzymes directly from environmental microorganisms is a more efficient and practical approach than conventional cultivation-dependent methods. Combined with activity-based functional screening, six clones with lipase activity were detected and a gene (termed lipZ01) isolated from a target clone with the highest lipase activity was cloned from an oil-contaminated soil-derived metagenomic library and then sequenced. Gene lipZ01 was expressed in Pichia pastoris GS115 and the molecular weight of the recombinant lipase LipZ01 was estimated by electrophoresis analysis to be approximately 50 kDa. The maximum activity of the purified lipase was 42 U/mL, and the optimum reaction temperature and pH value were 45 °C and 8.0, respectively. The enzyme was highly stable in the temperature range 35–60 °C and under alkaline conditions (pH 7–10). The presence of Ca²⁺ and Mn²⁺ ions could significantly enhance the activity of the lipase. The purified lipase preferentially hydrolysed triacylglycerols with acyl chain lengths ≥8 carbon atoms, and the conversion degree of biodiesel production was nearly 92% in a transesterification reaction using olive oil and methanol. Some attractive properties suggested that the recombinant lipase may be valuable in industrial applications.     

A new metriorhynchid crocodylomorph from the Lower Kimmeridge Clay Formation (Late Jurassic) of England,with implications for the evolution of dermatocranium ornamentation in Geosaurini

A new metriorhynchid crocodylomorph from the Lower Kimmeridge Clay Formation (Kimmeridgian, Upper Jurassic) of England is described. This specimen, a three‐dimensionally preserved skull and left mandibular ramus, is referred to a new species: T orvoneustes coryphaeus sp. nov. Within the genus Torvoneustes, T . coryphaeus sp. nov. is unique as it has a long anteromedial process of the frontal, ornamented dermatocranium, and the supraorbital notch forms a strongly acute angle. Our phylogenetic analysis confirms the placement of this specimen in Torvoneustes. The dentition of T . coryphaeus sp. nov. , like that of the type species, has a blunt apex, crown basal–mid regions with numerous tightly packed apicobasally aligned ridges, and apical region with an anastomosed pattern of ridges that interact with the carinae. Within Thalattosuchia these dental characteristics are only found in Torvoneustes and the teleosaurid Machimosaurus. The heavily ornamented dermatocranium of T . coryphaeus sp. nov. is in contrast to the unornamented (nasals and frontal)–lightly ornamented (maxillae and premaxillae) pattern seen in Torvoneustes carpenteri. Curiously, this pattern of reduction and loss of dermatocranium ornamentation is also observed in Metriorhynchus, Dakosaurus, and the subclade Rhacheosaurini. We hypothesize that the ‘smooth’ dermatocranium of Late Jurassic metriorhynchids evolved independently in each subclade (parallel evolution), and would have reduced drag, thereby making locomotion through water more energy efficient. © 2013 The Linnean Society of London     

Continuing decline of a keystone tree species in the Kruger National Park,South Africa

Sclerocarya birrea subsp. caffra (marula), a keystone large tree species in southern Africa and heavily utilized by people and herbivores, is declining at an unprecedented rate in the Kruger National Park (KNP), South Africa. Due to increasing concerns over large tree declines in the KNP, mirroring those in eastern Africa over the last 50 years, and local extinctions of marula populations in the north‐western KNP, adult trees in the southern KNP were monitored between 2001 and 2010. Annual mortality rates across all adult size classes ranged between 3.2 and 4.6%. Loss of adult marula trees in some areas over the last decade exceeded 25%. Rainfall had a strong influence on mortality rates temporally and spatially, but the distance to the nearest perennial river had little influence. Overall, marula populations continue to decline and further local extinctions are possible. Given the clearly unacceptable trends of decline, the next step is to utilize this information (i) to develop predictive models for the future dynamics of marula populations incorporating all drivers; (ii) to advocate active management of refugia within the park where marula populations are protected from elephant impacts; and in combination with (iii) continued monitoring.