Molecular dynamics simulation study of the binding of purine bases to the aptamer domain of the guanine sensing riboswitch

Riboswitches are a novel class of genetic control elements that function through the direct interaction of small metabolite molecules with structured RNA elements. The ligand is bound with high specificity and affinity to its RNA target and induces conformational changes of the RNA's secondary and tertiary structure upon binding. To elucidate the molecular basis of the remarkable ligand selectivity and affinity of one of these riboswitches, extensive all-atom molecular dynamics simulations in explicit solvent ({approx}1 µs total simulation length) of the aptamer domain of the guanine sensing riboswitch are performed. The conformational dynamics is studied when the system is bound to its cognate ligand guanine as well as bound to the non-cognate ligand adenine and in its free form. The simulations indicate that residue U51 in the aptamer domain functions as a general docking platform for purine bases, whereas the interactions between C74 and the ligand are crucial for ligand selectivity. These findings either suggest a two-step ligand recognition process, including a general purine binding step and a subsequent selection of the cognate ligand, or hint at different initial interactions of cognate and noncognate ligands with residues of the ligand binding pocket. To explore possible pathways of complex dissociation, various nonequilibrium simulations are performed which account for the first steps of ligand unbinding. The results delineate the minimal set of conformational changes needed for ligand release, suggest two possible pathways for the dissociation reaction, and underline the importance of long-range tertiary contacts for locking the ligand in the complex

Magnesium ion–water coordination and exchange in biomolecular simulations

Magnesium ions have an important role in the structure and folding mechanism of ribonucleic systems. To properly simulate these biophysical processes, the applied molecular models should reproduce, among others, the kinetic properties of the ions in water solution. Here, we have studied the kinetics of the binding of magnesium ions with water molecules and nucleic acids systems using molecular dynamics simulation in detail. We have validated the parameters used in biomolecular force fields, such as AMBER and CHARMM, for Mg2+ ions, and also for the biological relevant ions, Na+, K+ and Ca2+ together with three different water models (TIP3P, SPC/E and TIP5P). The results show that Mg2+ ions have a slower exchange rate than Na+, K+ and Ca2+ in agreement with experimental trend, but the simulated value underestimates the experimentally observed Mg2+-water exchange rate with several orders of magnitudes, irrespective of force field and water model. A new set of parameters for Mg2+ was developed to reproduce the experimental kinetic data. This set also leads to better reproduction of structural data than existing models. We have applied the new parameters set to Mg2+ binding with a mono-phosphate model system and with the purine riboswitch, add A-riboswitch. In line with the Mg2+-water results, the newly developed parameters show a better description of the structure and kinetic of the Mg2+-phosphate 2 binding than all other models. The characterization of the ion binding to the riboswitch system shows that the new parameter set does not affect the global structure of the ribonucleic acid system or the number of ions involved in direct or indirect binding. A slight decrease in the number of water-bridged contacts between A-riboswitch and Mg2+ ion is observed. The results support the ability of the newly developed parameters to improve the kinetic description of the Mg2+ and phosphate ions and their applicability in nucleic acid simulation.Swedish Research CouncilAccepte

Molecular dynamics simulation study of the binding of purine bases to the aptamer domain of the guanine sensing riboswitch

Riboswitches are a novel class of genetic control elements that function through the direct interaction of small metabolite molecules with structured RNA elements. The ligand is bound with high specificity and affinity to its RNA target and induces conformational changes of the RNA's secondary and tertiary structure upon binding. To elucidate the molecular basis of the remarkable ligand selectivity and affinity of one of these riboswitches, extensive all-atom molecular dynamics simulations in explicit solvent (≈1 μs total simulation length) of the aptamer domain of the guanine sensing riboswitch are performed. The conformational dynamics is studied when the system is bound to its cognate ligand guanine as well as bound to the non-cognate ligand adenine and in its free form. The simulations indicate that residue U51 in the aptamer domain functions as a general docking platform for purine bases, whereas the interactions between C74 and the ligand are crucial for ligand selectivity. These findings either suggest a two-step ligand recognition process, including a general purine binding step and a subsequent selection of the cognate ligand, or hint at different initial interactions of cognate and noncognate ligands with residues of the ligand binding pocket. To explore possible pathways of complex dissociation, various nonequilibrium simulations are performed which account for the first steps of ligand unbinding. The results delineate the minimal set of conformational changes needed for ligand release, suggest two possible pathways for the dissociation reaction, and underline the importance of long-range tertiary contacts for locking the ligand in the complex

Le partage des ‘droits’ sur l’œuvre littéraire à la renaissance. Les cas d’Isabella d’Este

Le déplacement d’abord, puis la perte partielle du décor et enfin la dispersion des collections qui jadis y furent réunies, empêchent aujourd’hui d’imaginer l’effet que pouvait produire, sur un visiteur du château San Giorgio à Mantoue, le studiolo d’Isabella d’Este. En pénétrant dans cet espace étroit par la porte en marbre, sculptée par Tullio Lombardo, le regard devait être capturé par les peintures de Mantegna, du Perugin et de Costa, qui occupaient entièrement la bande centrale des murs ..

EFFECTOF THE IONTREATMENTONAN RNA HAIRPIN: MOLECULAR DYNAMICS STUDY

Molecular dynamics has been employed to study the effect of ion treatment on the stability of 14-nucleQtide RNA hairpin of Coxsackievirus B3. Three AMBER force fields were used: AMBER94, AMBER98, and AMBER99, which showed no significant structural difference of the hairpin. Thereafter, we applied two different long-range electrostatic treatments that were reaction field and PME methods, and calculated the distribution of ions around the hairpin. Although the structural stabilities of the MD simulations using both methods were similar in 0.14 M Na+,ion environment around the hairpin was notably different. In particular, structural stabilition of the hairpin with increasing ion concentration and with ion Mi+ cannot be accommodated by simulations using reaction field method. Furthermore, the MD simulations using PME method suggested the strong similarity in structural and dynamical properties of the hairpin with 0.14 M Na+,0.50 M Na+, 1.03M Na+,and 0.08 M Mi+ concentrations. However, the simulations ravea/eddifferent ion occupations of Na+and Mg

Avaliaçao ambiental de qualidade da água do lago do Parque Barigui : potencial de poluiçao orgânica

Orientador: Cristovao Vicente Scapulatempo FernandesCo-orientador: José Eduardo GonçalvesInclui apendicesDissertaçao (mestrado) - Universidade Federal do Paraná, Setor de Tecnologia, Programa de Pós-Graduaçao em Recursos Hídricos e Ambientais. Defesa: Curitiba, 2005Inclui bibliografia e anexo

A multidimensional analysis of youth well-being

The phase of the life cycle of youth is characterised by a series of opportunities and challenges: the choice of whether or not to continue studying, the employment opportunities, the influence of the area and the social and relational context in which they live, the community and the role of institutions. The potential risks lurking in these transitions can have life-long effects on their well-being conditions. Following the methodological approach proposed by the OECD to calculate the Youth Multi-dimensional Deprivation Indicator (Y-MDI) (Oecd, 2017), in this study the well-being of young people is measured through the construction of a multi-deprivation indicator, similar in the calculation method, but different in the selection of relevant dimensions and indicators. The concept of deprivation is here understood, in line with the capability approach defined by Sen (Sen, 1998), such as the failure to achieve a plurality of factors (individual and context) acting in determining the well-being of young people. The approach proposed provides a synthetic (and easily representative) tool for the evaluation and monitoring of youth well-being, based on the conceptual framework of Equitable and Sustainable Well-being (Bes) developed in Italy by Istat (Istat, 2019). Overall, slightly less than half of the young people aged 18-34 years (47.8%) show no deprivation, while one out of three (33.5%) is deprived in one dimension of well-being and 18.7% (slightly less than 2 million young people) is multi-deprived, i.e. deprived in two or more dimensions