The development of Coleridge’s nature poetry, 1788-98

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Water permeation across biological membranes: Mechanism and dynamics of Aquaporin-1 and GlpF.

Real time” molecular dynamics simulations of water permeation through human aquaporin-1 (AQP1) and the bacterial glycerol facilitator GlpF are presented. We obtained time-resolved, atomic-resolution models of the permeation mechanism across these highly selective membrane channels. Both proteins act as two-stage filters: Conserved fingerprint [asparagine-proline-alanine (NPA)] motifs form a selectivity-determining region; a second (aromatic/arginine) region is proposed to function as a proton filter. Hydrophobic regions near the NPA motifs are rate-limiting water barriers. In AQP1, a fine-tuned water dipole rotation during passage is essential for water selectivity. In GlpF, a glycerol-mediated “induced fit” gating motion is proposed to generate selectivity for glycerol over water

Benchmarking Burgerzaken : een empirisch onderzoek naar de kostendoelmatigheid van burgerzaken

De noodzaak van productiviteitsgroei in de publieke sector is nu groter dan ooit. Aan deze noodzaak liggen twee ontwikkelingen ten grondslag. In de eerste plaats staan de financiën van de publieke sector onder druk als gevolg van bezuinigingen. In de tweede plaats worden er op de langere termijn knelpunten op de arbeidsmarkt verwacht als gevolg van vergrijzing en ontgroening van de bevolking. In de marksector dwingen concurrentieoverwegingen organisaties ertoe om voortdurend aandacht te hebben voor productiviteitsverbetering en deze waar mogelijk te realiseren. In de publieke sector ontbreken de prikkels van de markt en lijken productiviteitsverbeteringen moeizaam tot stand te komen

ATP-magnesium coordination: Protein structure-based force field evaluation and corrections

In the numerous molecular recognition and catalytic processes across biochemistry involving adenosine triphosphate (ATP), the common bioactive form is its magnesium chelate, ATP·Mg2+. In aqueous solution, two chelation geometries predominate, distinguished by bidentate and tridentate Mg2+–phosphate coordination. These are approximately isoenergetic but separated by a high energy barrier. Force field-based atomistic simulation studies of this complex require an accurate representation of its structure and energetics. Here we focused on the energetics of ATP·Mg2+ coordination. Applying an enhanced sampling scheme to circumvent prohibitively slow sampling of transitions between coordination modes, we observed striking contradictions between Amber and CHARMM force field descriptions, most prominently in opposing predictions of the favored coordination mode. Through further configurational free energy calculations, conducted against a diverse set of ATP·Mg2+–protein complex structures to supplement otherwise limited experimental data, we quantified systematic biases for each force field. The force field calculations were strongly predictive of experimentally observed coordination modes, enabling additive corrections to the coordination free energy that deliver close agreement with experiment. We reassessed the applicability of the thus corrected force field descriptions of ATP·Mg2+ for biomolecular simulation and observed that, while the CHARMM parameters display an erroneous preference for overextended triphosphate configurations that will affect many common biomolecular simulation applications involving ATP, the force field energy landscapes broadly agree with experimental measurements of solution geometry and the distribution of ATP·Mg2+ structures found in the Protein Data Bank. Our force field evaluation and correction approach, based on maximizing consistency with the large and heterogeneous collection of structural information encoded in the PDB, should be broadly applicable to many other systems

Energy and entropy of relativistic diffusing particles

We discuss energy-momentum tensor and the second law of thermodynamics for a system of relativistic diffusing particles. We calculate the energy and entropy flow in this system. We obtain an exact time dependence of energy, entropy and free energy of a beam of photons in a reservoir of a fixed temperature.Comment: 14 pages,some formulas correcte

Challenges encountered applying equilibrium and nonequilibrium binding free energy calculations

Binding free energy calculations have become increasingly valuable to drive decision making in drug discovery projects. However, among other issues, inadequate sampling can reduce accuracy, limiting the value of the technique. In this paper, we apply absolute binding free energy calculations to ligands binding to T4 lysozyme L99A and HSP90 using equilibrium and nonequilibrium approaches. We highlight sampling problems encountered in these systems, such as slow side chain rearrangements and slow changes of water placement upon ligand binding. These same types of challenges are also likely to show up in other protein–ligand systems, and we propose some strategies to diagnose and test for such problems in alchemical free energy calculations. We also explore similarities and differences in how the equilibrium and the nonequilibrium approaches handle these problems. Our results show the large amount of work still to be done to make free energy calculations robust and reliable and provide insight for future research in this area

Water permeation through gramicidin A: Desformylation and the double helix: A molecular dynamics study

Multinanosecond molecular dynamics simulations of gramicidin A embedded in a dimyristoylphosphatidylcholine bilayer show a remarkable structural stability for both experimentally determined conformations: the head-to-head helical dimer and the double helix. Water permeability was found to be much higher in the double helical conformation, which is explained by lower hydrogen bond-mediated enthalpic barriers at the channel entrance and its larger pore size. Free-energy perturbation calculations show that the double helical structure is stabilized by the positive charges at the N termini introduced by the desformylation, whereas the helical dimer is destabilized. Together with the recent experimental observation that desformyl gramicidin conducts water hundredfold better than gramicidin, this suggests that desformyl gramicidin A predominantly occurs in the double helical conformation