1,721,038 research outputs found
All-atom/coarse-grained hybrid predictions of distribution coefficients in SAMPL5
No full textWe present blind predictions submitted to the SAMPL5 challenge on calculating distribution coefficients. The predictions were based on estimating the solvation free energies in water and cyclohexane of the 53 compounds in the challenge. These free energies were computed using alchemical free energy simulations based on a hybrid all-atom/coarse-grained model. The compounds were treated with the general Amber force field, whereas the solvent molecules were treated with the Elba coarse-grained model. Considering the simplicity of the solvent model and that we approximate the distribution coefficient with the partition coefficient of the neutral species, the predictions are of good accuracy. The correlation coefficient, R is 0.64, 82% of the predictions have the correct sign and the mean absolute deviation is 1.8 log units. This is on a par with or better than the other simulation-based predictions in the challenge. We present an analysis of the deviations to experiments and compare the predictions to another submission that used all-atom solvent
G protein coupled receptor interactions with cholesterol deep in the membrane
Get PDFG-protein coupled receptors (GPCRs) are located in membranes rich in cholesterol. The membrane spanning surfaces of GPCRs contain exposed backbone carbonyl groups and residue side chains potentially capable of forming hydrogen bonds to cholesterol molecules buried deep within the hydrophobic core of the lipid bilayer. Coarse-grained molecular dynamics (CGMD) simulations allow the observation of GPCRs in cholesterol-containing lipid bilayersfor long times (50 ?s), sufficient to ensure equilibration of the system. We have detected a number of deep cholesterol binding sites on ?2adrenergic and A2Aadenosine receptors, and shown changes in these sites on agonist binding. The requirements for binding are modest, just a potential hydrogen bond partner close to a cleft or hole in the surface. This makes it likely that similar binding sites for cholesterol will exist on other classes of membrane protein
A simple and transferable all-atom/coarse-grained hybrid model to study membrane processes
No full textWe present an efficient all-atom/coarse-grained hybrid model and apply it to membrane processes. This model is an extension of the all-atom/ELBA model applied previously to processes in water. Here, we improve the efficiency of the model by implementing a multiple-timestep integrator that allows the atoms and the coarse-grained beads to be propagated at different timesteps. Furthermore, we fine-tune the interaction between the atoms and the coarse-grained beads by computing the potential of mean force of amino acid sidechain analogs along the membrane normal and comparing to atomistic simulations. The model was independently validated on the calculation of small-molecule partition coefficients. Finally, we apply the model to membrane peptides. We studied the tilt angle of the Walp23 and Kalp23 helices in two different model membranes and the stability of the glycophorin A dimer. The model is efficient, accurate and straightforward to use, as it does not require any extra interaction particles, layers of atomistic solvent molecules or tabulated potentials, thus offering a novel, simple approach to study membrane processes
Extensive all-atom Monte Carlo sampling and QM/MM corrections in the SAMPL4 hydration free energy challenge
No full textWe present our predictions for the SAMPL4 hydration free energy challenge. Extensive all-atom Monte Carlo simulations were employed to sample the compounds in explicit solvent. While the focus of our study was to demonstrate well-converged and reproducible free energies, we attempted to address the deficiencies in the general Amber force field force field with a simple QM/MM correction. We show that by using multiple independent simulations, including different starting configurations, and enhanced sampling with parallel tempering, we can obtain well converged hydration free energies. Additional analysis using dihedral angle distributions, torsion-root mean square deviation plots and thermodynamic cycles support this assertion. We obtain a mean absolute deviation of 1.7 kcal mol(-1) and a Kendall's tau of 0.65 compared with experiment
Free-energy perturbation and quantum mechanical study of SAMPL4 octa-acid host-guest binding energies.
Get PDFWe have estimated free energies for the binding of nine cyclic carboxylate guest molecules to the octa-acid host in the SAMPL4 blind-test challenge with four different approaches. First, we used standard free-energy perturbation calculations of relative binding affinities, performed at the molecular-mechanics (MM) level with TIP3P waters, the GAFF force field, and two different sets of charges for the host and the guest, obtained either with the restrained electrostatic potential or AM1-BCC methods. Both charge sets give good and nearly identical results, with a mean absolute deviation (MAD) of 4 kJ/mol and a correlation coefficient (R (2)) of 0.8 compared to experimental results. Second, we tried to improve these predictions with 28,800 density-functional theory (DFT) calculations for selected snapshots and the non-Boltzmann Bennett acceptance-ratio method, but this led to much worse results, probably because of a too large difference between the MM and DFT potential-energy functions. Third, we tried to calculate absolute affinities using minimised DFT structures. This gave intermediate-quality results with MADs of 5-9 kJ/mol and R (2) = 0.6-0.8, depending on how the structures were obtained. Finally, we tried to improve these results using local coupled-cluster calculations with single and double excitations, and non-iterative perturbative treatment of triple excitations (LCCSD(T0)), employing the polarisable multipole interactions with supermolecular pairs approach. Unfortunately, this only degraded the predictions, probably because of a mismatch between the solvation energies obtained at the DFT and LCCSD(T0) levels
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Are homology models sufficiently good for free-energy simulations?
No full textIn this paper, I evaluate the usefulness of protein homology models in rigorous free-energy simulations to determine ligand affinities. Two templates were used to create models of the factor Xa protein and one template was used for dihydrofolate reductase from Plasmodium falciparum. Then, the relative free energies for several pairs of ligands were estimated using thermodynamic integration with the homology models as starting point of the simulation. These binding affinities were compared to affinities obtained when using published crystal structures as starting point of the simulations. Encouragingly, the differences between the affinities obtained when starting from either homology models or crystal structure were not statistical significant for a majority of the considered pairs of ligands. Differences between 1 and 2 kJ/mol were observed for the dihydrofolate reductase ligands and differences between 0 and 8 kJ/mol were observed for the factor Xa ligands. The largest difference for factor Xa was caused by an erroneous modeling of a loop region close to two of the ligands, and it was only observed when using one of the templates. Therefore, it is advisible to always use more than one template when creating homology models if they should be used in free-energy simulations
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