| 1. |
- Aad, G., et al.
(författare)
-
- 2012
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Ingår i: The European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6052. ; 72:10
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Tidskriftsartikel (refereegranskat)
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| 2. |
- de Maré, Sofia W., et al.
(författare)
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Structural Basis for Glycerol Efflux and Selectivity of Human Aquaporin 7
- 2020
-
Ingår i: Structure. - : Elsevier BV. - 0969-2126. ; 28:2, s. 3-222
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Tidskriftsartikel (refereegranskat)abstract
- AQP7 is an important glycerol channel in human adipocytes, and its dysfunction is linked to metabolic disorders. The high-resolution X-ray structures of AQP7 unravels the molecular details of how glycerol travels through the channel and provide a structural basis for development of small-molecule drugs for targeting AQP7.
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| 3. |
- Aponte-Santamaria, Camilo, et al.
(författare)
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Dynamics and energetics of solute permeation through the Plasmodium falciparum aquaglyceroporin
- 2010
-
Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 12:35, s. 10246-10254
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Tidskriftsartikel (refereegranskat)abstract
- The aquaglyceroporin from Plasmodium falciparum (PfAQP) is a potential drug target for the treatment of malaria. It efficiently conducts water and other small solutes, and is proposed to intervene in several crucial physiological processes during the parasitic life cycle. Despite the wealth of experimental data available, a dynamical and energetic description at the single-molecule level of the solute permeation through PfAQP has been lacking so far. Here we address this question by using equilibrium and umbrella sampling molecular dynamics simulations. We computed the water osmotic permeability coefficient, the pore geometry and the potential of mean force for the permeation of water, glycerol and urea. Our simulations show that the PfAQP, the human aquaporin 1 (hAQP1) and the Escherichia coli glycerol facilitator (GlpF) have nearly identical water permeabilities. The Arg196 residue at the ar/R region was found to play a crucial role regulating the permeation of water, glycerol and urea. The computed free energy barriers at the ar/R selectivity filter corroborate that PfAQP conducts glycerol at higher rates than urea, and suggest that PfAQP is a more efficient glycerol and urea channel than GlpF. Our results are consistent with a solute permeation mechanism for PfAQP which is similar to the one established for other members of the aquaglyceroporin family. In this mechanism, hydrophobic regions near the NPA motifs are the main water rate limiting barriers, and the replacement of water-arg196 interactions and solute-matching in the hydrophobic pocket at the ar/R region are the main determinants underlying selectivity for the permeation of solutes like glycerol and urea.
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| 4. |
- Blau, Christian, et al.
(författare)
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Gromaps: A Gromacs-Based Toolset to Analyse Density Maps Derived from Molecular Dynamics Simulations
- 2019
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Ingår i: Biophysical Journal. - : Elsevier BV. - 0006-3495 .- 1542-0086. ; 116:1, s. 4-11
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Tidskriftsartikel (refereegranskat)abstract
- We introduce a computational toolset, named GROmaρs, to obtain and compare time-averaged density maps from molecular dynamics simulations. GROmaρs efficiently computes density maps by fast multi-Gaussian spreading of atomic densities onto a three-dimensional grid. It complements existing map-based tools by enabling spatial inspection of atomic average localization during the simulations. Most importantly, it allows the comparison between computed and reference maps (e.g., experimental) through calculation of difference maps and local and time-resolved global correlation. These comparison operations proved useful to quantitatively contrast perturbed and control simulation data sets and to examine how much biomolecular systems resemble both synthetic and experimental density maps. This was especially advantageous for multimolecule systems in which standard comparisons like RMSDs are difficult to compute. In addition, GROmaρs incorporates absolute and relative spatial free-energy estimates to provide an energetic picture of atomistic localization. This is an open-source GROMACS-based toolset, thus allowing for static or dynamic selection of atoms or even coarse-grained beads for the density calculation. Furthermore, masking of regions was implemented to speed up calculations and to facilitate the comparison with experimental maps. Beyond map comparison, GROmaρs provides a straightforward method to detect solvent cavities and average charge distribution in biomolecular systems. We employed all these functionalities to inspect the localization of lipid and water molecules in aquaporin systems, the binding of cholesterol to the G protein coupled chemokine receptor type 4, and the identification of permeation pathways through the dermicidin antimicrobial channel. Based on these examples, we anticipate a high applicability of GROmaρs for the analysis of molecular dynamics simulations and their comparison with experimentally determined densities.
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| 5. |
- Boukharta, Lars, et al.
(författare)
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Computer Simulations of Structure-Activity Relationships for hERG Channel Blockers
- 2011
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 50:27, s. 6146-6156
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Tidskriftsartikel (refereegranskat)abstract
- The hERG potassium channel is of major pharmaceutical importance, and its blockade by various compounds, potentially causing serious cardiac side effects, is a major problem in drug development. Despite the large amounts of existing biochemical data on blockade of hERG by drugs and druglike compounds, relatively little is known regarding the structural basis of binding of blockers to the channel. Here, we have used a recently developed homology model of hERG to conduct molecular docking experiments with a series of channel blockers, followed by molecular dynamics simulations of the complexes and evaluation of binding free energies with the linear interaction energy method. The calculations yield a remarkably good agreement with experimental binding affinities and allow for a rationalization of three-dimensional structure-activity relationships in terms of a number of key interactions. Two main interaction regions of the channel are thus identified with implications for further mutagenesis experiments and design of new compounds.
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| 6. |
- Chakrabarti, Kalyan S., et al.
(författare)
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A litmus test for classifying recognition mechanisms of transiently binding proteins
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Partner recognition in protein binding is critical for all biological functions, and yet, delineating its mechanism is challenging, especially when recognition happens within microseconds. We present a theoretical and experimental framework based on straight-forward nuclear magnetic resonance relaxation dispersion measurements to investigate protein binding mechanisms on sub-millisecond timescales, which are beyond the reach of standard rapid-mixing experiments. This framework predicts that conformational selection prevails on ubiquitin’s paradigmatic interaction with an SH3 (Src-homology 3) domain. By contrast, the SH3 domain recognizes ubiquitin in a two-state binding process. Subsequent molecular dynamics simulations and Markov state modeling reveal that the ubiquitin conformation selected for binding exhibits a characteristically extended C-terminus. Our framework is robust and expandable for implementation in other binding scenarios with the potential to show that conformational selection might be the design principle of the hubs in protein interaction networks.
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| 7. |
- Fischer, Gerhard, 1978, et al.
(författare)
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Crystal structure of a yeast aquaporin at 1.15 angstrom reveals a novel gating mechanism.
- 2009
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Ingår i: PLoS biology. - : Public Library of Science (PLoS). - 1545-7885 .- 1544-9173. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Aquaporins are transmembrane proteins that facilitate the flow of water through cellular membranes. An unusual characteristic of yeast aquaporins is that they frequently contain an extended N terminus of unknown function. Here we present the X-ray structure of the yeast aquaporin Aqy1 from Pichia pastoris at 1.15 A resolution. Our crystal structure reveals that the water channel is closed by the N terminus, which arranges as a tightly wound helical bundle, with Tyr31 forming H-bond interactions to a water molecule within the pore and thereby occluding the channel entrance. Nevertheless, functional assays show that Aqy1 has appreciable water transport activity that aids survival during rapid freezing of P. pastoris. These findings establish that Aqy1 is a gated water channel. Mutational studies in combination with molecular dynamics simulations imply that gating may be regulated by a combination of phosphorylation and mechanosensitivity.
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| 8. |
- Gapsys, Vytautas, et al.
(författare)
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Accurate absolute free energies for ligand-protein binding based on non-equilibrium approaches
- 2021
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Ingår i: Communications Chemistry. - : Springer Nature. - 2399-3669. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Molecular dynamics-based approaches to calculate absolute protein-ligand binding free energy often rely on equilibrium free energy perturbation (FEP) protocols. Here, the authors study ligands binding to bromodomains and T4 lysozyme and find that both equilibrium and non-equilibrium approaches converge to the same results with the non-equilibrium method converging faster than FEP. The accurate calculation of the binding free energy for arbitrary ligand-protein pairs is a considerable challenge in computer-aided drug discovery. Recently, it has been demonstrated that current state-of-the-art molecular dynamics (MD) based methods are capable of making highly accurate predictions. Conventional MD-based approaches rely on the first principles of statistical mechanics and assume equilibrium sampling of the phase space. In the current work we demonstrate that accurate absolute binding free energies (ABFE) can also be obtained via theoretically rigorous non-equilibrium approaches. Our investigation of ligands binding to bromodomains and T4 lysozyme reveals that both equilibrium and non-equilibrium approaches converge to the same results. The non-equilibrium approach achieves the same level of accuracy and convergence as an equilibrium free energy perturbation (FEP) method enhanced by Hamiltonian replica exchange. We also compare uni- and bi-directional non-equilibrium approaches and demonstrate that considering the work distributions from both forward and reverse directions provides substantial accuracy gains. In summary, non-equilibrium ABFE calculations are shown to yield reliable and well-converged estimates of protein-ligand binding affinity.
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| 9. |
- Huang, Peng, et al.
(författare)
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Molecular basis for human aquaporin inhibition
- 2024
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 1091-6490. ; 121:7
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Tidskriftsartikel (refereegranskat)abstract
- Cancer invasion and metastasis are known to be potentiated by the expression of aquaporins (AQPs). Likewise, the expression levels of AQPs have been shown to be prognostic for survival in patients and have a role in tumor growth, edema, angiogenesis, and tumor cell migration. Thus, AQPs are key players in cancer biology and potential targets for drug development. Here, we present the single-particle cryo-EM structure of human AQP7 at 3.2-Å resolution in complex with the specific inhibitor compound Z433927330. The structure in combination with MD simulations shows that the inhibitor binds to the endofacial side of AQP7. In addition, cancer cells treated with Z433927330 show reduced proliferation. The data presented here serve as a framework for the development of AQP inhibitors.
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| 10. |
- Hub, Jochen S., et al.
(författare)
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g_wham-A Free Weighted Histogram Analysis Implementation Including Robust Error and Autocorrelation Estimates
- 2010
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 6:12, s. 3713-3720
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Tidskriftsartikel (refereegranskat)abstract
- The Weighted Histogram Analysis Method (WHAM) is a standard technique used to compute potentials of mean force (PMFs) from a set of umbrella sampling simulations. Here, we present a new WHAM implementation, termed g_wham, which is distributed freely with the GROMACS molecular simulation suite. g_wham estimates statistical errors using the technique of bootstrap analysis. Three bootstrap methods are supported: (i) bootstrapping new trajectories based on the umbrella histograms, (ii) bootstrapping of complete histograms, and (iii) Bayesian bootstrapping of complete histograms, that is, bootstrapping via the assignment of random weights to the histograms. Because methods ii and iii consider only complete histograms as independent data points, these methods do not require the accurate calculation of autocorrelation times. We demonstrate that, given sufficient sampling, bootstrapping new trajectories allows for an accurate error estimate. In the presence of long autocorrelations, however, (Bayesian) bootstrapping of complete histograms yields a more reliable error estimate, whereas bootstrapping of new trajectories may underestimate the error. In addition, we emphasize that the incorporation of autocorrelations into WHAM reduces the bias from limited sampling, in particular, when computing periodic PMFs in inhomogeneous systems such as solvated lipid membranes or protein channels.
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| 11. |
- Hub, Jochen S., et al.
(författare)
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Potentials of Mean Force and Permeabilities for Carbon Dioxide, Ammonia, and Water Flux across a Rhesus Protein Channel and Lipid Membranes
- 2010
-
Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 132:38, s. 13251-13263
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Tidskriftsartikel (refereegranskat)abstract
- As a member of the ubiquitous ammonium transporter/methylamine permease/Rhesus (Amt/MEP/Rh) family of membrane protein channels, the 50 kDa Rhesus channel (Rh50) has been implicated in ammonia (NH3) and, more recently, also in carbon dioxide (CO2) transport. Here we present molecular dynamics simulations of spontaneous full permeation events of ammonia and carbon dioxide across Rh50 from Nitrosomonas europaea. The simulations show that Rh50 is functional in its crystallographic conformation, without the requirement for a major conformational change or the action of a protein partner. To assess the physiological relevance of NH3 and CO2 permeation across Rh50, we have computed potentials of mean force (PMFs) and permeabilities for NH3 and CO2 flux across Rh50 and compare them to permeation through a wide range of lipid membranes, either composed of pure lipids or composed of lipids plus an increasing cholesterol content. According to the PMFs, Rh50 is expected to enhance NH3 flux across dense membranes, such as membranes with a substantial cholesterol content. Although cholesterol reduces the intrinsic CO2 permeability of lipid membranes, the CO2 permeabilities of all membranes studied here are too high to allow significant Rh50-mediated CO2 flux. The increased barrier in the PMF for water permeation across Rh50 shows that Rh50 discriminates 40-fold between water and NH3. Thus, Rh50 channels complement aquaporins, allowing the cell to regulate water and NH3 flux independently. The PMFs for methylamine and NH3 are virtually identical, suggesting that methylamine provides an excellent model for NH3 in functional experiments.
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| 12. |
- Hub, Jochen S., et al.
(författare)
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Spontaneous Quaternary and Tertiary T-R Transitions of Human Hemoglobin in Molecular Dynamics Simulation
- 2010
-
Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 6:5, s. e1000774-
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Tidskriftsartikel (refereegranskat)abstract
- We present molecular dynamics simulations of unliganded human hemoglobin (Hb) A under physiological conditions, starting from the R, R2, and T state. The simulations were carried out with protonated and deprotonated HC3 histidines His(beta)146, and they sum up to a total length of 5.6 mu s. We observe spontaneous and reproducible T-->R quaternary transitions of the Hb tetramer and tertiary transitions of the alpha and beta subunits, as detected from principal component projections, from an RMSD measure, and from rigid body rotation analysis. The simulations reveal a marked asymmetry between the alpha and beta subunits. Using the mutual information as correlation measure, we find that the beta subunits are substantially more strongly linked to the quaternary transition than the alpha subunits. In addition, the tertiary populations of the alpha and beta subunits differ substantially, with the beta subunits showing a tendency towards R, and the alpha subunits showing a tendency towards T. Based on the simulation results, we present a transition pathway for coupled quaternary and tertiary transitions between the R and T conformations of Hb.
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| 13. |
- Hub, Jochen S., et al.
(författare)
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Voltage-Regulated Water Flux through Aquaporin Channels In Silico
- 2010
-
Ingår i: Biophysical Journal. - : Elsevier BV. - 0006-3495 .- 1542-0086. ; 99:12, s. L97-L99
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Tidskriftsartikel (refereegranskat)abstract
- Aquaporins (AQPs) facilitate the passive flux of water across biological membranes in response to an osmotic pressure. A number of AQPs, for instance in plants and yeast, have been proposed to be regulated by phosphorylation, cation concentration, pH change, or membrane-mediated mechanical stress. Here we report an extensive set of molecular dynamics simulations of AQP1 and AQP4 subject to large membrane potentials in the range of +/- 1.5 V, suggesting that AQPs may in addition be regulated by an electrostatic potential. As the regulatory mechanism we identified the relative population of two different states of the conserved arginine in the aromatic/arginine constriction region. A positive membrane potential was found to stabilize the arginine in an up-state, which allows rapid water flux, whereas a negative potential favors a down-state, which reduces the single-channel water permeability.
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| 14. |
- Jelen, Sabina, et al.
(författare)
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Aquaporin-9 Protein Is the Primary Route of Hepatocyte Glycerol Uptake for Glycerol Gluconeogenesis in Mice
- 2011
-
Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 286:52, s. 44319-44325
-
Tidskriftsartikel (refereegranskat)abstract
- It has been hypothesized that aquaporin-9 (AQP9) is part of the unknown route of hepatocyte glycerol uptake. In a previous study, leptin receptor-deficient wild-type mice became diabetic and suffered from fasting hyperglycemia whereas isogenic AQP9(-/-) knock-out mice remained normoglycemic. The reason for this improvement in AQP9(-/-) mice was not established before. Here, we show increased glucose output (by 123% +/- 36% S. E.) in primary hepatocyte culture when 0.5 mM extracellular glycerol was added. This increase depended on AQP9 because it was absent in AQP9(-/-) cells. Likewise, the increase was abolished by 25 mu M HTS13286 (IC(50) similar to 2 mu M), a novel AQP9 inhibitor, which we identified in a small molecule library screen. Similarly, AQP9 deletion or chemical inhibition eliminated glycerol-enhanced glucose output in perfused liver preparations. The following control experiments suggested inhibitor specificity to AQP9: (i) HTS13286 affected solute permeability in cell lines expressing AQP9, but not in cell lines expressing AQPs 3, 7, or 8. (ii) HTS13286 did not influence lactate-and pyruvate-dependent hepatocyte glucose output. (iii) HTS13286 did not affect glycerol kinase activity. Our experiments establish AQP9 as the primary route of hepatocyte glycerol uptake for gluconeogenesis and thereby explain the previously observed, alleviated diabetes in leptin receptor-deficient AQP9(-/-) mice.
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| 15. |
- Kirscht, Andreas, et al.
(författare)
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Crystal Structure of an Ammonia-Permeable Aquaporin
- 2016
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Ingår i: PLoS Biology. - : Public Library of Science (PLoS). - 1545-7885. ; 14:3
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Tidskriftsartikel (refereegranskat)abstract
- Aquaporins of the TIP subfamily (Tonoplast Intrinsic Proteins) have been suggested to facilitate permeation of water and ammonia across the vacuolar membrane of plants, allowing the vacuole to efficiently sequester ammonium ions and counteract cytosolic fluctuations of ammonia. Here, we report the structure determined at 1.18 Å resolution from twinned crystals of Arabidopsis thaliana aquaporin AtTIP2;1 and confirm water and ammonia permeability of the purified protein reconstituted in proteoliposomes as further substantiated by molecular dynamics simulations. The structure of AtTIP2;1 reveals an extended selectivity filter with the conserved arginine of the filter adopting a unique unpredicted position. The relatively wide pore and the polar nature of the selectivity filter clarify the ammonia permeability. By mutational studies, we show that the identified determinants in the extended selectivity filter region are sufficient to convert a strictly water-specific human aquaporin into an AtTIP2;1-like ammonia channel. A flexible histidine and a novel water-filled side pore are speculated to deprotonate ammonium ions, thereby possibly increasing permeation of ammonia. The molecular understanding of how aquaporins facilitate ammonia flux across membranes could potentially be used to modulate ammonia losses over the plasma membrane to the atmosphere, e.g., during photorespiration, and thereby to modify the nitrogen use efficiency of plants.
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| 16. |
- Kutzner, Carsten, et al.
(författare)
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Best bang for your buck : GPU nodes for GROMACS biomolecular simulations
- 2015
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Ingår i: Journal of Computational Chemistry. - : Wiley. - 0192-8651 .- 1096-987X. ; 36:26, s. 1990-2008
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Tidskriftsartikel (refereegranskat)abstract
- The molecular dynamics simulation package GROMACS runs efficiently on a wide variety of hardware from commodity workstations to high performance computing clusters. Hardware features are well-exploited with a combination of single instruction multiple data, multithreading, and message passing interface (MPI)-based single program multiple data/multiple program multiple data parallelism while graphics processing units (GPUs) can be used as accelerators to compute interactions off-loaded from the CPU. Here, we evaluate which hardware produces trajectories with GROMACS 4.6 or 5.0 in the most economical way. We have assembled and benchmarked compute nodes with various CPU/GPU combinations to identify optimal compositions in terms of raw trajectory production rate, performance-to-price ratio, energy efficiency, and several other criteria. Although hardware prices are naturally subject to trends and fluctuations, general tendencies are clearly visible. Adding any type of GPU significantly boosts a node's simulation performance. For inexpensive consumer-class GPUs this improvement equally reflects in the performance-to-price ratio. Although memory issues in consumer-class GPUs could pass unnoticed as these cards do not support error checking and correction memory, unreliable GPUs can be sorted out with memory checking tools. Apart from the obvious determinants for cost-efficiency like hardware expenses and raw performance, the energy consumption of a node is a major cost factor. Over the typical hardware lifetime until replacement of a few years, the costs for electrical power and cooling can become larger than the costs of the hardware itself. Taking that into account, nodes with a well-balanced ratio of CPU and consumer-class GPU resources produce the maximum amount of GROMACS trajectory over their lifetime.
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| 17. |
- Kutzner, Carsten, et al.
(författare)
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More bang for your buck : Improved use of GPU nodes for GROMACS 2018
- 2019
-
Ingår i: Journal of Computational Chemistry. - : Wiley. - 0192-8651 .- 1096-987X. ; 40:27, s. 2418-2431
-
Tidskriftsartikel (refereegranskat)abstract
- We identify hardware that is optimal to produce molecular dynamics (MD) trajectories on Linux compute clusters with the GROMACS 2018 simulation package. Therefore, we benchmark the GROMACS performance on a diverse set of compute nodes and relate it to the costs of the nodes, which may include their lifetime costs for energy and cooling. In agreement with our earlier investigation using GROMACS 4.6 on hardware of 2014, the performance to price ratio of consumer GPU nodes is considerably higher than that of CPU nodes. However, with GROMACS 2018, the optimal CPU to GPU processing power balance has shifted even more toward the GPU. Hence, nodes optimized for GROMACS 2018 and later versions enable a significantly higher performance to price ratio than nodes optimized for older GROMACS versions. Moreover, the shift toward GPU processing allows to cheaply upgrade old nodes with recent GPUs, yielding essentially the same performance as comparable brand-new hardware.
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| 18. |
- Kutzner, Carsten, et al.
(författare)
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Software news and update : Speeding up parallel GROMACS on high-latency networks
- 2007
-
Ingår i: Journal of Computational Chemistry. - : Wiley. - 0192-8651 .- 1096-987X. ; 28:12, s. 2075-84
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Tidskriftsartikel (refereegranskat)abstract
- We investigate the parallel scaling of the GROMACS molecular dynamics code on Ethernet Beowulf clusters and what prerequisites are necessary for decent scaling even on such clusters with only limited bandwidth and high latency. GROMACS 3.3 scales well on supercomputers like the IBM p690 (Regatta) and on Linux clusters with a special interconnect like Myrinet or Infiniband. Because of the high single-node performance of GROMACS, however, on the widely used Ethernet switched clusters, the scaling typically breaks down when more than two computer nodes are involved, limiting the absolute speedup that can be gained to about 3 relative to a single-CPU run. With the LAM MPI implementation, the main scaling bottleneck is here identified to be the all-to-all communication which is required every time step. During such an all-to-all communication step, a huge amount of messages floods the network, and as a result many TCP packets are lost. We show that Ethernet flow control prevents network congestion and leads to substantial scaling improvements. For 16 CPUs, e.g., a speedup of 11 has been achieved. However, for more nodes this mechanism also fails. Having optimized an all-to-all routine, which sends the data in an ordered fashion, we show that it is possible to completely prevent packet loss for any number of multi-CPU nodes. Thus, the GROMACS scaling dramatically improves, even for switches that lack flow control. In addition, for the common HP ProCurve 2848 switch we find that for optimum all-to-all performance it is essential how the nodes are connected to the switch's ports. This is also demonstrated for the example of the Car-Parinello MD code.
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| 19. |
- Kutzner, Carsten, et al.
(författare)
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Speeding up parallel GROMACS on high-latency networks
- 2007
-
Ingår i: Journal of Computational Chemistry. - : Wiley. - 0192-8651 .- 1096-987X. ; 28:12, s. 2075-2084
-
Tidskriftsartikel (refereegranskat)abstract
- We investigate the parallel scaling of the GROMACS molecular dynamics code on Ethernet Beowulf clusters and what prerequisites are necessary for decent scaling even on such clusters with only limited bandwidth and high latency. GROMACS 3.3 scales well on supercomputers like the IBM p690 (Regatta) and on Linux clusters with a special interconnect like Myrinet or Infiniband. Because of the high single-node performance of GROMACS, however, on the widely used Ethernet switched clusters, the scaling typically breaks down when more than two computer nodes are involved, limiting the absolute speedup that can be gained to about 3 relative to a single-CPU run. With the LAM MPI implementation, the main scaling bottleneck is here identified to be the all-to-all communication which is required every time step. During such an all-to-all communication step, a huge amount of messages floods the network, and as a result many TCP packets are lost. We show that Ethernet flow control prevents network congestion and leads to substantial scaling improvements. For 16 CPUs, e.g., a speedup of 11 has been achieved. However, for more nodes this mechanism also fails. Having optimized an all-to-all routine, which sends the data in an ordered fashion, we show that it is possible to completely prevent packet loss for any number of multi-CPU nodes. Thus, the GROMACS scaling dramatically improves, even for switches that lack flow control. In addition, for the common HP ProCurve 2848 switch we find that for optimum all-to-all performance it is essential how the nodes are connected to the switch's ports. This is also demonstrated for the example of the Car-Parinello MD code.
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| 20. |
- Lange, Oliver F., et al.
(författare)
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Scrutinizing Molecular Mechanics Force Fields on the Submicrosecond Timescale with NMR Data
- 2010
-
Ingår i: Biophysical Journal. - : Elsevier BV. - 0006-3495 .- 1542-0086. ; 99:2, s. 647-655
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Tidskriftsartikel (refereegranskat)abstract
- Protein dynamics on the atomic level and on the microsecond timescale has recently become accessible from both computation and experiment. To validate molecular dynamics (MD) at the submicrosecond timescale against experiment we present microsecond MD simulations in 10 different force-field configurations for two globular proteins, ubiquitin and the gb3 domain of protein G, for which extensive NMR data is available. We find that the reproduction of the measured NMR data strongly depends on the chosen force field and electrostatics treatment. Generally, particle-mesh Ewald outperforms cut-off and reaction-field approaches. A comparison to measured J-couplings across hydrogen bonds suggests that there is room for improvement in the force-field description of hydrogen bonds in most modern force fields. Our results show that with current force fields, simulations beyond hundreds of nanoseconds run an increased risk of undergoing transitions to nonnative conformational states or will persist within states of high free energy for too long, thus skewing the obtained population frequencies. Only for the AMBER99sb force field have such transitions not been observed. Thus, our results have significance for the interpretation of data obtained with long MD simulations, for the selection of force fields for MD studies and for force-field development. We hope that this comprehensive benchmark based on NMR data applied to many popular MD force fields will serve as a useful resource to the MD community. Finally, we find that for gb3, the force-field AMBER99sb reaches comparable accuracy in back-calculated residual dipolar couplings and J-couplings across hydrogen bonds to ensembles obtained by refinement against NMR data.
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| 21. |
- Stary, Anna, et al.
(författare)
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Toward a Consensus Model of the hERG Potassium Channel
- 2010
-
Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 5:3, s. 455-467
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Tidskriftsartikel (refereegranskat)abstract
- Malfunction of hERG potassium channels, due to inherited mutations or inhibition by drugs, can cause long QT syndrome, which can lead to life-threatening arrhythmias. A three-dimensional structure of hERG is a prerequisite to understand the molecular basis of hERG malfunction. To achieve a consensus model, we carried out an extensive analysis of hERG models based on various alignments of helix S5. We analyzed seven models using a combination of conventional geometry/packing/normality validation methods as well as molecular dynamics simulations and molecular docking. A synthetic test set with the X-ray crystal structure of K(v)1.2 with artificially shifted S5 sequences modeled into the structure served as a reference case. We docked the known hERG inhibitors (+)-cisapride, (S)-terfenadine, and MK-499 into the hERG models and simulation snapshots. None of the single analyses unambiguously identified a preferred model, but the combination of all three revealed that there is only one model that fulfils all quality criteria. This model is confirmed by a recent mutation scanning experiment (P. Ju, G. Pages, R. R Riek, P. C. Chen, A. M. Torres, R S. Bansal, S. Kuyucak, R W. Kuchel, J. I. Vandenberg, J. Biol. Chem. 2009, 284, 1000-1008).([1]) We expect the modeled structure to be useful as a basis both for computational studies of channel function and kinetics as well as the design of experiments.
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| 22. |
- Wacker, Soeren J., et al.
(författare)
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Identification of Selective Inhibitors of the Potassium Channel Kv1.1-1.2(3) by High-Throughput Virtual Screening and Automated Patch Clamp
- 2012
-
Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 7:10, s. 1775-1783
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Tidskriftsartikel (refereegranskat)abstract
- Two voltage-dependent potassium channels, Kv1.1 (KCNA1) and Kv1.2 (KCNA2), are found to co-localize at the juxtaparanodal region of axons throughout the nervous system and are known to co-assemble in heteromultimeric channels, most likely in the form of the concatemer Kv1.11.2(3). Loss of the myelin sheath, as is observed in multiple sclerosis, uncovers the juxtaparanodal region of nodes of Ranvier in myelinated axons leading to potassium conductance, resulting in loss of nerve conduction. The selective blocking of these Kv channels is therefore a promising approach to restore nerve conduction and function. In the present study, we searched for novel inhibitors of Kv1.11.2(3) by combining a virtual screening protocol and electrophysiological measurements on a concatemer Kv1.11.2(3) stably expressed in Chinese hamster ovary K1 (CHO-K1) cells. The combined use of four popular virtual screening approaches (eHiTS, FlexX, Glide, and Autodock-Vina) led to the identification of several compounds as potential inhibitors of the Kv1.11.2(3) channel. From 89 electrophysiologically evaluated compounds, 14 novel compounds were found to inhibit the current carried by Kv1.11.2(3) channels by more than 80?% at 10 mu M. Accordingly, the IC50 values calculated from concentrationresponse curve titrations ranged from 0.6 to 6 mu M. Two of these compounds exhibited at least 30-fold higher potency in inhibition of Kv1.11.2(3) than they showed in inhibition of a set of cardiac ion channels (hERG, Nav1.5, and Cav1.2), resulting in a profile of selectivity and cardiac safety. The results presented herein provide a promising basis for the development of novel selective ion channel inhibitors, with a dramatically lower demand in terms of experimental time, effort, and cost than a sole high-throughput screening approach of large compound libraries.
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| 23. |
- Wacker, Soeren J., et al.
(författare)
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The identification of novel, high affinity AQP9 inhibitors in an intracellular binding site
- 2013
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Ingår i: Molecular Membrane Biology. - : Informa UK Limited. - 0968-7688 .- 1464-5203. ; 30:3, s. 246-260
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Tidskriftsartikel (refereegranskat)abstract
- Background: The involvement of aquaporin (AQP) water and small solute channels in the etiology of several diseases, including cancer, neuromyelitis optica and body fluid imbalance disorders, has been suggested previously. Furthermore, results obtained in a mouse model suggested that AQP9 function contributes to hyperglycemia in type-2 diabetes. In addition, the physiological role of several AQP family members remains poorly understood. Small molecule inhibitors of AQPs are therefore desirable to further study AQP physiological and pathophysiological functions. Methods: The binding of recently established AQP9 inhibitors to a homology model of AQP9 was investigated by molecular dynamics simulations and molecular docking. Putative inhibitor binding sites identified with this procedure were modified by site-directed mutagenesis. Active compounds were measured in a mammalian cell water permeability assay of mutated AQP9 isoforms and tested for changes in inhibitory effects. Controls: Three independent cell lines were established for each mutated AQP9 isoform and functionality of mutant isoforms was established. Principal findings: We have identified putative binding sites of recently established AQP9 inhibitors. This information facilitated successful identification of novel AQP9 inhibitors with low micromolar IC50 values in a cell based assay by in silico screening of a compound library targeting specifically this binding site. Significance: We have established a successful strategy for AQP small molecule inhibitor identification. AQP inhibitors may be relevant as experimental tools, to enhance our understanding of AQP function, and in the treatment of various diseases.
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