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Benoit Roux - One of the best experts on this subject based on the ideXlab platform.
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energetics of double ion occupancy in the gramicidin a Channel
Journal of Physical Chemistry B, 2010Co-Authors: Yuhui Li, Olaf S. Andersen, Benoit RouxAbstract:To understand the energetics of double ion occupancy in gramicidin A (gA) Channels, the 2D potential of mean force (PMF) is calculated for two ions at different positions along the Channel Axis. The cross sections of this 2D PMF are compared with available 1-ion PMFs to highlight the effect of one ion on the permeation dynamics of the other. It is found that if the first ion stays on one side inside the Channel, the second ion has to pass over an additional new barrier to move into the outer binding site on the other side. At the same time both outer and inner binding sites for the second ion become shallower than those in the 1-ion PMF. The calculated ion-ion repulsion for a doubly occupied Channel is about 2 kcal/mol, in good agreement with previous experimental estimates. The number of water molecules inside the Channel and their dipole moment are calculated to interpret the energetics of double ion occupancy in gA Channels. As the first ion moves into the outer binding site and then further into the Channel, the oxygen atoms of the single-file water column in the Channel is oriented to point toward the ion. The observed dipole moment distribution of a singly occupied Channel has only one sharp peak and the water alignment is essentially perfect once the ion is in the inner binding site. For this reason, there is an energy penalty to accomodate a second ion at the opposive end of the Channel.
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comment on free energy simulations of single and double ion occupancy in gramicidin a j chem phys 126 105103 2007
Journal of Chemical Physics, 2008Co-Authors: Benoit Roux, Olaf S. Andersen, Toby W AllenAbstract:In a recent article published by Bastug and Kuyucak [J. Chem. Phys.126, 105103 (2007)] investigated the microscopic factors affecting double ion occupancy in the gramicidin Channel. The analysis relied largely on the one-dimensional potential of mean force of ions along the Axis of the Channel (the so-called free energy profile of the ion along the Channel Axis), as well as on the calculation of the equilibrium association constant of the ions in the Channel binding sites. It is the purpose of this communication to clarify this issue.
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comment on free energy simulations of single and double ion occupancy in gramicidin a
Journal of Chemical Physics, 2008Co-Authors: Benoit Roux, Olaf S. Andersen, Toby W AllenAbstract:In a recent article published by Bastug and Kuyucak [J. Chem. Phys.126, 105103 (2007)] investigated the microscopic factors affecting double ion occupancy in the gramicidin Channel. The analysis relied largely on the one-dimensional potential of mean force of ions along the Axis of the Channel (the so-called free energy profile of the ion along the Channel Axis), as well as on the calculation of the equilibrium association constant of the ions in the Channel binding sites. It is the purpose of this communication to clarify this issue.
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ion permeation through the α hemolysin Channel theoretical studies based on brownian dynamics and poisson nernst plank electrodiffusion theory
Biophysical Journal, 2004Co-Authors: Sergei Y Noskov, Benoit RouxAbstract:Identification of the molecular interaction governing ion conduction through biological pores is one of the most important goals of modern electrophysiology. Grand canonical Monte Carlo Brownian dynamics (GCMC/BD) and three- dimensional Poisson-Nernst-Plank (3d-PNP) electrodiffusion algorithms offer powerful and general approaches to study of ion permeation through wide molecular pores. A detailed analysis of ion flows through the staphylococcal a-hemolysin Channel based on series of simulations at different concentrations and transmembrane potentials is presented. The position-dependent diffusion coefficient is approximated on the basis of a hydrodynamic model. The Channel conductance calculated by GCMC/BD is ;10% higher than (electrophysiologically measured) experimental values, whereas results from 3d-PNP are always 30-50% larger. Both methods are able to capture all important electrostatic interactions in equilibrium conditions. The asymmetric conductance upon the polarity of the transmembrane potential observed experimentally is reproduced by GCMC/BD and 3d- PNP. The separation of geometrical and energetic influence of the Channel on ion conduction reveals that such asymmetries arise from the permanent charge distribution inside the pore. The major determinant of the asymmetry is unbalanced charge in the triad of polar residues D127, D128, and K131. The GCMC/BD or 3d-PNP calculations reproduce also experimental reversal potentials and permeability rations in asymmetric ionic solutions. The weak anionic selectivity of the Channel results from the presence of the salt bridge between E111 and K147 in the constriction zone. The calculations also reproduce the experimentally derived dependence of the reversible potential to the direction of the salt gradient. The origin of such effect arises from the asymmetrical distribution of energetic barriers along the Channel Axis, which modulates the preferential ion passage in different directions.
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the binding site of sodium in the gramicidin a Channel comparison of molecular dynamics with solid state nmr data
Biophysical Journal, 1997Co-Authors: Thomas B Woolf, Benoit RouxAbstract:The location of the main binding site for sodium in the gramicidin A (GA) Channel was investigated with molecular dynamics simulations, using an atomic model of the Channel embedded in a fully hydrated dimyristoyl phosphatidycholine (DMPC) bilayer. Twenty-four separate simulations in which a sodium was restrained at different locations along the Channel Axis were generated. The results are compared with carbonyl 13C chemical shift anisotropy solid-state NMR experimental data previously obtained with oriented GA:DMPC samples. Predictions are made for other solid-state NMR properties that could be observed experimentally. The combined information from experiment and simulation strongly suggests that the main binding sites for sodium are near the Channel's mouth, approximately 9.2 A from the center of the dimer Channel. The 13C chemical shift anisotropy of Leu10 is the most affected by the presence of a sodium ion in the binding site. In the binding site, the sodium ion is lying off-Axis, making contact with two carbonyl oxygens and two single-file water molecules. The main Channel ligand is provided by the carbonyl group of the Leu10-Trp11 peptide linkage, which exhibits the largest deviation from the ion-free Channel structure. Transient contacts with the carbonyl group of Val8 and Trp15 are also present. The influence of the tryptophan side chains on the Channel conductance is examined based on the current information about the binding site.
Toby W Allen - One of the best experts on this subject based on the ideXlab platform.
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comment on free energy simulations of single and double ion occupancy in gramicidin a j chem phys 126 105103 2007
Journal of Chemical Physics, 2008Co-Authors: Benoit Roux, Olaf S. Andersen, Toby W AllenAbstract:In a recent article published by Bastug and Kuyucak [J. Chem. Phys.126, 105103 (2007)] investigated the microscopic factors affecting double ion occupancy in the gramicidin Channel. The analysis relied largely on the one-dimensional potential of mean force of ions along the Axis of the Channel (the so-called free energy profile of the ion along the Channel Axis), as well as on the calculation of the equilibrium association constant of the ions in the Channel binding sites. It is the purpose of this communication to clarify this issue.
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comment on free energy simulations of single and double ion occupancy in gramicidin a
Journal of Chemical Physics, 2008Co-Authors: Benoit Roux, Olaf S. Andersen, Toby W AllenAbstract:In a recent article published by Bastug and Kuyucak [J. Chem. Phys.126, 105103 (2007)] investigated the microscopic factors affecting double ion occupancy in the gramicidin Channel. The analysis relied largely on the one-dimensional potential of mean force of ions along the Axis of the Channel (the so-called free energy profile of the ion along the Channel Axis), as well as on the calculation of the equilibrium association constant of the ions in the Channel binding sites. It is the purpose of this communication to clarify this issue.
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gramicidin a Channel as a test ground for molecular dynamics force fields
Biophysical Journal, 2003Co-Authors: Toby W Allen, Turgut Bastug, Serdar Kuyucak, Shin-ho ChungAbstract:We use the well-known structural and functional properties of the gramicidin A Channel to test the appropriateness of force fields commonly used in molecular dynamics (MD) simulations of ion Channels. For this purpose, the high-resolution structure of the gramicidin A dimer is embedded in a dimyristoylphosphatidylcholine bilayer, and the potential of mean force of a K+ ion is calculated along the Channel Axis using the umbrella sampling method. Calculations are performed using two of the most common force fields in MD simulations: CHARMM and GROMACS. Both force fields lead to large central barriers for K+ ion permeation, that are substantially higher than those deduced from the physiological data by inverse methods. In long MD simulations lasting over 60 ns, several ions are observed to enter the binding site but none of them crossed the Channel despite the presence of a large driving field. The present results, taken together with many earlier studies, highlights the shortcomings of the standard force fields used in MD simulations of ion Channels and calls for construction of more appropriate force fields for this purpose.
Serdar Kuyucak - One of the best experts on this subject based on the ideXlab platform.
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mechanism and energetics of charybdotoxin unbinding from a potassium Channel from molecular dynamics simulations
Biophysical Journal, 2009Co-Authors: Pochia Chen, Serdar KuyucakAbstract:Ion Channel-toxin complexes are ideal systems for computational studies of protein-ligand interactions, because, in most cases, the Channel Axis provides a natural reaction coordinate for unbinding of a ligand and a wealth of physiological data is available to check the computational results. We use a recently determined structure of a potassium Channel-charybdotoxin complex in molecular dynamics simulations to investigate the mechanism and energetics of unbinding. Pairs of residues on the Channel protein and charybdotoxin that are involved in the binding are identified, and their behavior is traced during umbrella-sampling simulations as charybdotoxin is moved away from the binding site. The potential of mean force for the unbinding of charybdotoxin is constructed from the umbrella sampling simulations using the weighted histogram analysis method, and barriers observed are correlated with specific breaking of interactions and influx of water molecules into the binding site. Charybdotoxin is found to undergo conformational changes as a result of the reaction coordinate choice—a nontrivial decision for larger ligands—which we explore in detail, and for which we propose solutions. Agreement between the calculated and the experimental binding energies is obtained once the energetic consequences of these conformational changes are included in the calculations.
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energetics of ion permeation rejection binding and block in gramicidin a from free energy simulations
Biophysical Journal, 2006Co-Authors: Turgut Bastug, Serdar KuyucakAbstract:The rigid force fields currently used in molecular dynamics (MD) simulations of biomolecules are optimized for globular proteins. Whether they can also be used in MD simulations of membrane proteins is an important issue that needs to be resolved. Here we address this issue using the gramicidin A Channel, which provides an ideal test case because of the simplicity of its structure and the availability of a wealth of functional data. Permeation properties of gramicidin A can be summarized as “it conducts monovalent cations, rejects anions, and binds divalent cations.” Hence, a comprehensive test should consider the energetics of permeation for all three types of ions. To that end, we construct the potential of mean force for K+, Cl−, and Ca2+ ions along the Channel Axis. For an independent check of the potential-of-mean-force results, we also calculate the free energy differences for these ions at the Channel center and binding sites relative to bulk. We find that “rejection of anions” is satisfied but there are difficulties in accommodating the other two properties using the current MD force fields.
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gramicidin a Channel as a test ground for molecular dynamics force fields
Biophysical Journal, 2003Co-Authors: Toby W Allen, Turgut Bastug, Serdar Kuyucak, Shin-ho ChungAbstract:We use the well-known structural and functional properties of the gramicidin A Channel to test the appropriateness of force fields commonly used in molecular dynamics (MD) simulations of ion Channels. For this purpose, the high-resolution structure of the gramicidin A dimer is embedded in a dimyristoylphosphatidylcholine bilayer, and the potential of mean force of a K+ ion is calculated along the Channel Axis using the umbrella sampling method. Calculations are performed using two of the most common force fields in MD simulations: CHARMM and GROMACS. Both force fields lead to large central barriers for K+ ion permeation, that are substantially higher than those deduced from the physiological data by inverse methods. In long MD simulations lasting over 60 ns, several ions are observed to enter the binding site but none of them crossed the Channel despite the presence of a large driving field. The present results, taken together with many earlier studies, highlights the shortcomings of the standard force fields used in MD simulations of ion Channels and calls for construction of more appropriate force fields for this purpose.
Julian Clark - One of the best experts on this subject based on the ideXlab platform.
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ichnofabric characterization of a deep marine clastic system a subsurface study of the middle eocene ainsa system spanish pyrenees
Sedimentology, 2014Co-Authors: Thomas G. Heard, Kevin T. Pickering, Julian ClarkAbstract:This paper documents a subsurface trace fossil and ichnofabric study of the proximal parts of a structurally confined and Channelized sand-rich, lower slope and proximal basin-floor deep-marine system in the Middle Eocene Ainsa basin, Spanish Pyrenees. Five depositional environments are recognized based on sedimentary facies associations, depositional architecture and stratigraphic context (Channel Axis, Channel off-Axis, Channel margin, levee-overbank and interfan), as well as a Channel abandonment phase. Each environment is characterized by distinct and recurring ichnofabrics. Ichnological measurements and observations were recorded from six cores recovered from six wells drilled at a spacing of between 400 m and 500 m at outcrop, and totalling 1213 m in length. From Channel Axis to levee-overbank environments, there is a trend of increasing bioturbation intensity and ichnodiversity. Ichnofabrics in Channel Axis and Channel off-Axis environments are characterized by low bioturbation intensity and low ichnodiversity. Thalassinoides-dominated firmground ichnofabrics associated with erosive sediment gravity flows are common in these environments. In contrast, Channel margin and levee-overbank environments are characterized by ichnofabrics associated with high bioturbation intensity and ichnodiversity. Sediments of the interfan are characterized by the highest bioturbation intensity, associated with burrow mottling and an absence of primary sedimentary structures. This paper demonstrates that in core-based studies, ichnofabric analysis is an important and valuable tool in discriminating between different environments in Channelized deep-marine siliciclastic systems. The results of this study should find wide applicability in reservoir characterization studies in the petroleum industry, in field-based analogue ichnofabric studies and other core-based studies in deep-water siliciclastic systems worldwide such as the Integrated Ocean Drilling Program.
K T Pickering - One of the best experts on this subject based on the ideXlab platform.
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Trace fossils as diagnostic indicators of deep-marine environments, Middle Eocene Ainsa-Jaca basin, Spanish Pyrenees
SEDIMENTOLOGY, 2008Co-Authors: K T PickeringAbstract:A quantitative study of trace fossil abundance in the Middle Eocene deep-marine clastic systems, Ainsa-Jaca basin, Spanish Pyrenees, shows that they are powerful discriminators of submarine fan and related environments. Sixteen fan and related environments are recognized from upper-slope gully to the distal basin-floor. For each environment, the degree of bioturbation (density), trace-fossil diversity, number of pre-depositional and post-depositional trace fossils, as well as the number of graphoglyptid ichnospecies were quantified. In the more laterally confined and Channel-dominated Ainsa basin, there is a trend of increasing bioturbation intensity and trace-fossil diversity away from Channel-Axis to off-Axis environments. In the more unconfined and distal Jaca basin, there is a trend of increasing trace-fossil diversity and number of pre-depositional trace fossils including graphoglyptids from the Channel-lobe transition to the fan-fringe. The trace-fossil assemblages of the Ainsa-Jaca basin are characteristic of a number of sub-ichnofacies of the Nereites ichnofacies. In the distal Jaca basin, the Paleodictyon sub-ichnofacies occurs in the lobe-fringe and fan-fringe, whereas the distal basin-floor has a trace-fossil assemblage typical of the Paleodictyon sub-ichnofacies, but with a high proportion of post-depositional fodinichnia. Trace-fossil assemblages of proximal basin, axial, environments are characteristic of the Ophiomorpha rudis sub-ichnofacies, whilst proximal off-Axis environments, have a mixed Paleodictyon-Ophiomorpha rudis sub-ichnofacies trace-fossil assemblage.
