Ion transport in the gramicidin channel: molecular dynamics study of single and double occupancy

Roux, Benoı̂t; Prod'hom, Blaise; Karplus, M.

doi:10.1016/s0006-3495(95)80264-x

Cited by 106 publications

(92 citation statements)

References 71 publications

(118 reference statements)

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“…73 The importance of nonadditivity in ion-peptide interactions has been investigated by studying the binding of NaC to the gramicidin channel using molecular dynamics simulations and ab initio calc u l a t i o n~.~~ Further tests of the potential function can be made by calculations of crystal structures of metal ions with NMA77 and by simulations of bulk solutions of a r n i d e~.~' ,~~ In future work, the ion-peptide potential energy function will be extended to describe the interaction of ions with protein sidechains as part of a project to develop a protein potential function including all atoms." …”

Section: Resultsmentioning

confidence: 99%

Potential energy function for cation–peptide interactions: An ab initio study

Roux

Karplus

1995

J Comput Chem

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A potential energy function is developed to represent the interaction of small monovalent cations, Li', Na', and K' , with the backbone of polypeptides. The results are based on ab initio calculations up to the 6-31G* level of the interactions of the ions with acetamide and N-methylacetamide. Basis set superposition errors are corrected with the counterpoise method. A systematic overestimate of the bond polarities is taken into account by an empirical scaling procedure that uses the ratio of the experimental to ab initio dipole moment. The calculated binding energies obtained with this procedure show consistent convergence with different basis sets and are in good agreement with experimental data on cation-water and cation-dimethylformamide systems. Investigations of the calculated ab initio potential energy surface indicate that the cation-peptide interaction is dominated by electrostatics and includes a nonnegligible contribution from polarization of the peptide group by the ion. The induced polarization results in a steeper-than-Coulombic interaction and cannot be described by fixed ion-peptide partial charges electrostatics. Atomic polarizabilities located on the atoms of the ligand molecule are introduced to account for the induced polarization in the empirical energy function. A -l/r4 attractive interaction appears in the potential function. The resulting radial and angular dependence of the potential energy surface is well reproduced. 0 1995

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Section: Resultsmentioning

confidence: 99%

Potential energy function for cation–peptide interactions: An ab initio study

Roux

Karplus

1995

J Comput Chem

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“…This may well influence the energetics of a second ion trying to enter the pore. In addition, the energetics of the doubly occupied state depend on how water molecules pack between the ions at their binding sites (26). An attempt to model these interactions by Brownian dynamics simulations would involve the introduction of additional empirical forces acting on the ions, including free parameters.…”

Section: Summary and Discussionmentioning

confidence: 99%

Numerical framework models of single proton conduction through Gramicidin

Schumaker¹

2003

Front Biosci

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“…This finding suggests the existence of structural long-range coupling across the pore that would be absent in continuum solvent models. However, because double occupancy perturbs the single-file column significantly (35), no conclusion about the likely positions of the ions in the doubly occupied state can be conjectured without further calculations.…”

Section: Equilibrium Dissociation Constantsmentioning

confidence: 99%

Energetics of ion conduction through the gramicidin channel

Allen

Andersen

Roux

2003

Proc. Natl. Acad. Sci. U.S.A.

364

521

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The free energy governing K ؉ conduction through gramicidin A channels is characterized by using over 0.1 s of all-atom molecular dynamics simulations with explicit solvent and membrane. The results provide encouraging agreement with experiments and insights into the permeation mechanism. The free energy surface of K ؉ , as a function of both axial and radial coordinates, is calculated. Correcting for simulation artifacts due to periodicity and the lack of hydrocarbon polarizability, the calculated singlechannel conductance for K ؉ ions is 0.8 pS, closer to experiment than any previous calculation. In addition, the estimated single ion dissociation constants are within the range of experimental determinations. The relatively small free energy barrier to ion translocation arises from a balance of large opposing contributions from protein, single-file water, bulk electrolyte, and membrane. Mean force decomposition reveals a remarkable ability of the single-file water molecules to stabilize K ؉ by ؊40 kcal͞mol, roughly half the bulk solvation free energy. M olecular dynamics (MD) simulation has become an essential tool for investigating a wide range of chemical and biological systems. Greater computational resources, improvements in simulation methodologies, and refinement of interaction potentials have made it possible to model increasingly complex processes that previously were intractable (1). It is important that the approach be thoroughly tested on systems that are small and yet possess the same ingredients and challenges as much larger and more complex biomolecular systems. These benchmarks serve to set standards on which studies of more complex problems can find foundation. For example, a single key protein secondary structure, the ␤ hairpin, has been used as a benchmark test in protein-folding studies (2). In the present study, we tackle the problem of ion permeation with a similar mindset. Ion permeation involves a seemingly straightforward process of an ion passing across the membrane through a molecular pore. However, this process is difficult to model because it entails the accurate representation of intermolecular interactions in vastly different environments (aqueous solution and narrow protein pore) for which there is little direct experimental data (3). As a rigorous examination of an all-atom force field to model ion permeation, we combine free energy methods with fully atomistic, dynamical simulations on a benchmark system. Atomic structures have been reported for many ion channels, but none is structurally and functionally as well characterized (4), or as amenable to computer simulation, as the gramicidin A (gA) channel. gA channels form by transmembrane dimerization of single-stranded, right-handed ␤ 6.3 -helices (5) with the sequence (underlined residues are D-amino acids): formyl-Val-Gly-AlaLeu-Ala-Val-Val-Val-Trp-Leu-Trp-Leu-Trp-Leu-Trp-ethanolamine (6). High resolution structures have been obtained for gA embedded in detergent micelles by using liquid-state NMR (7,8) and oriented dimyristoyl...

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Ion transport in the gramicidin channel: molecular dynamics study of single and double occupancy

Cited by 106 publications

References 71 publications

Potential energy function for cation–peptide interactions: An ab initio study

Potential energy function for cation–peptide interactions: An ab initio study

Numerical framework models of single proton conduction through Gramicidin

Energetics of ion conduction through the gramicidin channel

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