Ion Permeation through a Narrow Channel: Using Gramicidin to Ascertain All-Atom Molecular Dynamics Potential of Mean Force Methodology and Biomolecular Force Fields

Allen, Toby W.; Andersen, Olaf S.; Roux, Benoı̂t

doi:10.1529/biophysj.105.077073

Cited by 133 publications

(287 citation statements)

References 94 publications

Supporting

Mentioning

257

Contrasting

Order By: Relevance

“…Before studying the gating transition, we investigate the ion-conducting properties of the endpoint structures. To examine the ion permeability of the GLIC transmembrane pore, we calculate the one-dimensional free energy of a single Na þ ion and its mobility from umbrellasampling simulations, as done similarly for the gramicidin channel (23). With the TMD in the open conformation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Pore opening and closing of a pentameric ligand-gated ion channel

Zhu

Hummer

2010

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

148

208

View full text Add to dashboard Cite

Nerve signaling in humans and chemical sensing in bacteria both rely on the controlled opening and closing of the ion-conducting pore in pentameric ligand-gated ion channels. With the help of a multiscale simulation approach that combines mixed elastic network model calculations with molecular dynamics simulations, we study the opening and closing of the pore in Gloeobacter violaceus channel GLIC at atomic resolution. In our simulations of the GLIC transmembrane domain, we first verify that the two endpoints of the transition are open and closed to sodium ion conduction, respectively. We then show that a two-stage tilting of the porelining helices induces cooperative drying and iris-like closing of the channel pore. From the free energy profile of the gating transition and from unrestrained simulations, we conclude that the pore of the isolated GLIC transmembrane domain closes spontaneously. The mechanical work of opening the pore is performed primarily on the M2-M3 loop. Strong interactions of this short and conserved loop with the extracellular domain are therefore crucial to couple ligand binding to channel opening.ELIC | nicotinic acetylcholine receptor | hydrophobic gate | conformational change | string method P entameric ligand-gated ion channels (1) (pLGICs) form a large family of membrane proteins with a central role in biological signal transduction. These channels transmit an external signal-the binding of a ligand-through the opening of their ion-conducting pore. With their important physiological roles, in particular in nerve signaling, pLGICs are major pharmaceutical targets. Accordingly, the gating transition, as an essential element of their function, has been studied extensively. At the structural level, advances came from ∼4-Å resolution electron microscopy structures of the nicotinic acetylcholine receptor (nAChR) (2), followed by a breakthrough based on crystallographic structures of two prokaryotic members of the family, ELIC and GLIC (3-5). The structures of the Erwinia chrysanthemi channel ELIC and the Gloeobacter violaceus channel GLIC, two homologous proteins with ∼18% sequence identity, appear to capture the conformations of the channel in closed and open states, respectively. Here, we use multiscale simulations to connect these two endpoints of the gating transition, providing a molecular pathway of channel gating and offering a window into the function of pLGICs at atomic resolution.Complementary to experimental techniques, molecular dynamics (MD) simulation is a powerful tool to study ion channels (6-10), including the pLGICs nAChR (11-13), ELIC (14), and GLIC (5, 15). Remarkably, in a recent 1-μs MD simulation (15), pore closure could be induced in GLIC after the protonation states of 55 residues were simultaneously changed to mimic a pH jump from ∼4.6 to ∼7. However, even in this very long simulation under a strong driving force, the gating transition appeared to be only partial (15), without reaching a stable closed conformation. Furthermore, to obtain statistical properties such a...

show abstract

Section: Resultsmentioning

confidence: 99%

Pore opening and closing of a pentameric ligand-gated ion channel

Zhu

Hummer

2010

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

148

208

View full text Add to dashboard Cite

show abstract

“…Structures of all of the studied proteins, actin, BPTI, ubiquitin, hyperthermophilic rubredoxin, and RNase A, were downloaded from the Protein Data Bank (PDB) (27). Oligopeptides [Asp-Ser, Asp-Gly-Ser, (Asp) 10 , and (Glu) 10 ] were built from scratch by using amino acid templates and capped with the acetyl and methylamide groups at the N and C termini, respectively. Isolated amino acids (Asp and Glu) were terminated in the same way.…”

Section: Methodsmentioning

confidence: 99%

“…The principal goal of this article is to quantify and rationalize the different affinities of sodium and potassium to protein surfaces by means of molecular dynamics (MD) simulations, quantum chemistry calculations, and conductivity measurements for a series of proteins and protein fragments in aqueous solutions. Our effort, which is aimed at understanding the generic, thermodynamic Na ϩ ͞K ϩ ion specificity at protein surfaces, is thus complementary to recent computational studies of ion selectivity during active transport across the cellular membrane (7)(8)(9)(10).…”

mentioning

confidence: 99%

Quantification and rationalization of the higher affinity of sodium over potassium to protein surfaces

Vrbka

Vondrášek

Jagoda‐Cwiklik

et al. 2006

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

211

246

View full text Add to dashboard Cite

For a series of different proteins, including a structural protein, enzyme, inhibitor, protein marker, and a charge-transfer system, we have quantified the higher affinity of Na ؉ over K ؉ to the protein surface by means of molecular dynamics simulations and conductivity measurements. Both approaches show that sodium binds at least twice as strongly to the protein surface than potassium does with this effect being present in all proteins under study. Different parts of the protein exterior are responsible to a varying degree for the higher surface affinity of sodium, with the charged carboxylic groups of aspartate and glutamate playing the most important role. Therefore, local ion pairing is the key to the surface preference of sodium over potassium, which is further demonstrated and quantified by simulations of glutamate and aspartate in the form of isolated amino acids as well as short oligopeptides. As a matter of fact, the effect is already present at the level of preferential pairing of the smallest carboxylate anions, formate or acetate, with Na ؉ versus K ؉ , as shown by molecular dynamics and ab initio quantum chemical calculations. By quantifying and rationalizing the higher preference of sodium over potassium to protein surfaces, the present study opens a way to molecular understanding of many ion-specific (Hofmeister) phenomena involving protein interactions in salt solutions.ion-protein interaction ͉ molecular dynamics ͉ cell environment ͉ protein function ͉ Hofmeister series S odium and potassium represent the two most abundant monovalent cations in living organisms. Despite the fact that they possess the same charge and differ only in size [Na ϩ having a smaller ionic radius but a larger hydrated radius than K ϩ (1)], sodium versus potassium ion specificity plays a crucial role in many biochemical processes. More than 100 years ago, Hofmeister discovered that Na ϩ destabilizes (''salts out'') hens' egg white protein more efficiently than K ϩ does (2), analogous behavior being later shown also for other proteins (3). In a similar way, sodium was found to be significantly more efficient than potassium, e.g., in enhancing polymerization of rat brain tubulin (4). 23 Na NMR studies also were used to characterize cation-binding sites in proteins (5). The vital biological relevance of the difference between Na ϩ and K ϩ is exemplified by the low intracellular and high extracellular sodium͞potassium ratio maintained in living cells by ion pumps at a considerable energy cost (6). The principal goal of this article is to quantify and rationalize the different affinities of sodium and potassium to protein surfaces by means of molecular dynamics (MD) simulations, quantum chemistry calculations, and conductivity measurements for a series of proteins and protein fragments in aqueous solutions. Our effort, which is aimed at understanding the generic, thermodynamic Na ϩ ͞K ϩ ion specificity at protein surfaces, is thus complementary to recent computational studies of ion selectivity during active transport across ...

show abstract

“…For instance, the program HOLE [163] allows the calculation of the maximal radius of a spherical probe that will fit in the channel at a given depth by means of a Monte Carlo algorithm, and of the ion conductance through the pore. Furthermore, diffusion of ions or other molecules through the channel can be observed directly in the simulations [18,164,165]. By applying PMF methods it is possible to determine the free energy profile for the permeation process.…”

Section: MDmentioning

confidence: 99%

Fluorescence spectroscopy and molecular dynamics simulations in studies on the mechanism of membrane destabilization by antimicrobial peptides

Bocchinfuso

Bobone

Meisina

et al. 2011

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Since their initial discovery, 30 years ago, antimicrobial peptides (AMPs) have been intensely investigated as a possible solution to the increasing problem of drug-resistant bacteria. The interaction of antimicrobial peptides with the cellular membrane of bacteria is the key step of their mechanism of action. Fluorescence spectroscopy can provide several structural details on peptide-membrane systems, such as partition free energy, aggregation state, peptide position and orientation in the bilayer, and the effects of the peptides on the membrane order. However, these "low-resolution" structural data are hardly sufficient to define the structural requirements for the pore formation process. Molecular dynamics simulations, on the other hand, provide atomic-level information on the structure and dynamics of the peptide-membrane system, but they need to be validated experimentally. In this review we summarize the information that can be obtained by both approaches, highlighting their versatility and complementarity, suggesting that their synergistic application could lead to a new level of insight into the mechanism of membrane destabilization by AMPs.

show abstract

Ion Permeation through a Narrow Channel: Using Gramicidin to Ascertain All-Atom Molecular Dynamics Potential of Mean Force Methodology and Biomolecular Force Fields

Cited by 133 publications

References 94 publications

Pore opening and closing of a pentameric ligand-gated ion channel

Pore opening and closing of a pentameric ligand-gated ion channel

Quantification and rationalization of the higher affinity of sodium over potassium to protein surfaces

Fluorescence spectroscopy and molecular dynamics simulations in studies on the mechanism of membrane destabilization by antimicrobial peptides

Contact Info

Product

Resources

About