How Does a Voltage Sensor Interact with a Lipid Bilayer? Simulations of a Potassium Channel Domain

Sands, Zara A.; Sansom, Mark S. P.

doi:10.1016/j.str.2007.01.004

Cited by 94 publications

(111 citation statements)

References 48 publications

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“…Cysteine reactivity measurements first suggested the presence of water vestibules within VSDs (37)(38)(39)(40)(41)(42)(43)(44)(45). X-ray structures (6,20,30) show that bending of S3 away from the VSD core creates deep crevices at the center of the S1-S4 helical bundle that can be penetrated by water.…”

Section: Resultsmentioning

confidence: 99%

The activated state of a sodium channel voltage sensor in a membrane environment

Chakrapani

Sompornpisut

Intharathep

et al. 2010

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

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Direct structural insights on the fundamental mechanisms of permeation, selectivity, and gating remain unavailable for the Na þ and Ca 2þ channel families. Here, we report the spectroscopic structural characterization of the isolated Voltage-Sensor Domain (VSD) of the prokaryotic Na þ channel NaChBac in a lipid bilayer. Site-directed spin-labeling and EPR spectroscopy were carried out for 118 mutants covering all of the VSD. EPR environmental data were used to unambiguously assign the secondary structure elements, define membrane insertion limits, and evaluate the activated conformation of the isolated-VSD in the membrane using restrain-driven molecular dynamics simulations. The overall threedimensional fold of the NaChBac-VSD closely mirrors those seen in KvAP, Kv1.2, Kv1.2-2.1 chimera, and MlotiK1. However, in comparison to the membrane-embedded KvAP-VSD, the structural dynamics of the NaChBac-VSD reveals a much tighter helix packing, with subtle differences in the local environment of the gating charges and their interaction with the rest of the protein. Using cell complementation assays we show that the NaChBac-VSD can provide a conduit to the transport of ions in the resting or "down" conformation, a feature consistent with our EPR water accessibility measurements in the activated or "up" conformation. These results suggest that the overall architecture of VSD's is remarkably conserved among K þ and Na þ channels and that pathways for gating-pore currents may be intrinsic to most voltage-sensors. Cell complementation assays also provide information about the putative location of the gating charges in the "down/resting" state and hence a glimpse of the extent of conformational changes during activation.complementation assays | EPR spectroscopy | gating charges | electrical excitability

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Section: Resultsmentioning

confidence: 99%

The activated state of a sodium channel voltage sensor in a membrane environment

Chakrapani

Sompornpisut

Intharathep

et al. 2010

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

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“…It is thought that the voltage sensor domain move in response to changes in voltage across the membrane bilayer but the exact nature and extent of such motions is still undetermined. It is likely then, that simulations [110][111][112] in combination with experimental data will be able to provide information on the location of the voltage sensor relative to the membrane and a complete structural understanding of the conformational changes during the transition from the closed to the open state in Kv channels.…”

Section: Structural Changes During Ion Channel Gatingmentioning

confidence: 99%

Molecular dynamics simulations of potassium channels

Domene

2007

Open Chemistry

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Despite the complexity of ion-channels, MD simulations based on realistic all-atom models have become a powerful technique for providing accurate descriptions of the structure and dynamics of these systems, complementing and reinforcing experimental work. Successful multidisciplinary collaborations, progress in the experimental determination of three-dimensional structures of membrane proteins together with new algorithms for molecular simulations and the increasing speed and availability of supercomputers, have made possible a considerable progress in this area of biophysics. This review aims at highlighting some of the work in the area of potassium channels and molecular dynamics simulations where numerous fundamental questions about the structure, function, folding and dynamics of these systems remain as yet unresolved challenges.

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“…Furthermore, it has been postulated that the S4 transmembrane helix in the KvAP K ϩ channel, which contains four arginine side chains, moves within the membrane in response to a transmembrane potential (33,34). Molecular dynamics studies (35,36) have shown that arginine insertion into a bilayer is facilitated by a network of hydrogen bonds with the lipid phosphate groups and water molecules. A common feature of these mechanisms is that the lipid bilayer structure can undergo large perturbations in response to interactions with proteins.…”

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confidence: 99%

Molecular dynamics simulations suggest a mechanism for translocation of the HIV-1 TAT peptide across lipid membranes

Herce

Garcı́a

2007

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

397

454

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The recombinant HIV-1 Tat protein contains a small region corresponding to residues 47 YGRKKRRQRR 57 R, which is capable of translocating cargoes of different molecular sizes, such as proteins, DNA, RNA, or drugs, across the cell membrane in an apparently energy-independent manner. The pathway that these peptides follow for entry into the cell has been the subject of strong controversy for the last decade. This peptide is highly basic and hydrophilic. Therefore, a central question that any candidate mechanism has to answer is how this highly hydrophilic peptide is able to cross the hydrophobic barrier imposed by the cell membrane. We propose a mechanism for the spontaneous translocation of the Tat peptides across a lipid membrane. This mechanism involves strong interactions between the Tat peptides and the phosphate groups on both sides of the lipid bilayer, the insertion of charged side chains that nucleate the formation of a transient pore, followed by the translocation of the Tat peptides by diffusing on the pore surface. This mechanism explains how key ingredients, such as the cooperativity among the peptides, the large positive charge, and specifically the arginine amino acids, contribute to the uptake. The proposed mechanism also illustrates the importance of membrane fluctuations. Indeed, mechanisms that involve large fluctuations of the membrane structure, such as transient pores and the insertion of charged amino acid side chains, may be common and perhaps central to the functions of many membrane protein functions.cell-penetrating peptide ͉ antimicrobial peptide ͉ drug delivery ͉ membrane proteins ͉ pore formation T he HIV-1 Tat protein indicated that some proteins might have short sequence segments responsible for their translocation across cell membranes in a seemingly energy-independent manner (1-8). The sequence responsible for the cellular uptake of the HIV-1 Tat corresponds to residues 47 YGRKKRRQRR 57 R. This peptide is called the Tat peptide, and it has been categorized as a member of a family of peptides called cell-penetrating peptides. These peptides consist of short sequences (10-30 aa) that are highly basic and enter the cells in a seemingly energy-independent manner (1). This property makes them extraordinarily good candidates as transporters for drug delivery (7, 9-11). Therefore, significant effort is currently being invested to understand this phenomenon at a fundamental molecular level, as well as to employ these peptides as drug carriers (2,(12)(13)(14)(15)(16).Much debate exists around what makes it possible for these peptides to translocate across biological membranes. A diverse set of experiments indicates that there may be more than one mechanism contributing to the uptake of these peptides (1-7, 11, 17-20). Among those mechanisms is the possibility that these peptides may be able to spontaneously translocate across the cell membrane, as suggested by several experiments that indicate a nonendocytotic or energy-independent pathway for the uptake. Because these peptides are highly ...

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How Does a Voltage Sensor Interact with a Lipid Bilayer? Simulations of a Potassium Channel Domain

Cited by 94 publications

References 48 publications

The activated state of a sodium channel voltage sensor in a membrane environment

The activated state of a sodium channel voltage sensor in a membrane environment

Molecular dynamics simulations of potassium channels

Molecular dynamics simulations suggest a mechanism for translocation of the HIV-1 TAT peptide across lipid membranes

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