Amphotericin B assembles into seven-molecule ion channels: An NMR and molecular dynamics study

Umegawa, Yuichi; Yamamoto, Tomoya; Dixit, Manasvi; Funahashi, Kosuke; Seo, Sangjae; Nakagawa, Yasuo; Suzuki, Tsuneyuki; Matsuoka, Shigeru; Tsuchikawa, Hiroshi; Hanashima, Shinya; Oishi, Tohru; Matsumori, Nobuaki; Shinoda, Wataru; Murata, Michio

doi:10.1126/sciadv.abo2658

Cited by 31 publications

(16 citation statements)

References 86 publications

(117 reference statements)

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“…Although the encountering of end groups can be observed with a certain fraction, it is not sufficient to determine if the encountered end groups form a stable physical junction or cluster. To assess the stability of clusters, potentials of mean force (PMFs) are commonly employed. ,,− Hence, we performed calculations of the PMFs between the terminal groups employing the following equation W ( r ) = prefix− k normalB T log ( g false( r false) ) where k B denotes the Boltzmann constant in kJ mol –1 /K, T represents the system’s temperature, and g ( r ) corresponds to the RDF between the terminal groups. Figure illustrates the PMFs between the two terminal groups, displayed as a function of the distance.…”

Section: Resultsmentioning

confidence: 99%

Role of Terminal Groups of cis-1,4-Polyisoprene Chains in the Formation of Physical Junction Points in Natural Rubber

Dixit

Taniguchi

2023

Biomacromolecules

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The terminal structures of cis-1,4-polyisoprene (PI) chains play a vital role in the excellent comprehensive performance of Hevea natural rubber (NR) with properties such as high toughness, tear-resistance, and wet skid resistance. The cis-1,4polyisoprene chain constituting NR exhibits a distinct composition of terminal groups comprising two distinct types, namely, the ω and α terminal groups. The structures of the ω terminal [dimethyl allyl (DMA)-(trans-1,4-isoprene) 2 ] and six kinds of α end groups of the polymer chain of NR have been explored by utilizing a newly developed 2D NMR method. In the present work, we examine different kinds of PI melt systems, and we choose various combinations of terminal groups: Hydrogen, one DMA unit with two trans isoprene units as ω end groups and ester-terminated isopentene (α1), hydroxy-terminated isopentene (α2), ester-terminated isobutane (α3), hydroxy-terminated isobutane (α4), esterterminated 1,4-cis-isoprene (α5), and hydroxy-terminated 1,4-cis-isoprene (α6), i.e., H PI H (PI 0 )−pure PI (Hydrogen terminal), ω PI α1 (PI I ), ω PI α2 (PI II ), ω PI α3 (PI III ), ω PI α4 (PI IV ), ω PI α5 (PI V ), and ω PI α6 (PI VI ). We evaluated dynamic and static properties of PI chains such as the end-to-end vector autocorrelation function (C(t)), its average relaxation time (τ), end-to-end distance (R ee ), and radius of gyration (R g ). We also estimated the diffusion coefficients of polyisoprene chains and pair correlation functions [radial distribution functions (RDFs)], potentials of mean force (PMFs) in between end residues, and survival probability (P(τ)) of end groups around the end group by analyzing the equilibrated trajectories of full-atom MD simulations. As per the examination of C(t), rotational relaxation time τ, and RDFs, we discovered that the existence of a strong hydrogen bond in α2−α2, α4−α4, and α6−α6 residues makes the dynamics of hydroxy-terminated polyisoprene chains in ω PI α2,α4,α6 melt systems slower. From the analyses of RDFs and PMFs (W(r)), the association between [α2]−[α2], [α4]−[α4], and [α6]−[α6] terminals in ω PI α2,α4,α6 melt systems is significantly stronger than in [ISO]−[ISO] [Hydrogen terminated 1,4-cis-isoprene:(ISO)] in H PI H and ω−ω, [α1]−[α1], [α3]−[α3], and [α5]− [α5] in ω PI α1,α3,α5 systems. We quantified the fraction of cluster formation of terminal groups of a given size in the seven PI melt systems by employing the criteria of PMFs. It is revealed that no stable cluster exists in the H PI H , ω PI α1 , ω PI α3 , and ω PI α5 melt systems. Conversely, in the ω PI α2 , ω PI α4 , and ω PI α6 systems, we perceived stable clusters of [(α2) p ] [(α4) p ] and [(α6) p ] end groups where p (2 ≤ x ≤ 6). These stable clusters validate the presence of physical junction points in between hydroxy-terminated polyisoprene chains through their α2, α4, and α6 terminals. These physical junction points might be crucial for superior properties of NR such as high toughness, crack growth resistance, and strain-induced crystallization.

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Section: Resultsmentioning

confidence: 99%

Role of Terminal Groups of cis-1,4-Polyisoprene Chains in the Formation of Physical Junction Points in Natural Rubber

Dixit

Taniguchi

2023

Biomacromolecules

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“…In particular, antifungal polyene macrolide antibiotics, such as amphotericin B (AmB) and nystatin, are introduced from one side of the sterol-enriched membrane, forming asymmetric pores. The most widely accepted polyene channel model implies the formation of polyene–sterol complexes that are associated with a barrel-type structure [ 59 ], but their lengths are not long enough to penetrate the entire bilayer [ 60 , 61 , 62 ]. The induction of local positive curvature stress decreases the cost of pore formation by polyenes and increases their pore-forming activity.…”

Section: Resultsmentioning

confidence: 99%

Chromone-Containing Allylmorpholines Influence Ion Channels in Lipid Membranes via Dipole Potential and Packing Stress

Efimova

Martynyuk

Zakharova

et al. 2022

IJMS

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Herein, we report that chromone-containing allylmorpholines can affect ion channels formed by pore-forming antibiotics in model lipid membranes, which correlates with their ability to influence membrane boundary potential and lipid-packing stress. At 100 µg/mL, allylmorpholines 1, 6, 7, and 8 decrease the boundary potential of the bilayers composed of palmitoyloleoylphosphocholine (POPC) by about 100 mV. At the same time, the compounds do not affect the zeta-potential of POPC liposomes, but reduce the membrane dipole potential by 80–120 mV. The allylmorpholine-induced drop in the dipole potential produce 10–30% enhancement in the conductance of gramicidin A channels. Chromone-containing allylmorpholines also affect the thermotropic behavior of dipalmytoylphosphocholine (DPPC), abolishing the pretransition, lowering melting cooperativity, and turning the main phase transition peak into a multicomponent profile. Compounds 4, 6, 7, and 8 are able to decrease DPPC’s melting temperature by about 0.5–1.9 °C. Moreover, derivative 7 is shown to increase the temperature of transition of palmitoyloleoylphosphoethanolamine from lamellar to inverted hexagonal phase. The effects on lipid-phase transitions are attributed to the changes in the spontaneous curvature stress. Alterations in lipid packing induced by allylmorpholines are believed to potentiate the pore-forming ability of amphotericin B and gramicidin A by several times.

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“…Magic-angle spinning (MAS) was employed to enhance the spectral resolution by reducing the chemical shift anisotropy and magnetic dipolar interactions. Although the MAS technique has often been used to separate multiple 13 C NMR signals of membrane-bound peptides and antibiotics, its application for detecting 1 H signals is limited mainly due to the high dipolar interaction of 1 H nuclei. In this aspect, the choline group is suitable for 1 H NMR experiments because of its high mobility and low dipolar interaction with the surrounding 1 H nuclei.…”

Section: Introductionmentioning

confidence: 99%

Passive Translocation of Phospholipids in Asymmetric Model Membranes: Solid-State ¹H NMR Characterization of Flip–Flop Kinetics Using Deuterated Sphingomyelin and Phosphatidylcholine

Watanabe,

Hanashima,

Yano

et al. 2023

Langmuir

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Although lateral and inter-leaflet lipid–lipid interactions in cell membranes play roles in maintaining asymmetric lipid bilayers, the molecular basis of these interactions is largely unknown. Here, we established a method to determine the distribution ratio of phospholipids between the outer and inner leaflets of asymmetric large unilamellar vesicles (aLUVs). The trimethylammonium group, (CH3)3 N +, in the choline headgroup of N-palmitoyl-sphingomyelin (PSM) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) gave rise to a relatively sharp signal in magic-angle spinning solid-state 1H NMR (MAS-ss-1H NMR). PSM and DOPC have the same headgroup structure, but one phospholipid was selectively observed by deuterating the trimethylammonium group of the other phospholipid. The addition of Pr3+ to the medium surrounding aLUVs selectively shifted the chemical shift of the (CH3)3 N + group in the outer leaflet from that in the inner leaflet, which allowed estimation of the inter-leaflet distribution ratio of the unlabeled lipid in aLUVs. Using this method, we evaluated the translocation of PSM and DOPC between the outer and inner leaflets of the cholesterol-containing aLUVs, with PSM and DOPC mostly distributed in the outer and inner leaflets, respectively, immediately after aLUV preparation; their flip and flop rates were approximately 2.7 and 6.4 × 10–6 s–1, respectively. During the passive symmetrization of aLUVs, the lipid translocation rate was decreased due to changes in the membrane order, probably through the formation of the registered liquid-ordered domains. Comparison of the result with that of symmetric LUVs revealed that lipid asymmetry may not significantly affect the lipid translocation rates, while the lateral lipid–lipid interaction may be a dominant factor in lipid translocation under these conditions. These findings highlight the importance of considering the effects of lateral lipid interactions within the same leaflet on lipid flip–flop rates when evaluating the asymmetry of phospholipids in the cell membrane.

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Amphotericin B assembles into seven-molecule ion channels: An NMR and molecular dynamics study

Cited by 31 publications

References 86 publications

Role of Terminal Groups of cis-1,4-Polyisoprene Chains in the Formation of Physical Junction Points in Natural Rubber

Role of Terminal Groups of cis-1,4-Polyisoprene Chains in the Formation of Physical Junction Points in Natural Rubber

Chromone-Containing Allylmorpholines Influence Ion Channels in Lipid Membranes via Dipole Potential and Packing Stress

Passive Translocation of Phospholipids in Asymmetric Model Membranes: Solid-State ¹H NMR Characterization of Flip–Flop Kinetics Using Deuterated Sphingomyelin and Phosphatidylcholine

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Amphotericin B assembles into seven-molecule ion channels: An NMR and molecular dynamics study

Cited by 31 publications

References 86 publications

Role of Terminal Groups of cis-1,4-Polyisoprene Chains in the Formation of Physical Junction Points in Natural Rubber

Role of Terminal Groups of cis-1,4-Polyisoprene Chains in the Formation of Physical Junction Points in Natural Rubber

Chromone-Containing Allylmorpholines Influence Ion Channels in Lipid Membranes via Dipole Potential and Packing Stress

Passive Translocation of Phospholipids in Asymmetric Model Membranes: Solid-State 1H NMR Characterization of Flip–Flop Kinetics Using Deuterated Sphingomyelin and Phosphatidylcholine

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Product

Resources

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Passive Translocation of Phospholipids in Asymmetric Model Membranes: Solid-State ¹H NMR Characterization of Flip–Flop Kinetics Using Deuterated Sphingomyelin and Phosphatidylcholine