Structural Properties of Inverted Hexagonal Phase: A Hybrid Computational and Experimental Approach

Ramezanpour, Mohsen; Schmidt, Miranda L.; Bashe, B.Y.M.; Pruim, Jason R.; Link, M. L.; Cullis, Pieter R.; Harper, Paul E.; Thewalt, Jenifer; Tieleman, D. Peter

doi:10.1021/acs.langmuir.0c00600

Cited by 12 publications

(17 citation statements)

References 69 publications

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“…(C) Snapshots of the atomistic POPC system in the H II phase, as previously published. 8 Segmentation analysis reveals previously unnoticed connections between the initial four channels at the end of the simulation. The width of a segment in the graph indicates its relative size.…”

Section: Resultsmentioning

confidence: 99%

“…Related work was performed on an atomistic scale by Ramezanpour et al., in which they did not describe any of such channels. 8 After contacting the group and presenting this paradox to them, we were kindly allowed access to their data. We used MDVoxelSegmentation to find any possible unexpected and undescribed connective channels.…”

Section: Resultsmentioning

confidence: 99%

“… 2 − 7 The number of molecular aggregates in simulations has also increased, and nowadays it is not rare to see a mixture of micelles, bilayers, and vesicles in a single simulation. 4 , 8 − 11 This increase in complexity of both composition and aggregation state requires a higher level of abstraction in analysis than typically offered. During analysis, we would like to work with concepts such as bilayers, vesicles, leaflets, protein aggregates, phases, etc.…”

Section: Introductionmentioning

confidence: 99%

“…This is well illustrated in the field of biological applications. Such simulations changed from a single protein in vacuum in the late 1970s to complex membrane-based systems containing millions of molecules such as (phospho)lipids, cholesterol, proteins, DNA, drugs, water, etc. − The number of molecular aggregates in simulations has also increased, and nowadays it is not rare to see a mixture of micelles, bilayers, and vesicles in a single simulation. ,− This increase in complexity of both composition and aggregation state requires a higher level of abstraction in analysis than typically offered. During analysis, we would like to work with concepts such as bilayers, vesicles, leaflets, protein aggregates, phases, etc.…”

Section: Introductionmentioning

confidence: 99%

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Sequential Voxel-Based Leaflet Segmentation of Complex Lipid Morphologies

Thie

Souza

Wassenaar

et al. 2021

J. Chem. Theory Comput.

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As molecular dynamics simulations increase in complexity, new analysis tools are necessary to facilitate interpreting the results. Lipids, for instance, are known to form many complicated morphologies, because of their amphipathic nature, becoming more intricate as the particle count increases. A few lipids might form a micelle, where aggregation of tens of thousands could lead to vesicle formation. Millions of lipids comprise a cell and its organelle membranes, and are involved in processes such as neurotransmission and transfection. To study such phenomena, it is useful to have analysis tools that understand what is meant by emerging entities such as micelles and vesicles. Studying such systems at the particle level only becomes extremely tedious, counterintuitive, and computationally expensive. To address this issue, we developed a method to track all the individual lipid leaflets, allowing for easy and quick detection of topological changes at the mesoscale. By using a voxel-based approach and focusing on locality, we forego costly geometrical operations without losing important details and chronologically identify the lipid segments using the Jaccard index. Thus, we achieve a consistent sequential segmentation on a wide variety of (lipid) systems, including monolayers, bilayers, vesicles, inverted hexagonal phases, up to the membranes of a full mitochondrion. It also discriminates between adhesion and fusion of leaflets. We show that our method produces consistent results without the need for prefitting parameters, and segmentation of millions of particles can be achieved on a desktop machine.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sequential Voxel-Based Leaflet Segmentation of Complex Lipid Morphologies

Thie

Souza

Wassenaar

et al. 2021

J. Chem. Theory Comput.

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“…36 It has been experimentally proven that a lamellar-tohexagonal phase transition occurs following the change of CHSa into CHS. 27,33,34 Although it is not practically feasible to investigate the whole process of this phase transition using allatom MD simulations, large-scale simulations of lipid systems already in the hexagonal phase have been carried out for DOPE, POPE, 37 and galactolipids, 38 and using coarse-grained simulations, the phase transition of DOPE lipids from lamellar to hexagonal has been modeled; 39 it is however not possible to investigate the effect of PEGylation on this transition as current coarse-grained models of PEG fail to reproduce the relevant properties of PEG. In this study, using all-atom MD simulations, our focus is to elucidate the effect of charged and neutral forms of CHMS on the properties of DOPE lipid bilayers with and without PEGylation.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Insight into How PEGylation Reduces the Efficacy of pH-Sensitive Liposomes from Molecular Dynamics Simulations

et al. 2021

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Liposome-based drug delivery systems composed of DOPE stabilized with cholesteryl hemisuccinate (CHMS) have been proposed as a drug delivery mechanism with pH-triggered release as the anionic form (CHSa) is protonated (CHS) at reduced pH; PEGylation is known to decrease this pH sensitivity. In this manuscript, we set out to use molecular dynamics (MD) simulations with a model with all-atom resolution to provide insight into why incorporation of poly(ethyleneglycol) (PEG) into DOPE–CHMS liposomes reduces their pH sensitivity; we also address two additional questions: (1) How CHSa stabilizes DOPE bilayers into a lamellar conformation at a physiological pH of 7.4? and (2) how the change from CHSa to CHS at acidic pH triggers the destabilization of DOPE bilayers? We found that (A) CHSa stabilizes the DOPE lipid membrane by increasing the hydrophilicity of the bilayer surface, (B) when CHSa changes to CHS by pH reduction, DOPE bilayers are destabilized due to a reduction in bilayer hydrophilicity and a reduction in the area per lipid, and (C) PEG stabilizes DOPE bilayers into the lamellar phase, thus reducing the pH sensitivity of the liposomes by increasing the area per lipid through penetration into the bilayer, which is our main focus.

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