Determination of bending rigidity and tilt modulus of lipid membranes from real-space fluctuation analysis of molecular dynamics simulations

Doktorova, Milka; Harries, Daniel; Khelashvili, George

doi:10.1039/c7cp01921a

Cited by 114 publications

(158 citation statements)

References 73 publications

(100 reference statements)

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“…[54]). The similarity of TOCL's compressibility to that of a DOPG membrane (233 ± 19 mN/m) is particularly interesting because TOCL's bending rigidity modulus was found to be twice that of DOPG [18]. (Note that chemically, TOCL resembles 2 DOPG lipids with linked headgroups).…”

Section: Resultsmentioning

confidence: 94%

“…The following lipid names are abbreviated as shown in the parenthesis: 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC, di12:0), Table S1, some of the bilayers were taken from Ref. [18]. All remaining bilayers were constructed with CHARMM-GUI [36][37][38] and simulated with NAMD [39] using the CHARMM36 force field [40,41].…”

Section: Simulations and Analysismentioning

confidence: 99%

“…Various methods exist for measuring " both in vitro and in silico [16][17][18], but the equally important compressibility modulus $ is less well studied. It quantifies the response of membrane area to tension, which under physiological conditions may arise from various perturbations, such as changes in osmolarity across the membrane or the addition of lipids or other molecules to only one of the membrane's leaflets.…”

Section: Introductionmentioning

confidence: 99%

“…Like the existing methods, we take advantage of thermal fluctuations, but express the compressibility modulus as a function of leaflet thickness instead of bilayer area. Following our recent success in calculating each leaflet's bending rigidity from real-space analysis of local splay fluctuations [18], we base our method for $ estimation on sampling the leaflet thickness locally, and estimate the corresponding probability distribution and potential of mean force (PMF) profile as a function of changes in thickness. Finally, the $ is extracted from a quadratic fit of a small region of the PMF around the global minimum, according to the elastic energy of stretching (see Methods).…”

Section: Introductionmentioning

confidence: 99%

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A new computational method for membrane compressibility: Bilayer mechanical thickness revisited

Doktorova

Levine

Khelashvili

et al. 2018

Preprint

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Because lipid bilayers can bend and stretch in ways similar to thin elastic sheets, physical models of bilayer deformation have utilized mechanical constants such as the moduli for bending rigidity ( " ) and area compressibility ( $ ). However, the use of these models to quantify the energetics of membrane deformation associated with protein-membrane interactions and the membrane response to stress is often hampered by the shortage of experimental data suitable for the estimation of the mechanical constants of various lipid mixtures. While computational tools such as Molecular Dynamics (MD) simulations can provide alternative means to estimate $ values, current approaches suffer significant technical limitations. Here, we present a novel computational framework that allows for a direct estimation of $ values for individual bilayer leaflets. The theory is based on the concept of elasticity and derives $ from real-space analysis of local thickness fluctuations sampled in MD simulations. We explore and validate the model on a large set of single and multicomponent bilayers of different lipid composition and sizes, simulated at different temperatures. The calculated bilayer compressibility moduli agree with values estimated previously from experiments and those obtained from a standard computational method based on a series of constrained tension simulations. We further validate our framework in a comparison with an existing polymer brush model (PBM) and confirm the PBM's predicted linear relationship with proportionality coefficient of 24 using elastic parameters calculated from the simulation trajectories. The robustness of the results that emerge from the new method allows us to revisit the origins of the bilayer mechanical (compressible) thickness and in particular, its dependence on acyl chain unsaturation and the presence of cholesterol.All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Section: Resultsmentioning

confidence: 94%

Section: Simulations and Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A new computational method for membrane compressibility: Bilayer mechanical thickness revisited

Doktorova

Levine

Khelashvili

et al. 2018

Preprint

Self Cite

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“…S7). The strongest correlation was with the bending energy: "## exhibits an approximately linear dependence on the bending modulus # determined from molecular simulations (11).…”

Section: Statement Of Significancementioning

confidence: 93%

On the mechanism of bilayer separation by extrusion; or, why your large unilamellar vesicles are not really unilamellar

Scott

Skinkle

Kelley

et al. 2019

Preprint

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Extrusion through porous filters is a widely used method for preparing biomimetic model membranes. Of primary importance in this approach is the efficient production of single bilayer (unilamellar) vesicles that eliminate the influence of interlamellar interactions and strictly define the bilayer surface area available to external reagents such as proteins. Sub-microscopic vesicles produced using extrusion are widely assumed to be unilamellar, and large deviations from this assumption would dramatically impact interpretations from many model membrane experiments. Using three probe-free methods—small-angle X-ray and neutron scattering (SAXS and SANS) and cryogenic electron microscopy (cryoEM)—we report unambiguous evidence of extensive multilamellarity in extruded vesicles composed of neutral phosphatidylcholine lipids, including for the common case of neutral lipids dispersed in physiological buffer and extruded through 100 nm diameter pores. In such preparations, only ~35% of lipids are externally accessible, and this fraction is highly dependent on preparation conditions. Charged lipids promote unilamellarity, as does decreasing solvent ionic strength, indicating the importance of electrostatic interactions in determining the lamellarity of extruded vesicles. Smaller extrusion pore sizes also robustly increase the fraction of unilamellar vesicles, suggesting a role for membrane bending. Taken together, these observations suggest a mechanistic model for extrusion, wherein formation of unilamellar vesicles involves competition between bilayer bending and adhesion energies. The findings presented here have wide-ranging implications for the design and interpretation of model membrane studies, especially ensemble-averaged observations relying on the assumption of unilamellarity.STATEMENT OF SIGNIFICANCEExtruded vesicles are a ubiquitous tool in membrane research. It is widely presumed that extrusion produces unilamellar (i.e., single bilayer) vesicles, an assumption that is often crucial for data analysis and interpretation. Using X-ray and neutron scattering and cryogenic electron microscopy, we show that a substantial amount of lipid remains inaccessible after extrusion due to an abundance of multilamellar vesicles (MLVs). While this is a general phenomenon for neutral lipids, MLV contamination can be reduced by several complementary approaches such as including charged lipids in the mixture, reducing the ionic strength of the aqueous medium, and reducing the extrusion pore size. These observations together suggest a mechanism by which extrusion strips MLVs of their layers.

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Requirement of Cholesterol for Calcium‐Dependent Vesicle Fusion by Strengthening Synaptotagmin‐1‐Induced Membrane Bending

et al. 2023

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Cholesterol is essential for neuronal activity and function. Cholesterol depletion in the plasma membrane impairs synaptic transmission. However, the molecular mechanisms by which cholesterol deficiency leads to defects in vesicle fusion remain poorly understood. Here, it is shown that cholesterol is required for Ca2+‐dependent native vesicle fusion using the in vitro reconstitution of fusion and amperometry to monitor exocytosis in chromaffin cells. Purified native vesicles are crucial for the reconstitution of physiological Ca2+‐dependent fusion, because vesicle‐mimicking liposomes fail to reproduce the cholesterol effect. Intriguingly, cholesterol has no effect on the membrane binding of synaptotagmin‐1, a Ca2+ sensor for ultrafast fusion. Cholesterol strengthens local membrane deformation and bending induced by synaptotagmin‐1, thereby lowering the energy barrier for Ca2+‐dependent fusion to occur. The data provide evidence that cholesterol depletion abolishes Ca2+‐dependent vesicle fusion by disrupting synaptotagmin‐1‐induced membrane bending, and suggests that cholesterol is an essential lipid regulator for Ca2+‐dependent fusion.

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Determination of bending rigidity and tilt modulus of lipid membranes from real-space fluctuation analysis of molecular dynamics simulations

Cited by 114 publications

References 73 publications

A new computational method for membrane compressibility: Bilayer mechanical thickness revisited

A new computational method for membrane compressibility: Bilayer mechanical thickness revisited

On the mechanism of bilayer separation by extrusion; or, why your large unilamellar vesicles are not really unilamellar

Requirement of Cholesterol for Calcium‐Dependent Vesicle Fusion by Strengthening Synaptotagmin‐1‐Induced Membrane Bending

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