Fluid Phase Coexistence in Biological Membrane: Insights from Local Nonaffine Deformation of Lipids

Iyer, Sahithya S.; Tripathy, Madhusmita; Srivastava, Anand

doi:10.1016/j.bpj.2018.05.021

Cited by 19 publications

(39 citation statements)

References 92 publications

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“…Efficient lipid diffusion is a requirement for equilibrating domains or detecting protein-induced lipid sorting. Coarse-grained MD (CG-MD) has been used to great success in a number of simulations for both lipid-protein binding and membrane organization (103)(104)(105)(106)(107)(108) . Here we use CG-MD as a "computational microscope" to observe the equilibrium distribution of lipids local to the nAChR in a range of binary and ternary lipid mixtures inspired by native membranes.…”

Section: Introductionmentioning

confidence: 99%

Boundary lipids of the nicotinic acetylcholine receptor: Spontaneous partitioning via coarse-grained molecular dynamics simulation

Sharp¹,

Salari²,

Brannigan³

2019

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Reconstituted nicotinic acetylcholine receptors (nAChRs) exhibit significant gain-of-function upon addition of cholesterol to reconstitution mixtures, and cholesterol affects organization of nAChRs within domain-forming membranes, but whether nAChR partitions to cholesterol-rich liquid-ordered ("raft" or l o ) domains or cholesterol-poor liquiddisordered (l do ) domains is unknown. We use coarse-grained molecular dynamics simulations to observe spontaneous interactions of cholesterol, saturated lipids, and polyunsaturated (PUFA) lipids with nAChRs. In binary Dipalmitoylphosphatidylcholine:Cholesterol (DPPC:CHOL) mixtures, both CHOL and DPPC acyl chains were observed spontaneously entering deep "non-annular" cavities in the nAChR TMD, particularly at the subunit interface and the β subunit center, facilitated by the low amino acid density in the cryo-EM structure of nAChR in a native membrane. Cholesterol was highly enriched in the annulus around the TMD, but this effect extended over (at most) 5-10Å. In domain-forming ternary mixtures containing PUFAs, the presence of a single receptor did not significantly affect the likelihood of domain formation. nAChR partitioned to any cholesterol-poor l do domain that was present, regardless of whether the l do or l o domain lipids had PC or PE headgroups. Enrichment of PUFAs among boundary lipids was positively correlated with their propensity for demixing from cholesterol-rich phases. Long n − 3 chains (tested here with Docosahexaenoic Acid, DHA) were highly enriched in annular and non-annular embedded sites, partially displacing cholesterol and completely displacing DPPC, and occupying sites even deeper within the bundle. Shorter n − 6 chains were far less effective at displacing cholesterol from non-annular sites.

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Section: Introductionmentioning

confidence: 99%

Boundary lipids of the nicotinic acetylcholine receptor: Spontaneous partitioning via coarse-grained molecular dynamics simulation

Sharp¹,

Salari²,

Brannigan³

2019

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…7(D) show the L o and L d phases identified based on a cut-off on thickness and φ 6 respectively. While φ 6 is a good marker to distinguish between gel-fluid co-existing phases, we find that it is a poor marker to distinguish liquid-liquid co-existing phases [50]. The boundary marked in black in Fig.…”

Section: Choice Of Order Parameter and Boundary Profilesmentioning

confidence: 73%

“…Besides these commonly used markers, we also use the degree of non-affine displacements (χ 2 ) [49] to distinguish between the different phases in the lipid bilayer systems. We recently showed that χ 2 works as a high-fidelity marker between the liquid order (L o ) and liquid disordered (L d ) regions in the membrane system at molecular length scales [31,50,51]. χ 2 was originally applied on granular material by Falk and Langer ( [49]) and is given as:…”

Section: Order Parameters Used As Domain Boundary Classifiersmentioning

confidence: 99%

Interpretation of Phase Boundary Fluctuation Spectra in Biological Membranes with Nanoscale Organization

Iyer

Negi

Srivastava

2019

Preprint

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In this work, we use Support Vector Machine algorithm to detect simple and complex interfaces in atomistic and coarse-grained molecular simulation trajectories of phase separating lipid bilayer systems. We show that the power spectral density of the interfacial height fluctuations and in turn the line tension of the lipid bilayer systems depend on the order parameter used to identify the intrinsic interface. To highlight the effect of artificial smoothing of the interface on the fluctuation spectra and the ensuing line tension calculations, we perform a convolution of the boundaries identified at molecular resolution with a 2D Gaussian function of variance ε 2 equal to the resolution limit, (1/2πε 2 )exp(−|r| 2 /2ε 2 ).The convolution function is given by h⊗g, where h is the instantaneous height fluctuation and g is the Gaussian function. This is similar to the effect of point spread functions in experiments. We find that the region of fluctuation spectra that scales according to capillary wave theory formalism depends on the complexity of the interfacial geometry, which may not always be detected at experimental resolutions. We propose that the different q-regimes in the fluctuation spectra can be used to characterize mode dependent interfacial tensions to understand the interfaces beyond the linear line tension calculations.This could also be useful in interpretation of fluctuating boundaries in out-of-equilibrium in-vivo membrane systems that carry information about the nature of non-thermal (active) fluctuations in these systems.

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“…We then calculate the interaction energies between lipids as a function of a newly defined order parameter (χ 2 ) that utilizes the information on topological changes and displacements of neighbouring lipids to locally characterize the extent of order/disorder in the membrane without any knowledge of the chemical identity of the lipids. 74,75 Formulations and schematic related to measurement of non-affine (χ 2 ) value ( Figure S1a) and details of calculations of interaction energy ( Figure S1b) is discussed in the supporting information (SI). The χ 2 values of the three phase separated systems shows a bimodal distribution and is able to capture the ordered and disordered phases without the knowledge of chemical identity of the lipids ( Figure S2 and S3).…”

mentioning

confidence: 99%

“…This characterization was first used as a measure of shear stress propagation in metallic glasses to study irreversible plastic deformations 76 and have been extensively applied recently on soft matter systems 77-79 and on biological systems. 74,75,80,81 Figure S5 shows the calculated interaction energies for each lipid as a function of its χ 2 values for the three systems of interest. We observe that degree of positive correlation between lipid-lipid interaction energies and χ 2 values gradually decreases from DPPC/DOPC/CHOL to PSM/DOPC/CHOL and PSM/POPC/CHOL.…”

mentioning

confidence: 99%

Intrinsic Disorder and Degeneracy in Molecular Scale Organization of Biological Membrane

Iyer

Srivastava

2019

Preprint

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The scale-rich spatiotemporal organization in biological membrane dictates the "molecular encounter" and in turn the larger scale biological processes such as molecular transport, trafficking and cellular signalling. In this work, we explore the degeneracy in lateral organization in lipid bilayer systems from the perspective of energy landscape theory. Our analysis on molecular trajectories show that bilayers with lipids having in-vivo characteristics have a highly frustrated energy landscape as opposed to a funnel-like energy landscape in in-vitro systems. Lattice evolution simulations, with Hamiltonian trained from atomistic trajectories using lipids topology and non-affine displacement measures to characterize the extent of order-disorder in the bilayer, show that the inherent frustration in in-vivo like systems renders them with the ability to access a wide range of nanoscale patterns with equivalent energy penalty. We posit that this structural degeneracy could provide for a larger repository to functionally important molecular organization in in-vivo settings.1 From the emerging field of lipidomics research, it is now known that there are more that 37,500 unique lipid species in Eukaryotic and Prokaryotic cells. The plasma membrane itself has more than 500 different molecular species of lipids. 1-5 One of the fundamental questions in the field is "Why are there so many lipids" ? 6,7 From being considered simply as a "selectively permeable barrier" made up of lipid bilayer, 8-10 it is now well established that lipids in biological membrane have a wide range of functional roles. 11-15 Lipid environments modulate innumerable biological processes 16-27 and in certain cases, specific lipids are critical for a given biological function. For example, protein p24 in COPI machinery recognizes a single sphingolipid species to induce oligomerization and vesicle transport in the ER. 28 Another example in which lipids play a crucial role is that of the very rare highly phosphatidylinositol lipid which drive activation of K+ channels 29,30 besides several other biological functions by specific interactions. 31,32 In all the examples discussed above, lipid interactions range from being extremely non-selective to highly discriminating 33-35 and such a range of interaction is possibly facilitated by their large diversity and chemical complexity. Though the rationale behind diversity in lipid structures in biological membranes is appreciated from the examples related to the folding, dynamics and functions of membrane proteins 36-40 and other molecular-scale processes such as drug binding, 41 and lipid defects driven selective peptide partitioning, 42,43 the evolutionary advantage of such a huge variety and complexity in lipid species is yet to be fully understood especially in the light of the high metabolic expense of lipid synthesis and the cost of maintaining the required lipid homeostasis in the cellular membranes. With the advent of super-resolution imaging techniques, there is now compelling evidence proving that lipid...

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Fluid Phase Coexistence in Biological Membrane: Insights from Local Nonaffine Deformation of Lipids

Cited by 19 publications

References 92 publications

Boundary lipids of the nicotinic acetylcholine receptor: Spontaneous partitioning via coarse-grained molecular dynamics simulation

Boundary lipids of the nicotinic acetylcholine receptor: Spontaneous partitioning via coarse-grained molecular dynamics simulation

Interpretation of Phase Boundary Fluctuation Spectra in Biological Membranes with Nanoscale Organization

Intrinsic Disorder and Degeneracy in Molecular Scale Organization of Biological Membrane

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