FATSLiM: a fast and robust software to analyze MD simulations of membranes

Buchoux, Sébastien

doi:10.1093/bioinformatics/btw563

Cited by 170 publications

(179 citation statements)

References 9 publications

Supporting

Mentioning

177

Contrasting

Order By: Relevance

“…Area per lipid (APL) for each membrane, separated by intracellular and extracellular leaflet, were calculated using the program FATSLiM 85 , and used as an indicator of equilibration of the lipid systems (Extended Data Fig. 9a).…”

Section: Methodsmentioning

confidence: 99%

Connexin-46/50 in a dynamic lipid environment resolved by CryoEM at 1.9 Å

Flores

Haddad

Dolan

et al. 2020

Preprint

View full text Add to dashboard Cite

32Gap junctions establish direct pathways for connected cells and tissues to transfer metabolic and 33 electrical messages 1 . The local lipid environment is known to affect the structure, stability and 34 intercellular channel activity of gap junctions 2-5 ; however, the molecular basis for these effects 35 remains unknown. To gain insight toward how gap junctions interact with their local membrane 36 environment, we used lipid nanodisc technology to incorporate native connexin-46/50 (Cx46/50) 37 intercellular channels into a dual lipid membrane system, closely mimicking a native cell-to-cell 38 junction. Structural characterization of Cx46/50 lipid-embedded channels by single particle 39 CryoEM revealed a lipid-induced stabilization to the channel, resulting in a 3D reconstruction at 40 1.9 Å resolution. Together with all-atom molecular dynamics (MD) simulations and 3D 41 heterogeneity analysis of the ensemble CryoEM data, it is shown that Cx46/50 in turn imparts 42 long-range stabilization to the dynamic local lipid environment that is specific to the extracellular 43 lipid leaflet of the two opposed membranes. In addition, nearly 400 water molecules are resolved 44 in the CryoEM map, localized throughout the intercellular permeation pathway and contributing to 45 the channel architecture. These results illustrate how the aqueous-lipid environment is integrated 46 with the architectural stability, structure and function of gap junction communication channels, 47 and demonstrates the ability of CryoEM to effectively characterize dynamical protein-lipid 48 interactions. 49 50 Main 51The connexins are a family of transmembrane proteins (21 isoforms in human) that form 52 intercellular channels for cell-to-cell communication 6 . These intercellular channels establish a 53 ~1.4 nm pore that couples the cytoplasms of neighboring cells, and enable direct passage of 54 electrical and small molecule signals (such as, ions, second messengers, hormones and 55 metabolites) 7 and therapeutic agents 8 . 10's -1000's of connexin channels may assemble 56 together to form large hexagonally packed arrays, a.k.a. plaques, known as gap junctions. In this 57 way, gap junctions enable the near instantaneous response of electrical synapses in the brain 58 and heart, and contribute to the long-range signaling and metabolic coupling of most tissues. 59Because of these fundamental roles, aberrant gap junctional coupling is associated with a variety 60 of human diseases, including blindness, deafness, skin disorders, arrhythmia, stroke and 61 cancers 9-11 . 63Gap junction intercellular communication is facilitated by a unique macromolecular architecture, 64where intercellular channels directly couple the plasma membranes of two neighboring cells. The 65 3 lipid bilayers of opposing cells are separated by a characteristic gap of ~3.5 nm 12 , a feature for 66 which these structures were first recognized in electron micrographs of cell sections 5,13 . 67Furthermore, large-scale gap junctional plaque formation is dependent upon a dense mosa...

show abstract

Section: Methodsmentioning

confidence: 99%

Connexin-46/50 in a dynamic lipid environment resolved by CryoEM at 1.9 Å

Flores

Haddad

Dolan

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The vesicle properties were determined using the last 500 ns of simulation time. The bilayer thickness was interpreted using the radial distribution function of the selected phosphate groups in the inner and outer leaflets of the OMV with respect to the center of mass of vesicle, and the area per lipid was estimated by calculating Voronoi cells for each of these isolated lipid phosphate groups . Vesicle radii were estimated using an in‐house script by calculating the distance between the center of mass of the OM and the vesicle center .…”

Section: Methodsmentioning

confidence: 99%

CHARMM‐GUI Martini Maker for modeling and simulation of complex bacterial membranes with lipopolysaccharides

et al. 2017

View full text Add to dashboard Cite

A complex cell envelope, composed of a mixture of lipid types including complex lipopolysaccharides, protects bacteria from the external environment. Clearly, the proteins embedded within the various components of the cell envelope have an intricate relationship with their local environment. Therefore, to obtain meaningful results, molecular simulations need to mimic as far as possible this chemically heterogeneous system. However, setting up such systems for computational studies is far from trivial, and consequently the vast majority of simulations of outer membrane proteins still rely on oversimplified phospholipid membrane models. This work presents an update of CHARMM-GUI Martini Maker for coarse-grained modeling and simulation of complex bacterial membranes with lipopolysaccharides. The qualities of the outer membrane systems generated by Martini Maker are validated by simulating them in bilayer, vesicle, nanodisc, and micelle environments (with and without outer membrane proteins) using the Martini force field. We expect this new feature in Martini Maker to be a useful tool for modeling large, complicated bacterial outer membrane systems in a user-friendly manner.

show abstract

“…The obtained trajectories were analyzed using the built-in analysis tools of GROMACS version 2018.2 [56]. The deuterium order parameters of the acyl chains, density of the membrane environment, area per lipid head group, and bilayer thickness were analyzed using GROMACS utility tools and FATSLiM [58] to ensure optimal quality control of the protein-membrane…”

Section: Trajectory Analysismentioning

confidence: 99%

Molecular dynamics of C99-bound γ-secretase reveal two binding modes with distinct compactness, stability, and active-site retention: implications for Aβ production

Dehury

Tang

Kepp

2019

Biochemical Journal

View full text Add to dashboard Cite

The membrane protease γ-secretase cleaves the C99 fragment of the amyloid precursor protein, thus producing the Aβ peptides central to Alzheimer's disease. Cryo-electron microscopy has provided the topology but misses the membrane and loop parts that contribute to substrate binding. We report here an essentially complete atomic model of C99 within wild-type γ-secretase that respects all the experimental constraints and additionally describes loop, helix, and C99 substrate dynamics in a realistic all-atom membrane. Our model represents the matured auto-cleaved state required for catalysis. From two independent 500-ns molecular dynamic simulations, we identify two conformation states of C99 in equilibrium, a compact and a loose state. Our simulations provide a basis for C99 processing and Aβ formation and explain the production of longer and shorter Aβ, as the compact state retains C99 for longer and thus probably trims to shorter Aβ peptides. We expect pathogenic presenilin mutations to stabilize the loose over the compact state. The simulations detail the role of the Lys53–Lys54–Lys55 anchor for C99 binding, a loss of helicity of bound C99, and positioning of Thr48 and Leu49 leading to alternative trimming pathways on opposite sides of the C99 helix in three amino acid steps. The C99 binding topology resembles that of C83-bound γ-secretase without membrane but lacks a presenilin 1-C99 β-sheet, which could be induced by C83's stronger binding. The loose state should be selectively disfavored by γ-secretase modulators to increase C99 trimming and reduce the formation of longer Aβ, a strategy that is currently much explored but has lacked a structural basis.

show abstract

FATSLiM: a fast and robust software to analyze MD simulations of membranes

Cited by 170 publications

References 9 publications

Connexin-46/50 in a dynamic lipid environment resolved by CryoEM at 1.9 Å

Connexin-46/50 in a dynamic lipid environment resolved by CryoEM at 1.9 Å

CHARMM‐GUI Martini Maker for modeling and simulation of complex bacterial membranes with lipopolysaccharides

Molecular dynamics of C99-bound γ-secretase reveal two binding modes with distinct compactness, stability, and active-site retention: implications for Aβ production

Contact Info

Product

Resources

About