Assessing the Extent of Structural and Dynamic Modulation of Membrane Lipids due to Pore Forming Toxins: Insights from Molecular Dynamics Simulations

Varadarajan, Vadhana; Desikan, Rajat; Ayappa, K. G.

doi:10.1101/2020.01.13.905463

Cited by 4 publications

(10 citation statements)

References 71 publications

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“…The membrane thickness 43 is computed using the 'Membplugin' 1.1 tool 73 in VMD and visualized using MATLAB. Similar to a previous study 74 , lipid tilt angles from MARTINI membranes ( vs.…”

Section: Analysis and Visualizationsupporting

confidence: 77%

Evaluating Coarse-Grained MARTINI Force-Fields for Capturing the Ripple Phase of Lipid Membranes

Sharma

Desikan

Ayappa

2020

Preprint

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Phospholipids, which are an integral component of cell membranes, exhibit a rich variety of lamellar phases modulated by temperature and composition. Molecular dynamics (MD) simulations have greatly enhanced our understanding of phospholipid membranes by capturing experimentally observed phases and phase transitions at molecular resolution. However, the ripple (Pβ′) membrane phase, observed as an intermediate phase below the main gel-to-liquid crystalline transition with some lipids, has been challenging to capture with MD simulations, both at all-atom and coarse-grained resolution. Here, we systematically assess the ability of five coarse-grained MARTINI 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid force-field (FF) variants, parametrized to reproduce the DPPC gel and fluid phases, for their ability to capture the Pβ′ phase. Upon cooling from the fluid phase to below the phase transition temperature with smaller (380-lipid) and larger (> 2200-lipid) MARTINI and all-atom (CHARMM36 FF) DPPC lipid bilayers, we observed that smaller bilayers with both all-atom and MARTINI FFs sampled interdigitated Pβ′ and ripple-like states, respectively. However, while all-atom simulations of the larger DPPC membranes exhibited the formation of the Pβ′ phase, similar to previous studies, MARTINI membranes did not sample interdigitated ripple-like states at larger system sizes. We then demonstrated that the ripple-like states in smaller MARTINI membranes were kinetically-trapped structures caused by finite size effects rather than being representative of true Pβ′ phases. We showed that even a MARTINI FF variant that could capture the tilted Lβ′ gel phase, a prerequisite for stabilizing the Pβ′ phase, could not capture the rippled phase upon cooling. Our study reveals that the current MARTINI FFs may require specific re-parametrization of the interaction potentials to stabilize lipid interdigitation, a characteristic of the ripple phase.

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Section: Analysis and Visualizationsupporting

confidence: 77%

Evaluating Coarse-Grained MARTINI Force-Fields for Capturing the Ripple Phase of Lipid Membranes

Sharma

Desikan

Ayappa

2020

Preprint

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“…This therefore increases and decreases respectively, the underlying lipid fluidity in DMPC and DOPC membranes. In addition recent MD simulations ( Varadarajan et al, 2020 ) of the dodecameric ClyA pore complex in a pure DMPC bilayer indicates the localized extent of a small hydrophobic mismatch induced by ClyA. The hydrophobic mismatch is expected to be greater for the longer tailed DOPC bilayers.…”

Section: Lipid Reorganisation and Dynamics During Pft Interaction: Llo And Clyamentioning

confidence: 96%

“…In addition to static structural characterization involving the density variations, and lipid order parameters, several dynamical quantities such as the MSD ( Eq. 1 ), time correlation and scattering functions can be obtained from the particle trajectories ( Varadarajan et al, 2020 ) as illustrated in Figure 4B . The transition of the dynamics from sub-diffusive to diffusive regimes ( Javanainen et al, 2013 ) can also be evaluated provided the simulations have been carried out for sufficiently long times (>1 µs).…”

Section: Biomembrane Dynamicsmentioning

confidence: 99%

“…At the molecular level, molecular dynamics (MD) simulations have provided several novel insights into local structure and dynamic reorganization that occurs during pore formation ( Cheerla and Ayappa, 2020 ; Desikan et al, 2020 ; Varadarajan et al, 2020 ). MD simulations of PFT pore assemblies are computationally challenging due to the large extracellular regions.…”

Section: Introductionmentioning

confidence: 99%

“…MD simulations of PFT pore assemblies are computationally challenging due to the large extracellular regions. Simulations at different levels of coarse graining that reduce the degrees of freedom and hence the computational overhead have been carried out in our laboratory ( Desikan et al, 2017 ; Sathyanarayana et al, 2017 ; Sathyanarayana et al, 2018 ; Cheerla and Ayappa, 2020 ; Desikan et al, 2020 ; Varadarajan et al, 2020 ) to shed light on the molecular mechanisms of pore formation and assembly. MD simulation methodologies that include all atom simulations with explicit solvent, coarse grained MARTINI models as well as structure based models to study PFTs have been recently reviewed by Desikan et al (2021) .…”

Section: Introductionmentioning

confidence: 99%

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Pore Forming Protein Induced Biomembrane Reorganization and Dynamics: A Focused Review

Ponmalar

Sarangi

Basu

et al. 2021

Front. Mol. Biosci.

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Pore forming proteins are a broad class of pathogenic proteins secreted by organisms as virulence factors due to their ability to form pores on the target cell membrane. Bacterial pore forming toxins (PFTs) belong to a subclass of pore forming proteins widely implicated in bacterial infections. Although the action of PFTs on target cells have been widely investigated, the underlying membrane response of lipids during membrane binding and pore formation has received less attention. With the advent of superresolution microscopy as well as the ability to carry out molecular dynamics (MD) simulations of the large protein membrane assemblies, novel microscopic insights on the pore forming mechanism have emerged over the last decade. In this review, we focus primarily on results collated in our laboratory which probe dynamic lipid reorganization induced in the plasma membrane during various stages of pore formation by two archetypal bacterial PFTs, cytolysin A (ClyA), an α-toxin and listeriolysin O (LLO), a β-toxin. The extent of lipid perturbation is dependent on both the secondary structure of the membrane inserted motifs of pore complex as well as the topological variations of the pore complex. Using confocal and superresolution stimulated emission depletion (STED) fluorescence correlation spectroscopy (FCS) and MD simulations, lipid diffusion, cholesterol reorganization and deviations from Brownian diffusion are correlated with the oligomeric state of the membrane bound protein as well as the underlying membrane composition. Deviations from free diffusion are typically observed at length scales below ∼130 nm to reveal the presence of local dynamical heterogeneities that emerge at the nanoscale—driven in part by preferential protein binding to cholesterol and domains present in the lipid membrane. Interrogating the lipid dynamics at the nanoscale allows us further differentiate between binding and pore formation of β- and α-PFTs to specific domains in the membrane. The molecular insights gained from the intricate coupling that occurs between proteins and membrane lipids and receptors during pore formation are expected to improve our understanding of the virulent action of PFTs.

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Membrane binding of pore-forming γ-hemolysin components studied at different lipid compositions

Tarenzi¹,

Lattanzi²,

Potestio³

2022

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Assessing the Extent of Structural and Dynamic Modulation of Membrane Lipids due to Pore Forming Toxins: Insights from Molecular Dynamics Simulations

Cited by 4 publications

References 71 publications

Evaluating Coarse-Grained MARTINI Force-Fields for Capturing the Ripple Phase of Lipid Membranes

Evaluating Coarse-Grained MARTINI Force-Fields for Capturing the Ripple Phase of Lipid Membranes

Pore Forming Protein Induced Biomembrane Reorganization and Dynamics: A Focused Review

Membrane binding of pore-forming γ-hemolysin components studied at different lipid compositions

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