Probing a Continuous Polar Defect: A Reaction Coordinate for Pore Formation in Lipid Membranes

Hub, Jochen S.; Awasthi, Neha

doi:10.1021/acs.jctc.7b00106

Cited by 61 publications

(204 citation statements)

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“…The fact that our systematic and unbiased search highlighted this RC, corroborates its mechanistic relevance and utility in continuum modeling. Our RC φ NP is also similar to the slab occupancy metric [14] referred to above. Both RCs essentially measure the gap between the penetrating hydrophilic material, but for different groups of atoms, which turned out to be an important distinction.…”

Section: Discussionmentioning

confidence: 75%

“…Among the headgroup RCs (and among all RCs tested), rz NP 4 (φ NP ), which essentially measures the gap between two penetrating lipid headgroups, provided the best description of the commitor RC. Interestingly, none of the combinations of φ NP and CVs involving larger numbers (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) of atoms, which measure larger collective motion, substantially outperformed φ NP alone. This result suggests that barrier crossing is more localized than one might have expected.…”

Section: Discussionmentioning

confidence: 99%

“…Several previous simulation studies of poration have proposed and employed one or a few possible RCs, considering specific atom groups and CVs in isolation. These approaches include restraining a single lipid headgroup relative to the bilayer midplane [17,21,22,49,50], biasing hydrophilic atoms to occupy a stack of cylindrical slabs spanning the membrane [14], biasing water to occupy a cylindrical column [51], and growing a lateral depletion of lipid centers of mass [52].…”

Section: Discussionmentioning

confidence: 99%

“…When all system coordinates are projected onto the z-axis, thermal fluctuations can create non-local projection artefacts, giving the false appearance of membrane penetration. These include "hanging droplets" (described in [14]), where two laterally distant indentations partially penetrate the bilayer, and low-wavenumber thermal undulations [25]. To avoid these effects, we preselected the 100 atoms closest to y 0 prior to projection and sorting.…”

Section: Collective Variables To Describe Pore Formationmentioning

confidence: 99%

“…Pore nucleation is key to transmembrane transport [1], ion permeation [2,3], antimicrobial peptide function [4,5], and bilayer equilibration [6,7] and is the essential step of synaptic transmission [8][9][10]. Despite the evidence for small, metastable aqueous pores from conductivity [11] and tension [12] experiments, as well as molecular simu-lations [13][14][15], the atomistic details, driving forces, and kinetics of their formation and closure are not entirely understood [16,17].…”

Section: Introductionmentioning

confidence: 99%

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Sequential water and headgroup merger: Membrane poration paths and energetics from MD simulations

Bubnis

Grubmüller

2020

Preprint

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Membrane topology changes such as poration, stalk formation, and hemi-fusion rupture are essential to cellular function, but their molecular details, energetics, and kinetics are still not fully understood. Here we present a unified energetic and mechanistic picture of metastable pore defects in tensionless lipid membranes. We used an exhaustive committor analysis to test and select optimal reaction coordinates and also to determine the nucleation mechanism. These reaction coordinates were used to calculate free energy landscapes that capture the full process and end states. The identified barriers agree with the committor analysis. To enable sufficient sampling of the complete transition path for our atomistic simulations, we developed a novel "gizmo" potential biasing scheme. The simulations suggest that the essential step in the nucleation is the initial merger of lipid headgroups at the nascent pore center. To facilitate this event, an indentation pathway is energetically preferred to a hydrophobic defect. Continuous water columns that span the indentation were determined to be on-path transients that precede the nucleation barrier. This study gives a quantitative description of the nucleation mechanism and energetics of small metastable pores and illustrates a systematic approach to uncover the mechanisms of diverse cellular membrane remodeling processes. STATEMENT OF SIGNIFICANCEThe primary steps and nucleation of lipid membrane pore formation are key to membrane fusion, viral infection, and vesicular cellular transport. Despite decades experimental and theoretical studies, the underlying mechanisms are still not fully understood at the atomic level. Using a committor-based reaction coordinate and atomistic simulations, we report new structural and energetics insight into the full poration process. We find that the pore nucleates via an elastic indentation rather than by forming a hydrophobic defect. Subsequently, water pierces the thinned slab as a prerequisite for the following axial merger of the first lipid headgroups from opposite monolayers, which precedes and best characterizes the transition state. We also identify a metastable prepore basin, thereby explaining previous indirect experimental evidence.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Collective Variables To Describe Pore Formationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sequential water and headgroup merger: Membrane poration paths and energetics from MD simulations

Bubnis

Grubmüller

2020

Preprint

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Cardiolipin prevents pore formation in phosphatidylglycerol bacterial membrane models

et al. 2021

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Several antimicrobial peptides, including magainin and the human cathelicidin LL‐37, act by forming pores in bacterial membranes. Bacteria such as Staphylococcus aureus modify their membrane's cardiolipin composition to resist such types of perturbations that compromise their membrane stability. Here, we used molecular dynamic simulations to quantify the role of cardiolipin on the formation of pores in simple bacterial‐like membrane models composed of phosphatidylglycerol and cardiolipin mixtures. Cardiolipin modified the structure and ordering of the lipid bilayer, making it less susceptible to mechanical changes. Accordingly, the free‐energy barrier for the formation of a transmembrane pore and its kinetic instability augmented by increasing the cardiolipin concentration. This is attributed to the unfavorable positioning of cardiolipin near the formed pore, due to its small polar head and bulky hydrophobic body. Overall, our study demonstrates how cardiolipin prevents membrane‐pore formation and this constitutes a plausible mechanism used by bacteria to act against stress perturbations and, thereby, gain resistance to antimicrobial agents.

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How arginine derivatives alter the stability of lipid membranes: dissecting the roles of side chains, backbone and termini

et al. 2021

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Arginine (R)-rich peptides constitute the most relevant class of cell-penetrating peptides and other membrane-active peptides that can translocate across the cell membrane or generate defects in lipid bilayers such as water-filled pores. The mode of action of R-rich peptides remains a topic of controversy, mainly because a quantitative and energetic understanding of arginine effects on membrane stability is lacking. Here, we explore the ability of several oligo-arginines R$$_n$$ n and of an arginine side chain mimic R$$_\mathrm {Side}$$ Side to induce pore formation in lipid bilayers employing MD simulations, free-energy calculations, breakthrough force spectroscopy and leakage assays. Our experiments reveal that R$$_\mathrm {Side}$$ Side but not R$$_n$$ n reduces the line tension of a membrane with anionic lipids. While R$$_n$$ n peptides form a layer on top of a partly negatively charged lipid bilayer, R$$_\mathrm {Side}$$ Side leads to its disintegration. Complementary, our simulations show R$$_\mathrm {Side}$$ Side causes membrane thinning and area per lipid increase beside lowering the pore nucleation free energy. Model polyarginine R$$_8$$ 8 similarly promoted pore formation in simulations, but without overall bilayer destabilization. We conclude that while the guanidine moiety is intrinsically membrane-disruptive, poly-arginines favor pore formation in negatively charged membranes via a different mechanism. Pore formation by R-rich peptides seems to be counteracted by lipids with PC headgroups. We found that long R$$_n$$ n and R$$_\mathrm {Side}$$ Side but not short R$$_n$$ n reduce the free energy of nucleating a pore. In short R$$_n$$ n , the substantial effect of the charged termini prevent their membrane activity, rationalizing why only longer $$\mathrm {R}_{n}$$ R n are membrane-active.

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Probing a Continuous Polar Defect: A Reaction Coordinate for Pore Formation in Lipid Membranes

Cited by 61 publications

References 58 publications

Sequential water and headgroup merger: Membrane poration paths and energetics from MD simulations

Sequential water and headgroup merger: Membrane poration paths and energetics from MD simulations

Cardiolipin prevents pore formation in phosphatidylglycerol bacterial membrane models

How arginine derivatives alter the stability of lipid membranes: dissecting the roles of side chains, backbone and termini

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