Multiscale Simulations of Biological Membranes: The Challenge To Understand Biological Phenomena in a Living Substance

Enkavi, Giray; Javanainen, Matti; Kulig, Waldemar; Róg, Tomasz; Vattulainen, Ilpo

doi:10.1021/acs.chemrev.8b00538

Cited by 233 publications

(237 citation statements)

References 1,602 publications

(2,906 reference statements)

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“…Further, the lipid compositions of the inner and outer leaflets of membranes can be quite different. Most computational and experimental studies consider simple membrane models composed of only one or at best a few lipid types (18). To examine whether such simple models capture the HIV-1 fusion process, we performed simulations with the HIV-1 vesicle and the apposed cell membrane both composed of POPC (80%) and POPS (20%) CG lipids, tethered by 4 gp41 trimers ( Fig.…”

Section: Viral and Cell Lipidomes Promote Membrane Fusionmentioning

confidence: 99%

Concerted interactions between multiple gp41 trimers and the target cell lipidome may be required for HIV-1 entry

Gorai

Sahoo

Srivastava

et al. 2020

Preprint

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The HIV-1 envelope glycoprotein gp41 mediates the fusion between viral and host cell membranes leading to virus entry and target cell infection. Despite years of research, important aspects of this process such as the number of gp41 trimers involved and how they orchestrate the rearrangement of the lipids in the apposed membranes along the fusion pathway remain obscure. To elucidate these molecular underpinnings, we performed coarse-grained molecular dynamics simulations of HIV-1 virions pinned to the CD4 T cell membrane by different numbers of gp41 trimers. We built realistic cell and viral membranes by mimicking their respective lipid compositions. We found that a single gp41 was inadequate for mediating fusion. Lipid mixing between membranes, indicating the onset of fusion, was efficient when 3 or more gp41 trimers pinned the membranes. The gp41 trimers interacted strongly with many different lipids in the host cell membrane, triggering lipid configurational rearrangements, exchange, and mixing. Simpler membranes, comprising fewer lipid types, displayed strong resistance to fusion, revealing the crucial role of the lipidomes in HIV-1 entry. Performing simulations at different temperatures, we estimated the free energy barrier to lipid mixing, and hence membrane stalk formation, with 4 tethering gp41 trimers to be ∼6.2 kcal/mol, a >4-fold reduction over estimates without gp41. Together, these findings present molecular-level, quantitative insights into the early stages of gp41-mediated HIV-1 entry. Preventing the requisite gp41 molecules from tethering the membranes or altering membrane lipid compositions may be potential intervention strategies. SIGNIFICANCEInteractions between viral envelope proteins and host cell surface receptors leading to HIV-1 entry are well studied, however the role of membrane lipids remains obscure, although entry hinges on lipid mixing and the fusion of viral and cell membranes. We performed detailed simulations of HIV-1 and target cell membranes tethered by viral gp41 trimeric proteins to elucidate the proteo-lipidic contributions to viral entry. We found that the cooperative effects of multiple gp41 trimers and natural lipidomes of the membranes facilitate membrane fusion. The functional domains of gp41 altered local lipid concentrations, reduced membrane repulsions, and facilitated inter-membrane lipid mixing. These molecular-level insights offer a glimpse of the cryptic mechanisms underlying HIV-1 entry and suggest new interventions to combat HIV-1 infection.

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Section: Viral and Cell Lipidomes Promote Membrane Fusionmentioning

confidence: 99%

Concerted interactions between multiple gp41 trimers and the target cell lipidome may be required for HIV-1 entry

Gorai

Sahoo

Srivastava

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…6). There is also an increasing understanding of the complexity of lipid membranes, the diversity of such complexity, and the impact this lipid complexity has on membrane function, particularly on protein-lipid interactions (7)(8)(9).…”

mentioning

confidence: 99%

Defining how multiple lipid species interact with inward rectifier potassium (Kir2) channels

Duncan

Corey

Sansom

2020

Proc. Natl. Acad. Sci. U.S.A.

118

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Protein–lipid interactions are a key element of the function of many integral membrane proteins. These potential interactions should be considered alongside the complexity and diversity of membrane lipid composition. Inward rectifier potassium channel (Kir) Kir2.2 has multiple interactions with plasma membrane lipids: Phosphatidylinositol (4, 5)-bisphosphate (PIP2) activates the channel; a secondary anionic lipid site has been identified, which augments the activation by PIP2; and cholesterol inhibits the channel. Molecular dynamics simulations are used to characterize in molecular detail the protein–lipid interactions of Kir2.2 in a model of the complex plasma membrane. Kir2.2 has been simulated with multiple, functionally important lipid species. From our simulations we show that PIP2interacts most tightly at the crystallographic interaction sites, outcompeting other lipid species at this site. Phosphatidylserine (PS) interacts at the previously identified secondary anionic lipid interaction site, in a PIP2concentration-dependent manner. There is interplay between these anionic lipids: PS interactions are diminished when PIP2is not present in the membrane, underlining the need to consider multiple lipid species when investigating protein–lipid interactions.

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“…In order to provide atomistic insight into the mechanism of membrane permeation and disruption, however, accurate models of the microbial cell membrane and cell wall are essential. Computational models of realistic cell membranes have been recently extensively reviewed, [ 149 ] and a web‐based interface for the construction of lipopolysaccharides found in Gram‐negative bacterial cell walls has been developed. [ 150 ] This can aid in the modeling of bacterial membranes even for inexperienced users.…”

Section: Molecular Modeling To Enhance Antimicrobial Nanomaterials Devmentioning

confidence: 99%

Antimicrobial Metal Nanomaterials: From Passive to Stimuli‐Activated Applications

et al. 2020

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The development of antimicrobial drug resistance among pathogenic bacteria and fungi is one of the most significant health issues of the 21st century. Recently, advances in nanotechnology have led to the development of nanomaterials, particularly metals that exhibit antimicrobial properties. These metal nanomaterials have emerged as promising alternatives to traditional antimicrobial therapies. In this review, a broad overview of metal nanomaterials, their synthesis, properties, and interactions with pathogenic micro‐organisms is first provided. Secondly, the range of nanomaterials that demonstrate passive antimicrobial properties are outlined and in‐depth analysis and comparison of stimuli‐responsive antimicrobial nanomaterials are provided, which represent the next generation of microbiocidal nanomaterials. The stimulus applied to activate such nanomaterials includes light (including photocatalytic and photothermal) and magnetic fields, which can induce magnetic hyperthermia and kinetically driven magnetic activation. Broadly, this review aims to summarize the currently available research and provide future scope for the development of metal nanomaterial‐based antimicrobial technologies, particularly those that can be activated through externally applied stimuli.

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Multiscale Simulations of Biological Membranes: The Challenge To Understand Biological Phenomena in a Living Substance

Cited by 233 publications

References 1,602 publications

Concerted interactions between multiple gp41 trimers and the target cell lipidome may be required for HIV-1 entry

Concerted interactions between multiple gp41 trimers and the target cell lipidome may be required for HIV-1 entry

Defining how multiple lipid species interact with inward rectifier potassium (Kir2) channels

Antimicrobial Metal Nanomaterials: From Passive to Stimuli‐Activated Applications

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