The Role of Cholesterol in M2 Clustering and Viral Budding Explained.

The influenza A M2 homotetrameric channel consists of four transmembrane (TM) and four amphipathic helices (AHs). This viral proton channel is suggested to form clusters in the catenoid budding neck areas in raft-like domains of the plasma membrane, resulting in cell membrane scission and viral release. The channel clustering environment is rich in cholesterol.

Recent Advances in Modeling Membrane β-Barrel Proteins Using Molecular Dynamics Simulations: From Their Lipid Environments to Their Assemblies.

Spurred by advances in AI-driven modeling and experimental methods, molecular dynamics simulations are now acting as a platform to integrate these different approaches. This combination of methods is especially useful to understand β-barrel proteins from the molecular level, e.g.

Do Naturalistic Developmental Behavioral Interventions improve family quality of life? A systematic review and meta-analysis.

Naturalistic Developmental Behavioral Interventions have been described as culturally responsive and family-friendly interventions, with research demonstrating improvements in children's development following the receipt of these interventions. Given the child-directed nature of Naturalistic Developmental Behavioral Interventions and the intervention's integration within families' daily routines, many studies have examined the impact of Naturalistic Developmental Behavioral Interventions on family and family member quality of life. We conducted a systematic review and meta-analysis to explore the relationship between Naturalistic Developmental Behavioral Interventions and family quality of life.

LipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins.

Cryo-electron microscopy (cryo-EM) enables the determination of membrane protein structures in native-like environments. Characterising how membrane proteins interact with the surrounding membrane lipid environment is assisted by resolution of lipid-like densities visible in cryo-EM maps. Nevertheless, establishing the molecular identity of putative lipid and/or detergent densities remains challenging.

Physiological and regenerative functions of sterile-α motif protein-14 in hematopoiesis.

Sterile α-motif domain-14 (Samd14) protein expression increases the regenerative capacity of the erythroid system. Samd14 is transcriptionally upregulated and promotes cell signaling via the receptor tyrosine kinase Kit in a critical window of acute erythroid regeneration. We generated a hematopoietic-specific conditional Samd14 knockout mouse model (Samd14-CKO) to study the role of Samd14 in hematopoiesis.

Direct determination of oligomeric organization of integral membrane proteins and lipids from intact customizable bilayer.

Hierarchical organization of integral membrane proteins (IMP) and lipids at the membrane is essential for regulating myriad downstream signaling. A quantitative understanding of these processes requires both detections of oligomeric organization of IMPs and lipids directly from intact membranes and determination of key membrane components and properties that regulate them. Addressing this, we have developed a platform that enables native mass spectrometry (nMS) analysis of IMP-lipid complexes directly from intact and customizable lipid membranes.

Mesoscale simulations: An indispensable approach to understand biomembranes.

Computer simulation techniques form a versatile tool, a computational microscope, for exploring biological processes. This tool has been particularly effective in exploring different features of biological membranes. In recent years, thanks to elegant multiscale simulation schemes, some fundamental limitations of investigations by distinct simulation techniques have been resolved.

Cardiolipin, and not monolysocardiolipin, preferentially binds to the interface of complexes III and IV.

The mitochondrial electron transport chain comprises a series of protein complexes embedded in the inner mitochondrial membrane that generate a proton motive force oxidative phosphorylation, ultimately generating ATP. These protein complexes can oligomerize to form larger structures called supercomplexes. Cardiolipin (CL), a conical lipid, unique within eukaryotes to the inner mitochondrial membrane, has proven essential in maintaining the stability and function of supercomplexes.

The guidance and adhesion protein FLRT2 dimerizes in cis via dual small-X-small transmembrane motifs.

Fibronectin Leucine-rich Repeat Transmembrane (FLRT 1-3) proteins are a family of broadly expressed single-spanning transmembrane receptors that play key roles in development. Their extracellular domains mediate homotypic cell-cell adhesion and heterotypic protein interactions with other receptors to regulate cell adhesion and guidance. These in trans FLRT interactions determine the formation of signaling complexes of varying complexity and function.

What have molecular simulations contributed to understanding of Gram-negative bacterial cell envelopes?

Bacterial cell envelopes are compositionally complex and crowded and while highly dynamic in some areas, their molecular motion is very limited, to the point of being almost static in others. Therefore, it is no real surprise that studying them at high resolution across a range of temporal and spatial scales requires a number of different techniques. Details at atomistic to molecular scales for up to tens of microseconds are now within range for molecular dynamics simulations.

PyLipID: A Python Package for Analysis of Protein-Lipid Interactions from Molecular Dynamics Simulations.

Lipids play important modulatory and structural roles for membrane proteins. Molecular dynamics simulations are frequently used to provide insights into the nature of these protein-lipid interactions. Systematic comparative analysis requires tools that provide algorithms for objective assessment of such interactions.

Identification and assessment of cardiolipin interactions with inner membrane proteins.

Integral membrane proteins are localized and/or regulated by lipids present in the surrounding bilayer. While bacteria have relatively simple membranes, there is ample evidence that many bacterial proteins bind to specific lipids, especially the anionic lipid cardiolipin. Here, we apply molecular dynamics simulations to assess lipid binding to 42 different inner membrane proteins.

Modulation of adenosine A2a receptor oligomerization by receptor activation and PIP interactions.

GPCRs have been shown to form oligomers, which generate distinctive signaling outcomes. However, the structural nature of the oligomerization process remains uncertain. We have characterized oligomeric configurations of the adenosine A2a receptor (A2aR) by combining large-scale molecular dynamics simulations with Markov state models.

Splenectomy in Jamaican children with sickle cell disease: Outcome of selective blood transfusion.

We reviewed the post-operative morbidity and mortality of open splenectomy undertaken in conjunction with selective blood transfusion in Jamaican children with sickle cell disease. Data were collected on 150 splenectomies performed between November 1994 and October 2017. Selective blood transfusion involved raising haemoglobin levels to approximately 100 g/L in patients with admission haemoglobin ≥10 g/L below steady state.

Origin and diversification of the cardiolipin biosynthetic pathway in the Eukarya domain.

Cardiolipin (CL) and its precursor phosphatidylglycerol (PG) are important anionic phospholipids widely distributed throughout all domains of life. They have key roles in several cellular processes by shaping membranes and modulating the activity of the proteins inserted into those membranes. They are synthesized by two main pathways, the so-called eukaryotic pathway, exclusively found in mitochondria, and the prokaryotic pathway, present in most bacteria and archaea.

Monolysocardiolipin (MLCL) interactions with mitochondrial membrane proteins.

Monolysocardiolipin (MLCL) is a three-tailed variant of cardiolipin (CL), the signature lipid of mitochondria. MLCL is not normally found in healthy tissue but accumulates in mitochondria of people with Barth syndrome (BTHS), with an overall increase in the MLCL:CL ratio. The reason for MLCL accumulation remains to be fully understood.

Computational Investigation of Voltage-Gated Sodium Channel β3 Subunit Dynamics.

Voltage-gated sodium (Na ) channels form the basis for the initiation of the action potential in excitable cells by allowing sodium ions to pass through the cell membrane. The Na channel α subunit is known to function both with and without associated β subunits. There is increasing evidence that these β subunits have multiple roles that include not only influencing the voltage-dependent gating but also the ability to alter the spatial distribution of the pore-forming α subunit.

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

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.

More Favorable Palmitic Acid Over Palmitoleic Acid Modification of Wnt3 Ensures Its Localization and Activity in Plasma Membrane Domains.

While the lateral organization of plasma membrane components has been shown to control binding of Wnt ligands to their receptors preferentially in the ordered membrane domains, the role of posttranslational lipid modification of Wnt on this selective binding is unknown. Here, we identify that the canonical Wnt is presumably acylated by palmitic acid, a saturated 16-carbon fatty acid, at a conserved serine residue. Acylation of Wnt3 is dispensable for its secretion and binding to Fz8 while it is essential for Wnt3's proper binding and domain-like diffusion in the ordered membrane domains.

Lipid-Dependent Regulation of Ion Channels and G Protein-Coupled Receptors: Insights from Structures and Simulations.

Ion channels and G protein-coupled receptors (GPCRs) are regulated by lipids in their membrane environment. Structural studies combined with biophysical and molecular simulation investigations reveal interaction sites for specific lipids on membrane protein structures. For K channels, PIP plays a key role in regulating Kv and Kir channels.

How nanoscale protein interactions determine the mesoscale dynamic organisation of bacterial outer membrane proteins.

The spatiotemporal organisation of membranes is often characterised by the formation of large protein clusters. In Escherichia coli, outer membrane protein (OMP) clustering leads to OMP islands, the formation of which underpins OMP turnover and drives organisation across the cell envelope. Modelling how OMP islands form in order to understand their origin and outer membrane behaviour has been confounded by the inherent difficulties of simulating large numbers of OMPs over meaningful timescales.

Interactions of the EphA2 Kinase Domain with PIPs in Membranes: Implications for Receptor Function.

EphA2 is a member of the receptor tyrosine kinase family. Interactions of the cytoplasmic region of EphA2 with the cell membrane are functionally important and yet remain incompletely characterized. Molecular dynamics simulations combined with biochemical studies reveal the interactions of the transmembrane, juxtamembrane (JM), and kinase domains with the membrane.

Cardiolipin dynamics and binding to conserved residues in the mitochondrial ADP/ATP carrier.

Cardiolipin in eukaryotes is found in the mitochondrial inner membrane, where it interacts with membrane proteins and, although not essential, is necessary for the optimal activity of a number of proteins. One of them is the mitochondrial ADP/ATP carrier, which imports ADP into the mitochondrion and exports ATP. In the crystal structures, cardiolipin is bound to three equivalent sites of the ADP/ATP carrier, but its role is unresolved.

Protein crowding and lipid complexity influence the nanoscale dynamic organization of ion channels in cell membranes.

Cell membranes are crowded and complex environments. To investigate the effect of protein-lipid interactions on dynamic organization in mammalian cell membranes, we have performed coarse-grained molecular dynamics simulations containing >100 copies of an inwardly rectifying potassium (Kir) channel which forms specific interactions with the regulatory lipid phosphatidylinositol 4,5-bisphosphate (PIP). The tendency of protein molecules to cluster has the effect of organizing the membrane into dynamic compartments.