Hexokinase-I directly binds to a charged membrane-buried glutamate of mitochondrial VDAC1 and VDAC2.

Binding of hexokinase HKI to mitochondrial voltage-dependent anion channels (VDACs) has far-reaching physiological implications. However, the structural basis of this interaction is unclear. Combining computer simulations with experiments in cells, we here show that complex assembly relies on intimate contacts between the N-terminal α-helix of HKI and a charged membrane-buried glutamate on the outer wall of VDAC1 and VDAC2.

A Narrative Review of the Impact of Sleep on Athletes: Sleep Restriction Causes and Consequences, Monitoring, and Interventions.

This narrative review synthesizes evidence on the impact of sleep on athletic performance, the prevalence and causes of sleep disturbances, and effective monitoring and intervention strategies to enhance sleep quality and duration. A comprehensive review of case studies, observational studies, randomized controlled trials, systematic reviews, and meta-analyses was conducted using PubMed, Cochrane Library, and Google Scholar up to July 2024. Sleep plays a crucial role in the overall well-being and performance of athletes, yet sleep issues are highly prevalent due to factors such as competition schedules, psychological stress, and travel across time zones.

Viral entry mechanisms: the role of molecular simulation in unlocking a key step in viral infections.

Viral infections are a major global health concern, affecting millions of people each year. Viral entry is one of the crucial stages in the infection process, but its details remain elusive. Enveloped viruses are enclosed by a lipid membrane that protects their genetic material and these viruses are linked to various human illnesses, including influenza, and COVID-19.

Lipid unsaturation promotes BAX and BAK pore activity during apoptosis.

BAX and BAK are proapoptotic members of the BCL2 family that directly mediate mitochondrial outer membrane permeabilition (MOMP), a central step in apoptosis execution. However, the molecular architecture of the mitochondrial apoptotic pore remains a key open question and especially little is known about the contribution of lipids to MOMP. By performing a comparative lipidomics analysis of the proximal membrane environment of BAK isolated in lipid nanodiscs, we find a significant enrichment of unsaturated species nearby BAK and BAX in apoptotic conditions.

Xport-A functions as a chaperone by stabilizing the first five transmembrane domains of rhodopsin-1.

Rhodopsin-1 (Rh1), the main photosensitive protein of , is a seven-transmembrane domain protein, which is inserted co-translationally in the endoplasmic reticulum (ER) membrane. Biogenesis of Rh1 occurs in the ER, where various chaperones interact with Rh1 to aid in its folding and subsequent transport from the ER to the rhabdomere, the light-sensing organelle of the photoreceptors. Xport-A has been proposed as a chaperone/transport factor for Rh1, but the exact molecular mechanism for Xport-A activity upon Rh1 is unknown.

A sporulation signature protease is required for assembly of the spore surface layers, germination and host colonization in Clostridioides difficile.

A genomic signature for endosporulation includes a gene coding for a protease, YabG, which in the model organism Bacillus subtilis is involved in assembly of the spore coat. We show that in the human pathogen Clostridioidesm difficile, YabG is critical for the assembly of the coat and exosporium layers of spores. YabG is produced during sporulation under the control of the mother cell-specific regulators σE and σK and associates with the spore surface layers.

Martini 3 Coarse-Grained Force Field for Cholesterol.

Cholesterol plays a crucial role in biomembranes by regulating various properties, such as fluidity, rigidity, permeability, and organization of lipid bilayers. The latest version of the Martini model, Martini 3, offers significant improvements in interaction balance, molecular packing, and inclusion of new bead types and sizes. However, the release of the new model resulted in the need to reparameterize many core molecules, including cholesterol.

Rotation of the c-Ring Promotes the Curvature Sorting of Monomeric ATP Synthases.

ATP synthases are proteins that catalyse the formation of ATP through the rotatory movement of their membrane-spanning subunit. In mitochondria, ATP synthases are found to arrange as dimers at the high-curved edges of cristae. Here, a direct link is explored between the rotatory movement of ATP synthases and their preference for curved membranes.

Activity modulation of the FF ATP synthase by a designed antimicrobial peptide via cardiolipin sequestering.

Most antimicrobial peptides (AMPs) exert their microbicidal activity through membrane permeabilization. The designed AMP EcDBS1R4 has a cryptic mechanism of action involving the membrane hyperpolarization of , suggesting that EcDBS1R4 may hinder processes involved in membrane potential dissipation. We show that EcDBS1R4 can sequester cardiolipin, a phospholipid that interacts with several respiratory complexes of .

Studies on the Interaction between Model Proteins and Fluorinated Ionic Liquids.

Proteins are inherently unstable, which limits their use as therapeutic agents. However, the use of biocompatible cosolvents or surfactants can help to circumvent this problem through the stabilization of intramolecular and solvent-mediated interactions. Ionic liquids (ILs) have been known to act as cosolvents or surface-active compounds.

Temperature-Dependent Re-alignment of the Short Multifunctional Peptide BP100 in Membranes Revealed by Solid-State NMR Spectroscopy and Molecular Dynamics Simulations.

BP100 is a cationic undecamer peptide with antimicrobial and cell-penetrating activities. The orientation of this amphiphilic α-helix in lipid bilayers was examined under numerous conditions using solid-state F, N and H NMR. At high temperatures in saturated phosphatidylcholine lipids, BP100 lies flat on the membrane surface, as expected.

SARS-CoV-2 variants impact RBD conformational dynamics and ACE2 accessibility.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed over 6 million people and is having a devastating social and economic impact around the world. The rise of new variants of concern (VOCs) represents a difficult challenge due to the loss of vaccine and natural immunity, as well as increased transmissibility. All VOCs contain mutations in the spike glycoprotein, which mediates fusion between the viral and host cell membranes.

Core-shell polycationic polyurea pharmadendrimers: new-generation of sustainable broad-spectrum antibiotics and antifungals.

The efficacy of conventional antimicrobials is falling to critical levels and raising alarming concerns around the globe. In this scenery, engineered nanoparticles emerged as a solid strategy to fight growing deadly infections. Here, we show the and performance of pharmadendrimers, a novel class of engineered polyurea dendrimers that are synthetic mimics of antibacterial peptides, against a collection of both Gram-positive and Gram-negative bacteria and fungi.

Parainfluenza Fusion Peptide Promotes Membrane Fusion by Assembling into Oligomeric Porelike Structures.

Paramyxoviruses are enveloped viruses harboring a negative-sense RNA genome that must enter the host's cells to replicate. In the case of the parainfluenza virus, the cell entry process starts with the recognition and attachment to target receptors, followed by proteolytic cleavage of the fusion glycoprotein (F) protein, exposing the fusion peptide (FP) region. The FP is responsible for binding to the target membrane, and it is believed to play a crucial role in the fusion process, but the mechanism by which the parainfluenza FP (PIFP) promotes membrane fusion is still unclear.

Coarse-Grain Simulations of Membrane-Adsorbed Helical Peptides.

The amphipathic α-helix is a common motif for peptide adsorption to membranes. Many physiologically relevant events involving membrane-adsorbed peptides occur over time and size scales readily accessible to coarse-grain molecular dynamics simulations. This methodological suitability, however, comes with a number of pitfalls.

Improved Parameterization of Phosphatidylinositide Lipid Headgroups for the Martini 3 Coarse-Grain Force Field.

Phosphoinositides are a family of membrane phospholipids that play crucial roles in membrane regulatory events. As such, these lipids are often a key part of molecular dynamics simulation studies of biological membranes, in particular of those employing coarse-grain models because of the potential long times and sizes of the involved membrane processes. Version 3 of the widely used Martini coarse-grain force field has been recently published, greatly refining many aspects of biomolecular interactions.

Acyl-chain saturation regulates the order of phosphatidylinositol 4,5-bisphosphate nanodomains.

Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P) plays a critical role in the regulation of various plasma membrane processes and signaling pathways in eukaryotes. A significant amount of cellular resources are spent on maintaining the dominant 1-stearoyl-2-arachidonyl PI(4,5)P acyl-chain composition, while less abundant and more saturated species become more prevalent in response to specific stimuli, stress or aging. Here, we report the impact of acyl-chain structure on the biophysical properties of cation-induced PI(4,5)P nanodomains.

Overlapping Properties of the Short Membrane-Active Peptide BP100 With (i) Polycationic TAT and (ii) α-helical Magainin Family Peptides.

BP100 is a short, designer-made membrane-active peptide with multiple functionalities: antimicrobial, cell-penetrating, and fusogenic. Consisting of five lysines and 6 hydrophobic residues, BP100 was shown to bind to lipid bilayers as an amphipathic α-helix, but its mechanism of action remains unclear. With these features, BP100 embodies the characteristics of two distinctly different classes of membrane-active peptides, which have been studied in detail and where the mechanism of action is better understood.

Coarse-Grained Parameterization of Nucleotide Cofactors and Metabolites: Protonation Constants, Partition Coefficients, and Model Topologies.

Nucleotides are structural units relevant not only in nucleic acids but also as substrates or cofactors in key biochemical reactions. The size- and timescales of such nucleotide-protein interactions fall well within the scope of coarse-grained molecular dynamics, which holds promise of important mechanistic insight. However, the lack of specific parameters has prevented accurate coarse-grained simulations of protein interactions with most nucleotide compounds.

Localization Preference of Antimicrobial Peptides on Liquid-Disordered Membrane Domains.

We performed coarse-grained simulations of the antimicrobial peptides Magainin-2, BP100, MSI-103, and MSI-78 on a phase-separated membrane to study their preference for the different domains. All the peptides displayed a clear preference for the liquid-disordered (Ld) phase over the liquid-ordered (Lo) one. For BP100, MSI-103, and MSI-78 there was a further preference of the peptides for the domain interface.

Charge-dependent interactions of monomeric and filamentous actin with lipid bilayers.

The cytoskeletal protein actin polymerizes into filaments that are essential for the mechanical stability of mammalian cells. In vitro experiments showed that direct interactions between actin filaments and lipid bilayers are possible and that the net charge of the bilayer as well as the presence of divalent ions in the buffer play an important role. In vivo, colocalization of actin filaments and divalent ions are suppressed, and cells rely on linker proteins to connect the plasma membrane to the actin network.

Pitfalls of the Martini Model.

The computational and conceptual simplifications realized by coarse-grain (CG) models make them a ubiquitous tool in the current computational modeling landscape. Building block based CG models, such as the Martini model, possess the key advantage of allowing for a broad range of applications without the need to reparametrize the force field each time. However, there are certain inherent limitations to this approach, which we investigate in detail in this work.

Ceramides bind VDAC2 to trigger mitochondrial apoptosis.

Ceramides draw wide attention as tumor suppressor lipids that act directly on mitochondria to trigger apoptotic cell death. However, molecular details of the underlying mechanism are largely unknown. Using a photoactivatable ceramide probe, we here identify the voltage-dependent anion channels VDAC1 and VDAC2 as mitochondrial ceramide binding proteins.

Atrioventricular valves dysplasia in a newborn.

A newborn with prenatally diagnosed dysplasia of both atrioventricular valves presented after birth with signs and symptoms of low cardiac output, severe regurgitation of both mitral and tricuspid valves. This combination is as rare as challenging, since it regards both the timing and management of this complex cardiac malformation. We report an early surgical repair of both atrioventricular valves in a symptomatic newborn, which improved his clinical status and, so far, delayed valve replacement.