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Lipid membrane interfaces are complex environments that host essential cellular processes such as binding of proteins or drug molecules. A key open question is how water molecules at the interface of membranes with anionic lipids participate in protein binding. To address this question, we studied the dynamics of water hydrogen bonding at the interface of membranes composed of phosphatidylcholine and phosphatidylglycerol, and implemented an algorithm to identify hydrogen-bonded networks at the interface of a lipid membrane, and to characterize their dynamics and linear connections. We find that the membrane interface is characterized by a rich network of hydrogen-bonded water chains that bridge lipid headgroups, some of which form transient lipid clusters. Water-mediated bridges between with lipid phosphate groups are dynamic, with residence lifetimes on the order of picoseconds. These clusters of water/lipid headgroup hydrogen bonds could provide a platform for the binding of proteins or of drug molecules with cationic groups.

Cationic ultrashort lipopeptides (USLPs) are promising antimicrobial candidates to combat multidrug-resistant bacteria. Using DICAMs, a newly synthesized family of tripeptides with net charges from −2 to +1 and a fatty amine conjugated to the C -terminus, we demonstrate that anionic and neutral zwitterionic USLPs can possess potent antimicrobial and membrane-disrupting activities against prevalent human pathogens such as Streptococcus pneumoniae and Streptococcus pyogenes. The strongest antimicrobials completely halt bacterial growth at low micromolar concentrations, reduce bacterial survival by several orders of magnitude, and may kill planktonic cells and biofilms. All of them comprise either an anionic or neutral zwitterionic peptide attached to a long fatty amine (16–18 carbon atoms) and show a preference for anionic lipid membranes enriched in phosphatidylglycerol (PG), which excludes electrostatic interactions as the main driving force for DICAM action. Hence, the hydrophobic contacts provided by the long aliphatic chains of their fatty amines are needed for DICAM’s membrane insertion, while negative-charge shielding by salt counterions would reduce electrostatic repulsions. Additionally, we show that other components of the bacterial envelope, including the capsular polysaccharide, can influence the microbicidal activity of DICAMs. Several promising candidates with good-to-tolerable therapeutic ratios are identified as potential agents against S. pneumoniae and S. pyogenes . Structural characteristics that determine the preference for a specific pathogen or decrease DICAM toxicity have also been investigated.

Cytochrome c is one of the most prominent representatives of peripheral membrane proteins. Besides functioning as an electron transfer carrier in the mitochondrial respiratory chain, it can acquire peroxidase capability, promote the self-assembly of α-synuclein, and function as a scavenger of superoxide. An understanding of its function requires knowledge of how the protein interacts with the inner membrane of mitochondria. The first part of this article provides an overview of a variety of experiments that were aimed at exploring the details of cytochrome c binding to anionic lipid liposomes, which serve as a model system for the inner membrane. While cytochrome c binding involves a conformational change from a folded into a partially disordered state, α-synuclein is intrinsically disordered in solution and subjected to a partial coil -> helix transition on membranes. Depending on the solution conditions and the surface density of α-synuclein, the protein facilitates the self-assembly into oligomers and fibrils. As for cytochrome c, results of binding experiments are discussed. In addition, the article analyzes experiments that explored α-synuclein aggregation. Similarities and differences between cytochrome c and α-synuclein binding are highlighted. Finally, the article presents a brief account of the interplay between cytochrome c and α-synuclein and its biological relevance.

Many proteins reside at the cell poles in rod-shaped bacteria. Several hypotheses have drawn a connection between protein localization and the large cell-wall curvature at the poles. One hypothesis has centered on the formation of microdomains of the lipid cardiolipin (CL), its localization to regions of high membrane curvature, and its interaction with membrane-associated proteins. A lack of experimental techniques has left this hypothesis unanswered. This paper describes a microtechnology-based technique for manipulating bacterial membrane curvature and quantitatively measuring its effect on the localization of CL and proteins in cells. We confined Escherichia coli spheroplasts in microchambers with defined shapes that were embossed into a layer of polymer and observed that the shape of the membrane deformed predictably to accommodate the walls of the microchambers. Combining this technique with epifluorescence microscopy and quantitative image analyses, we characterized the localization of CL microdomains in response to E. coli membrane curvature. CL microdomains localized to regions of high intrinsic negative curvature imposed by microchambers. We expressed a chimera of yellow fluorescent protein fused to the N-terminal region of MinD--a spatial determinant of E. coli division plane assembly--in spheroplasts and observed its colocalization with CL to regions of large, negative membrane curvature. Interestingly, the distribution of MinD was similar in spheroplasts derived from a CL synthase knockout strain. These studies demonstrate the curvature dependence of CL in membranes and test whether these structures participate in the localization of MinD to regions of negative curvature in cells.

The molecular events of protein misfolding and self-aggregation of tau and amylin are associated with the progression of Alzheimer’s and diabetes, respectively. Recent studies suggest that tau and amylin can form hetero-tau-amylin oligomers. Those hetero-oligomers are more neurotoxic than homo-tau oligomers. So far, the detailed interactions between the hetero-oligomers and the neuronal membrane are unknown. Using multiscale MD simulations, the lipid binding and protein folding behaviors of hetero-oligomers on asymmetric lipid nanodomains or raft membranes were examined. Our raft membranes contain phase-separated phosphatidylcholine (PC), cholesterol, and anionic phosphatidylserine (PS) or ganglioside (GM1) in one leaflet of the lipid bilayer. The hetero-oligomers bound more strongly to the PS and GM1 than other lipids via the hydrophobic and hydrophilic interactions, respectively, in the raft membranes. The hetero-tetramer disrupted the acyl chain orders of both PC and PS in the PS-containing raft membrane, but only the GM1 in the GM1-containing raft membrane as effectively as the homo-tau-tetramer. We discovered that the alpha-helical content in the heterodimer was greater than the sum of alpha-helical contents from isolated tau and amylin monomers on both raft membranes, indicative of a synergetic effect of tau-amylin interactions in surface-induced protein folding. Our results provide new molecular insights into understanding the cross-talk between Alzheimer’s and diabetes.

Trp is unique among the amino acids since it is involved in many different types of noncovalent interactions such as electrostatic and hydrophobic ones, but also in π-π, π-cation, π-anion and π-ion pair interactions. In membranotropic peptides and proteins, Trp locates preferentially at the water-membrane interface. In antimicrobial or cell-penetrating peptides (AMPs and CPPs respectively), Trp is well-known for its strong role in the capacity of these peptides to interact and affect the membrane organisation of both bacteria and animal cells at the level of the lipid bilayer. This essential amino acid can however be involved in other types of interactions, not only with lipids, but also with other membrane partners, that are crucial to understand the functional roles of membranotropic peptides. This review is focused on this latter less known role of Trp and describes in details, both in qualitative and quantitative ways: (i) the physico-chemical properties of Trp; (ii) its effect in CPP internalisation; (iii) its importance in AMP activity; (iv) its role in the interaction of AMPs with glycoconjugates or lipids in bacteria membranes and the consequences on the activity of the peptides; (v) its role in the interaction of CPPs with negatively charged polysaccharides or lipids of animal membranes and the consequences on the activity of the peptides. We intend to bring highlights of the physico-chemical properties of Trp and describe its extensive possibilities of interactions, not only at the well-known level of the lipid bilayer, but with other less considered cell membrane components, such as carbohydrates and the extracellular matrix. The focus on these interactions will allow the reader to reevaluate reported studies. Altogether, our review gathers dedicated studies to show how unique are Trp properties, which should be taken into account to design future membranotropic peptides with expected antimicrobial or cell-penetrating activity.

Supported lipid bilayers (SLBs) on quartz crystals are employed as versatile model systems for studying cell membrane behavior with the use of the highly sensitive technique of quartz crystal microbalance with dissipation monitoring (QCM-D). Since the lipids constituting cell membranes vary from predominantly zwitterionic lipids in mammalian cells to predominantly anionic lipids in the inner membrane of Gram-positive bacteria, the ability to create SLBs of different lipid compositions is essential for representing different cell membranes. While methods to generate stable zwitterionic SLBs and zwitterionic-dominant mixed zwitterionic–anionic SLBs on quartz crystals have been well established, there are no reports of being able to form predominantly or fully anionic SLBs. We describe here a method for forming entirely anionic SLBs by treating the quartz crystal with cationic (3-aminopropyl) trimethoxysilane (APTMS). The formation of the anionic SLB was tracked using QCM-D by monitoring the adsorption of anionic lipid vesicles to a quartz surface and subsequent bilayer formation. Anionic egg L-α-phosphatidylglycerol (PG) vesicles adsorbed on the surface-treated quartz crystal, but did not undergo the vesicle-to-bilayer transition to create an SLB. However, when PG was mixed with 10–40 mole% 1-palmitoyl-2-hydroxy-sn-glycero-3-phospho-(1′-rac-glycerol) (LPG), the mixed vesicles led to the formation of stable SLBs. The dynamics of SLB formation monitored by QCM-D showed that while SLB formation by zwitterionic lipids followed a two-step process of vesicle adsorption followed by the breakdown of the adsorbed vesicles (which in turn is a result of multiple events) to create the SLB, the PG/LPG mixed vesicles ruptured immediately on contacting the quartz surface resulting in a one-step process of SLB formation. The QCM-D data also enabled the quantitative characterization of the SLB by allowing estimation of the lipid surface density as well as the thickness of the hydrophobic region of the SLB. These fully anionic SLBs are valuable model systems to conduct QCM-D studies of the interactions of extraneous substances such as antimicrobial peptides and nanoparticles with Gram-positive bacterial membranes.

Numerous studies highlight the therapeutic potential of G protein-coupled receptor (GPCR) heterodimers, emphasizing their significance in various pathological contexts. Despite extensive basic research and promising outcomes in animal models, the translation of GPCR heterodimer-targeting drugs into clinical use remains limited. The complexities of in vivo conditions, particularly within thecomplex central nervous system, pose challenges in fully replicating physiological environments, hindering clinical success. This review discusses examples of the most studied heterodimers, their involvement in nervous system pathology, and the available data on their potential ligands. In addition, this review highlights the intricate interplay between lipids and GPCRs as a potential key factor in understanding the complexity of cell signaling. The multifaceted role of lipids in modulating the dynamics of GPCR dimerization is explored, shedding light on the elaborate molecular mechanisms governing these interactions.

In addition to playing a central role as a permeability barrier for controlling the diffusion of molecules and ions in and out of bacterial cells, phospholipid (PL) membranes regulate the spatial and temporal position and function of membrane proteins that play an essential role in a variety of cellular functions. Based on the very large number of membrane-associated proteins encoded in genomes, an understanding of the role of PLs may be central to understanding bacterial cell biology. This area of microbiology has received considerable attention over the past two decades, and the local enrichment of anionic PLs has emerged as a candidate mechanism for biomolecular organization in bacterial cells. In this review, we summarize the current understanding of anionic PLs in bacteria, including their biosynthesis, subcellular localization, and physiological relevance, discuss evidence and mechanisms for enriching anionic PLs in membranes, and conclude with an assessment of future directions for this area of bacterial biochemistry, biophysics, and cell biology.

Flaviviruses, such as dengue virus and West Nile virus, are enveloped viruses that infect cells through receptor-mediated endocytosis and fusion from within acidic endosomes. The cell entry process of flaviviruses is mediated by the viral E glycoprotein. This short review will address recent advances in the understanding of flavivirus cell entry with specific emphasis on the recent study of Zaitseva and coworkers, indicating that anionic lipids might play a crucial role in the fusion process of dengue virus [1].