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The lipid bilayer membrane is increasingly recognized as a promising target for medicine, as exemplified by the recent surge in the development of membrane targeting antimicrobials (MTAs) against methicillin-resistant Staphylococcus aureus (MRSA), a superbug posing significant challenges to public health. Interestingly, the effectiveness of MTAs seems to vary markedly between the exponential growth and stationary phases of bacteria, a phenomenon that remains poorly understood. Here, we perform molecular dynamics (MD) simulations of the lipid bilayer membrane of S. aureus across different phases of bacteria growth, examining equilibrium properties and free energies associated with pore nucleation, the initial stage of membrane perforation preceding pore expansion and rupture. Our findings reveal that pore nucleation in the stationary phase bacterial membrane requires more energy compared to the exponential phase due to the increased concentration of cardiolipin, a type of mechanically resilient lipids, in the former, which provides a physical explanation for why the stationary phase is more tolerant of MTAs. The insights gained from this study not only deepen our understanding of the mechanics of bacterial membrane but can also help lay a foundation for simulation-assisted discovery and evaluation of MTAs for optimized treatments. • Atomistic models are developed to investigate the properties of bacterial lipid membranes across different growth phases. • Variations in lipid compositions across different growth phases can result in different lipid distributions. • Pore nucleation energy of bacterial membrane is greater in the stationary phase compared to the exponential phase. • The strength of bacterial membrane in the stationary phase can be tuned by the lipid composition. [ABSTRACT FROM AUTHOR]

Carbon nanotube (CNT) based transmembrane porins have attracted a lot of recent interest due to their excellent transport properties for water, ions and biomolecules. In experiments, CNTs with a length of about 10 nm can penetrate and form stable transmembrane channels across lipid membranes, while in sharp contrast, similar 10 nm long pristine CNTs were found parallelly clamped inside the hydrophobic core of a lipid bilayer in simulations. This apparent paradox has motivated the present study, where we performed all-atom molecular dynamics simulations to show that lipid molecules initially coated on the CNTs play an essential role in the formation and stabilization of the CNT porins. We demonstrate that, as a lipid coated CNT is inserted into the membrane, lipid molecules arrange themselves into a bicelle on the CNT outside the membrane, providing mechanical support to stabilize the transmembrane configuration of the CNT porin. Further analysis shows that the lipid coating density and end-functionalization strongly influence the CNT insertion into a lipid membrane. These findings shed light on the mechanism of formation and stabilization of CNT porins and provide a theoretical basis to design related transmembrane transport systems. Image 1 [ABSTRACT FROM AUTHOR]

Understanding the interaction of 2D materials including graphene, boron nitride and MoS 2 with biological systems is a growing topic of interest to many applications such as biosensors, drug delivery, gene therapy and nano-toxicity. In this paper, we show that the interaction of 2D materials with cellular membranes at its early stage of approaching is dominantly controlled by entropic forces. Recent experiments indicate that graphene sheets, depending on their size, can either undergo a near-orthogonal cutting or a parallel attachment mode of interaction with cell membranes. Here, we perform a set of integrated theoretical statistical mechanics analysis and coarse-grained molecular dynamics simulations to quantify the entropic energy barrier for these modes of interactions. Our results indicate that micro-sized graphene sheets prefer approaching a fluctuating membrane through a sharp corner, while nano-sized sheets are more likely to adhere to the cell membrane surface due to relatively low entropic energy cost that is comparable with thermal energy from random Brownian motions. • The interaction of 2D nanomaterials with biological systems is studied in this paper. • This interaction is dominantly controlled by entropic forces. • The entropic forces and energetic costs are calculated for two modes of interactions. • We show that micro-sized sheets always approach a cell membrane in perpendicular mode. [ABSTRACT FROM AUTHOR]

The opportunistic human pathogen Staphylococcus aureus can evade antibiotics by acquiring antibiotic resistance genes or by entering into a non-growing dormant state. Moreover, the particular circumstances of a specific infection site, such as acidity or anaerobicity, often weaken antibiotic potency. Decreased bacterial susceptibility combined with diminished antibiotic potency is responsible for high failure rates when treating S. aureus infections. Here, we report that the membrane-active antimicrobial agent nTZDpa does not only exhibit enhanced antibiotic activity against multidrug-resistant Gram-positive pathogens in acidic pH, but also retains antimicrobial potency under anaerobic conditions. This agent completely eradicated highly antibiotic-tolerant cells and biofilms formed by methicillin-resistant S. aureus at pH 5.5 at concentrations at which it was not potent at pH 7.4. Furthermore, nTZDpa was more potent at synergistically potentiating gentamicin killing against antibiotic-tolerant MRSA cells at low pH than at high pH. All-atom molecular dynamics simulations combined with membrane-permeabilization assays revealed that the neutral form of nTZDpa, which contains carboxylic acid, is more effective than the deprotonated form at penetrating the bacterial membrane and plays an essential role in membrane activity. An acidic pH increases the proportion of the neutrally charged nTZDpa, which results in antimicrobial enhancement. Our results provide key insights into rational design of pH-sensitive membrane-active antimicrobials and antibiotic adjuvants that are effective in an infection environment. These findings demonstrate that nTZDpa is a promising lead compound for developing new therapeutics against hard-to-cure infections caused by drug-resistant and -tolerant S. aureus. • Membrane-active nTZDpa shows enhanced antimicrobial activity in acidic conditions. • nTZDpa exhibits enhanced killing of antibiotic-tolerant persister cells at low pH. • Non-ionized neutral nTZDpa penetrates and embeds into bacterial lipid bilayers. • The proportion of neutral nTZDpa increases as pH decreases. • The antimicrobial synergism of nTZDpa plus gentamicin is enhanced at low pH. [ABSTRACT FROM AUTHOR]

[Display omitted] Soft polymer gels encounter difficulties in meeting the demanding requirements of real-life applications due to the long-standing challenge to reproduce the excellent mechanical properties and multifunctionalities observed in natural soft tissues. Here, a skin-like hierarchically structured organo-hydrogel with an all-around performance that matches and outperforms mammalian skin is reported, including high stretchability of 2227% strain, remarkable strength of 20.78 MPa, record-breaking fracture toughness up to 260 MJ/m3, together with excellent resistance to fracture and fatigue (fatigue threshold over 30.4 kJ/m2), superior long-term stability and tolerance to freezing and elevated temperatures. It also shows high conductivity and excellent electrical sensing capability. The underlying synergistic multi-scale reinforcement mechanisms of the organo-hydrogel are also validated via molecular dynamics simulations and experimental results. Hence, this work formulates a model design applicable to various polymer gels to expand their potential in applications including flexible electronics, multi-functional bionic sensors, energy storage devices and soft robotics. [ABSTRACT FROM AUTHOR]