Bulletin of the American Physical Society
APS March Meeting 2023
Volume 68, Number 3
Las Vegas, Nevada (March 5-10)
Virtual (March 20-22); Time Zone: Pacific Time
Session D10: Membranes IIFocus
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Sponsoring Units: DBIO Chair: Rana Ashkar, Virginia Tech Room: Room 202 |
Monday, March 6, 2023 3:00PM - 3:12PM |
D10.00001: Effects of membrane viscoelasticity on the red blood cell dynamics in a microcapillary Ali Gurbuz, On Shun Pak, Michael Taylor, Mettupalayam V Sivaselvan, Frederick Sachs The mechanical properties of red blood cells (RBCs) play key roles in their biological functions in microcirculation. In particular, RBCs must deform significantly to travel through microcapillaries with sizes comparable to or even smaller than their own. While the dynamics of RBCs in microcapillaries have received considerable attention, the effect of membrane viscoelasticity has been largely overlooked. In this work, we present a computational study based on the boundary integral method and thin-shell mechanics to examine how membrane viscoelasticity influences the dynamics of RBCs flowing through straight and constricted microcapillaries. Our results reveal that the cell with a viscoelastic membrane undergoes substantially different motion and deformation compared to results based on a purely elastic membrane model. Comparisons with experimental data also suggest the importance of accounting for membrane viscoelasticity in order to properly capture the transient dynamics of an RBC flowing through a microcapillary. Taken together, these findings demonstrate the significant effects of membrane viscoelasticity on RBC dynamics in different microcapillary environments. The computational framework also lays the groundwork for more accurate quantitative modeling of the mechanical response of RBCs in their mechanotransduction process in subsequent investigations. |
Monday, March 6, 2023 3:12PM - 3:24PM |
D10.00002: Lipid bilayer thickness effects on spectroscopic measurements Zachary G Lipel, Dimitrios Fraggedakis, Yannick A Omar, Kranthi K Mandadapu Lipid bilayer membranes are biological structures that bound cells and organelles and are vital to several cellular processes, such as endocytosis and action potential propagation. Therefore, it is crucial to understand how the material properties of membranes govern their dynamics across multiple lengthscales. Dynamics on the order of membrane thickness are commonly described by phenomenological models and are attributed to competition between bending relaxation and intermonolayer friction. In this work, we provide a theory that explicitly accounts for finite membrane thickness effects, and we show that the linear response at these lengthscales is dominated by a non-equilibrium shear mechanism different from the commonly assumed intermonolayer friction. Using these insights, we calculate the dynamic structure factor and compare it to the relaxation spectra of lipid bilayer membranes obtained through Neutron Spin Echo spectroscopy. We discuss the effects of the inclusion of membrane thickness on the interpretation of the observed relaxation dynamics and the necessity of phenomenology. |
Monday, March 6, 2023 3:24PM - 4:00PM |
D10.00003: Sensing a little friction: how interleaflet friction depends on membrane composition and controls membrane bending dynamics Invited Speaker: Aurelia R Honerkamp-Smith Along with membrane viscosity, interleaflet friction determines the dynamics of membrane deformation. The two leaflets that form a lipid membrane must slide past each other when the membrane bends, as occurs when vesicles are formed, or membrane tethers are pulled. However, measurements of this parameter are sparse and have previously been accomplished by a large variety of different experimental techniques, making it difficult to compare them or to identify trends. We adapted a recently developed method to determine how interleaflet friction varies with membrane lipid composition. In this method, fluid shear stress is applied to continuous, flat supported lipid bilayers at such high rates that the top leaflet slides over the lower leaflet. We show that this method gives reproducible results and can detect changes to interleaflet friction resulting from even small differences in acyl chain structure. In particular, we observe dramatic changes to friction when cholesterol is included in the bilayer. Our measurements complement current theory and experiments which predict this parameter and use it to understand membrane bending dynamics. |
Monday, March 6, 2023 4:00PM - 4:12PM |
D10.00004: The Effects of Domain Formation on Lipid Membrane Dynamics Rana Ashkar, Sudipta Gupta, Henry J Lessen, Frederick Heberle, Alexander J Sodt Cell membranes control life functions with unparalleled efficiency through highly regulated spatiotemporal interactions between membrane components. The rich diversity of membrane lipids plays a key role in this regulation, resulting in dynamic phase separation into distinct lipid domains that differ in their composition and biophysical properties. However, how domain formation influences membrane dynamics remains poorly understood. Here, we use neutron spectroscopy and molecular dynamics (MD) simulations to selectively study the dynamic response of the lipid matrix to the formation and growth of ordered domains. Our studies utilize binary mixtures of DMPC (14:0 PC) and DSPC (18:0 PC). Experiments show that the presence of DSPC-rich domains causes an effective slowdown in the bending fluctuations and diffusive dynamics of the otherwise fluid DMPC-rich matrix. Complementary MD simulations on analogous bilayers suggest that the measured changes in diffusive and collective matrix dynamics are mediated by interfacial DMPC lipids that experience constrained diffusional jumps and longer residence times at the domain boundaries. These findings present striking evidence of dynamic coupling between lipid domains and their surrounding lipid environment. More importantly, this interplay occurs on ns timescales of protein conformational changes – suggesting an intriguing mechanism by which domain formation regulates functional processes through synergistic modulation of membrane dynamics. |
Monday, March 6, 2023 4:12PM - 4:24PM |
D10.00005: Effect of bottlebrush poloxamer architecture on binding to liposomes Joseph Hassler, Adelyn Crabtree, Lucy Liberman, Frank S Bates, Benjamin Hackel, Timothy P Lodge Poloxamers – triblock copolymers consisting of poly(ethylene oxide) and poly(propylene oxide) – have demonstrated cell membrane stabilization efficacy against numerous types of stress. However, the mechanism responsible for this effect remains elusive, hindering engineering of effective therapeutics. Bottlebrush polymers have a wide parameter space and known relationships between architectural parameters and properties, enabling their use as a tool for mechanistic investigations of polymer-lipid bilayer interactions. In this work, we utilized a versatile synthetic platform to create novel bottlebrush analogs to poloxamers, and then employed pulsed-field-gradient NMR, and an in vitro osmotic stress assay to explore the effects of bottlebrush architectural parameters on binding to, and protection of, phospholipid bilayers. We found that the binding affinity of a bottlebrush poloxamer (BBP) is about three times higher than a linear poloxamer with a similar composition and number of PPO units. BBP binding is sensitive to overall molecular weight, side chain length, and architecture (statistical versus block). All tested BBPs exhibit a protective effect on cell membranes under stress at sub-μM concentrations. As the factors controlling membrane affinity and protection efficacy of bottlebrush poloxamers are not understood, these results provide important insight into how they adhere to and stabilize a lipid bilayer surface. |
Monday, March 6, 2023 4:24PM - 4:36PM |
D10.00006: Phospholipid flipping into the outer leaflet of the bacterial outer membrane compensates for severe reduction in protein content Jiawei Sun, Kerwyn C Huang The Gram-negative bacterial outer membrane (OM) is a critical and versatile surface layer that provides selective permeability to nutrients and antimicrobial agents and protection against environmental mechanical stress. Studying the biophysical properties of the OM, e.g., mechanical stiffness and permeability, and their underlying molecular interactions offers structural insights into the essentiality of the OM and mechanisms to destabilize or bypass this barrier for conquering antimicrobial resistance. Here, we characterized an E. coli mutant with a global reduction in OM proteins due to the deletion of bamD, which causes reduction in OM stiffness, increased membrane permeability, and OM rupture in spent medium. The suppression of OM rupture required the additional deletion of pldA, which encodes a phospholipase that removes mislocated phospholipids on the outer leaflet of the OM, suggesting that phospholipids flipping into the outer leaflet is required to fill the space vacated by the loss of major OM proteins, which otherwise causes imbalanced material content between leaflets and an interleaflet stress that weakens the OM. Despite rescuing OM rupture, these suppressor mutants with abundant phospholipids on the OM outer leaflet did not restore the mechanical stiffness of the OM and showed rapid cell lysis upon oscillatory hyperosmotic loading, suggesting that beta-barrel proteins are required for OM mechanical strength. |
Monday, March 6, 2023 4:36PM - 4:48PM |
D10.00007: Disruption without disintegration: How are membranes targeted by antimicrobial peptides Shuo Qian, Veerendra K Sharma, Piotr A Zolnierczuk, Durgesh K Rai Antimicrobial peptides (AMPs) are a class of promising broad-spectrum antibiotics against drug-resistant bacteria. Many of them are found to bind bacterial membranes spontaneously, and cause disruption to membrane integrity by forming membrane pores or increasing membrane permeability, yet more details are needed to understand the delicate interaction under conditions that no pore is present in membranes. The contrast variation technique in neutron scattering affords us to probe the interaction in multi-component fluid model lipid membranes. By taking advantage of the contrast between protiated and deuterated lipids, we have found some AMPs induce a more asymmetric and lateral segregated lipid bilayers with redistribution of charged lipid within intact membranes. For example, Aurein 1.2, a 13-amino acid AMP discovered in Australia frog Litoria genus, drives anionic lipid from the inner leaflet of a bilayer to the outer leaflet. It leads to lateral segregation that is similar to the domain formed below the lipid order−disorder phase-transition temperature. The neutron membrane diffraction results revealed its association mostly with the acyl chain-headgroup region without deep penetration. With neutron spectroscopic techniques such as quasi-elastic neutron scattering and neutron spin echo, we found that Aurein 1.2 restricts the lipid lateral motion in the fluid phase significantly and modifies the elasticity of membranes. With this and our other studies on AMPs such as Alamethicin and melittin, the results point to an alternate mechanism of AMPs on disrupting membrane without disintegrating it. This also provides insights on how cell membranes respond to external stimuli to maintain the integration of the cell boundary. I will discuss how we used neutron scattering to understand more complex membrane systems and the implication for many research on membrane-active molecules. |
Monday, March 6, 2023 4:48PM - 5:00PM |
D10.00008: Erythro-PmBs: A selective polymyxin B delivery system using antibody-conjugated hybrid erythrocyte liposomes Hannah Krivic The growing world-wide antibiotic resistance crisis has caused many currently existing antibiotics to become ineffective due to bacteria developing resistive mechanisms. There are a limited number of potent antibiotics that are successful at suppressing microbial growth; however, these are often deemed as a last resort due to toxicity. We present a novel PmB delivery system constructed by conjugating hybrid erythrocyte liposomes with antibacterial antibodies to combine a high loading efficiency with guided delivery. PmB retention is enhanced through incorporation of the negatively charged lipid, DMPS, into the red blood cell’s cytoplasmic membrane1. Molecular dynamics (MD) simulations reveal an optimal DMPS fraction that allows for complete anchorage of PmB through acyl tail insertion into the hydrophobic membrane core. Anti-Escherichia coli antibodies are attached to these hybrid erythrocyte liposomes by inclusion of DSPE-PEG maleimide linkers. We show that these erythro-PmBs have a loading efficiency of ~90% and are effective in delivering PmB to E.coli, with values for the minimum inhibitory concentration (MIC) comparable to those of free PmB. MD simulations further suggest a fusion or lipid exchange mechanism between the erythro-PmBs and outer E.coli membrane. The MIC values for Klebsiella aerogenes, however, significantly increased, indicating that anti-E.coli antibody inclusion enables the erythro-PmBs to selectively deliver antibiotics to specific targets. |
Monday, March 6, 2023 5:00PM - 5:12PM |
D10.00009: Probing Interactions of PQS Analogs with Outer Membranes of Pseudomonas Aeruginosa Bacteria Emad Pirhadi, Hasan Al Tarify, Jeffrey Schertzer, Xin Yong Outer membrane vesicles (OMV) released from the outer membrane (OM) of gram-negative bacteria play an undeniable role in their survival by improving signaling process, nutrient acquisition, and antibiotic resistance. Previous studies revealed that Pseudomonas aeruginosa bacterium is incapable of producing OMV without access to the self-secreted Pseudomonas Quinolone Signal (PQS). It has been shown that this signaling molecule can also stimulate OMV formation in other closely related organisms, suggesting small molecule induced OMV biogenesis is a widely conserved process. This work aims to provide fundamental insight into the effect of key functional groups of PQS on its interaction with the bacteria OM by investigating a variety of structural analogs. Using all-atom molecular dynamics, we model the P. aeruginosa OM composed of hexa-acylated PA14 Lipid A in the outer leaflet and a mixture of POPE-POPG phospholipids in the inner leaflet. We probe the membrane interaction with PQS and its analogs, including 2-heptyl-4-quinolone (HHQ), 4-quinolinol, 2-naphthol, and 3-heptyl-2-naphthol to illuminate the role of the third position hydroxy, alkyl side chain, and most importantly the heterocyclic amine. The transmembrane free energy calculations of insertion, as well as hydrogen bonding analyses, show significant differences between these molecules, indicating that all these functional groups have a critical role in the intercalation of PQS into the membrane and hence OMV formation. |
Monday, March 6, 2023 5:12PM - 5:24PM |
D10.00010: Effect of Weak Magnetic Field on the Antibacterial Properties of Antibiotics Samina S Masood We are conducting a comparative study of weak electromagnetic field on inhibitive properties on antibiotics and see if an exposure to weak magnetic field can enhance the bacterial inhibition of pathegenic bacterial and reduce the side effects of drugs. |
Monday, March 6, 2023 5:24PM - 5:36PM |
D10.00011: Specific iron binding to natural sphingomyelin membrane induced by non-specific co-solutes in solutions David Vaknin, Honghu Zhang, Wenjie Wang Sphingomyelin (SPM), a ceramide derived phospholipid with a phosphatidyl choline (PC) moiety, is abundant in the myelin sheath that with proteins forms an extended plasma membrane that is wrapped around nerve fibers. The myelin sheath provides electrical insulation to facilitate conduction between neuronal nodes. To achieve electrical insulation the SPM membrane has to be intact and damages to the myelin sheath has been implicated in a variety of brain diseases. Understanding the structural integrity of SPM in different salt solutions and its interactions with different ions would provide the basis for exploring the potential physiological pathways in the ion-associated neurodegenerative diseases. In this study, using spinal bovine SPM as a model system, we form and study a monomolecular layer (ML) at a physiological solution interface to determine the effect of various ions and their complexes on the PC-template formed by the SPM. Surface sensitive synchrotron X-ray diffraction and spectroscopic techniques demonstrate that only under salt (NaCl or KCl) concentration close to physiological conditions, dilute concentrations of iron [Fe(III)] complexes in solution spontaneously bind to the charge-neutral PC group and affect its structure. More importantly, we find that iron does not accumulate at the interface in the absence of co-salt species such as KCl, NaCl, KI, or CaCl2. Other cations such as (La3+ or Ca2+), under similar conditions, do not accumulate at the interface indicating the nature of iron accumulation is unique and involves a special mechanism. The X-ray diffraction at grazing incidence, indicates in-plane deteriorated organization of the SPM in the monolayer upon iron binding. Our study implies that PC rich cell-plasma membranes are highly susceptible to the binding of iron complexes, even at minute concentrations. Such binding can propagate and alter membrane integrity and can be a factor that damages the myelin sheath. |
Monday, March 6, 2023 5:36PM - 5:48PM |
D10.00012: Glycocalyx-induced cell membrane protrusions at the cell-substrate interface Ethan Coburn, Shlomi Cohen, Yu Jing, Jennifer E Curtis This work examines the interplay of hyaluronan-rich glycocalyx with the cell membrane and its role in generating membrane protrusions. Previous work has shown that densely grafted polymers on a cell membrane surface lead to an instability which drives the formation of micron-sized membrane protrusions. These protrusions, such as long, thin microvilli, are more sharply curved than the rest of the cell, which reduces the strength of repulsive steric and electrostatic interactions between neighboring polymers. We examine that model in the context of hyaluronan-rich glycocalyx both theoretically and experimentally. Then we extend the model to examine whether such membrane instabilities can occur at the cell-substrate interface, where growing protrusions from the membrane will encounter addition mechanical resistance arising from the compressed glycocalyx between the substrate and the cell. Understanding of the occurrence and conditions for glycocalyx-induced membrane protrusions is important for studies of cell-extracellular matrix and cell-cell interactions, in particular in the context of cell adhesion and migration and the shedding of extracellular vesicles. |
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