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DOE OSTI2024

Membrane lipids drive formation of KRAS4b-RAF1 RBDCRD nanoclusters on the membrane

The oncogene RAS, extensively studied for decades, presents persistent gaps in understanding, hindering the development of effective therapeutic strategies due to a lack of precise details on how RAS initiates MAPK signaling with RAF effector proteins at the plasma membrane. Recent advances in X-ray crystallography, cryo-EM, and super-resolution fluorescence microscopy offer structural and spatial insights, yet the molecular mechanisms involving protein-protein and protein-lipid interactions in RAS-mediated signaling require further characterization. This study utilizes single-molecule experimental techniques, nuclear magnetic resonance spectroscopy, and the computational Machine-Learned Modeling Infrastructure (MuMMI) to examine KRAS4b and RAF1 on a biologically relevant lipid bilayer. MuMMI captures long-timescale events while preserving detailed atomic descriptions, providing testable models for experimental validation. Both in vitro and computational studies reveal that RBDCRD binding alters KRAS lateral diffusion on the lipid bilayer, increasing cluster size and decreasing diffusion. RAS and membrane binding cause hydrophobic residues in the CRD region to penetrate the bilayer, stabilizing complexes through β-strand elongation. These cooperative interactions among lipids, KRAS4b, and RAF1 are proposed as essential for forming nanoclusters, potentially a critical step in MAP kinase signal activation.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

The regulation of the cell wall by glycosylphosphatidylinositol-anchored proteins in Arabidopsis

A polysaccharides-based cell wall covers the plant cell, shaping it and protecting it from the harsh environment. Cellulose microfibrils constitute the cell wall backbone and are embedded in a matrix of pectic and hemicellulosic polysaccharides and glycoproteins. Various environmental and developmental cues can regulate the plant cell wall, and diverse glycosylphosphatidylinositol (GPI)-anchored proteins participate in these regulations. GPI is a common lipid modification on eukaryotic proteins, which covalently tethers the proteins to the membrane lipid bilayer. Catalyzed by a series of enzymic complexes, protein precursors are post-translationally modified at their hydrophobic carboxyl-terminus in the endomembrane system and anchored to the lipid bilayer through an oligosaccharidic GPI modification. Ultimately, mature proteins reach the plasma membrane via the secretory pathway facing toward the apoplast and cell wall in plants. In Arabidopsis, more than three hundred GPI-anchored proteins (GPI-APs) have been predicted, and many are reported to be involved in diverse regulations of the cell wall. In this review, we summarize GPI-APs involved in cell wall regulation. GPI-APs are proposed to act as structural components of the cell wall, organize cellulose microfibrils at the cell surface, and during cell wall integrity signaling transduction. Besides regulating protein trafficking, the GPI modification is potentially governed by a GPI shedding system that cleaves and releases the GPI-anchored proteins from the plasma membrane into the cell wall.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2025

Neuronal Plasma Membranes as Supramolecular Assemblies for Biological Memory

Biological memory is the ability to develop, retain, and retrieve information over time. Currently, it is widely accepted that memories are stored in synapses (i.e., connections between brain cells throughout the brain) through a process known as synaptic plasticity, which leads to either long-term potentiation (LTP) or long-term depression (LTD). However, the strengthening (LTP) and weakening (LTD) of synapses involve post-translational modifications to neural networks requiring de novo gene expression, a lengthy and energetically expensive process. Recently, we observed that lipid bilayers in the absence of peptides/proteins are capable of LTP, not unlike what has been observed in mammals and birds. As such, this finding has prompted us to postulate that the lipid bilayer provides a good model for understanding the molecular basis of biological memory. Here, in this article, we discuss the status, challenges, and opportunities of neuronal plasma membranes as structures for biological memory and learning, therapeutic targets for various brain disorders, and platforms for neural network developments.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

Structure-Based Design of Dual Bactericidal and Bacteria-Releasing Nanosurfaces

Here, we report synergistic nanostructured surfaces combining bactericidal and bacteria-releasing properties. A polystyrene-block-poly(methyl methacrylate) (PS-block-PMMA) diblock copolymer is used to fabricate vertically oriented cylindrical PS structures (“PS nanopillars”) on silicon substrates. The results demonstrate that the PS nanopillars (with a height of about 10 nm, size of about 50 nm, and spacing of about 70 nm) exhibit highly effective bactericidal and bacteria-releasing properties (“dual properties”) against Escherichia coli for at least 36 h of immersion in an E. coli solution. Interestingly, the PS nanopillars coated with a thin layer (≈3 nm thick) of titanium oxide (TiO 2 ) (“TiO 2 nanopillars”) show much improved dual properties against E. coli (a Gram-negative bacterium) compared to the PS nanopillars. Moreover, the dual properties emerge against Listeria monocytogenes (a Gram-positive bacterium). To understand the mechanisms underlying the multifaceted property of the nanopillars, coarse-grained molecular dynamics (MD) simulations of a lipid bilayer (as a simplified model for E. coli) in contact with a substrate containing hexagonally packed hydrophilic nanopillars were performed. The MD results demonstrate that when the bacterium–substrate interaction is strong, the lipid heads adsorb onto the nanopillar surfaces, conforming the shape of a lipid bilayer to the structure/curvature of nanopillars and generating high stress concentrations within the membrane (i.e., the driving force for rupture) at the edge of the nanopillars. Membrane rupture begins with the formation of pores between nanopillars (i.e., bactericidal activity) and ultimately leads to the membrane withdrawal from the nanopillar surface (i.e., bacteria-releasing activity). In the case of Gram-positive bacteria, the adhesion area to the pillar surface is limited due to the inherent stiffness of the bacteria, creating higher stress concentrations within a bacterial cell wall. In conclusion, the present study provides insight into the mechanism underlying the “adhesion-mediated” multifaceted property of nanosurfaces, which is crucial for the development of next-generation antibacterial surface coatings for relevant medical applications.

36 MATERIALS SCIENCE↗

DOE OSTI2024

Effects of Normal and Lateral Electric Fields on Membrane Mechanical Properties

As a core component of biological and synthetic membranes, lipid bilayers are key to compartmentalizing chemical processes. Bilayer morphology and mechanical properties are heavily influenced by electric fields such as those caused by biological ion concentration gradients. We present atomistic simulations exploring the effects of electric fields applied normally and laterally to lipid bilayers. We find that normal fields decrease membrane tension, while lateral fields increase it. Free energy perturbation calculations indicate the importance of dipole-dipole interactions to these tension changes, especially for lateral fields. We additionally show that membrane area compressibilities can be related to their cohesive energies, allowing us to estimate changes in membrane bending rigidity under applied fields. We find that normal fields decrease bending rigidity, while lateral fields increase it. Furthermore, these results point to the use of directed electric fields to locally control membrane stiffness, thereby modulating associated cellular processes.

Chemistry↗

DOE OSTI2022

Evidence for long-term potentiation in phospholipid membranes

Biological supramolecular assemblies, such as phospholipid bilayer membranes, have been used to demonstrate signal processing via short-term synaptic plasticity (STP) in the form of paired pulse facilitation and depression, emulating the brain’s efficiency and flexible cognitive capabilities. However, STP memory in lipid bilayers is volatile and cannot be stored or accessed over relevant periods of time, a key requirement for learning. Using droplet interface bilayers (DIBs) composed of lipids, water and hexadecane, and an electrical stimulation training protocol featuring repetitive sinusoidal voltage cycling, we show that DIBs displaying memcapacitive properties can also exhibit persistent synaptic plasticity in the form of long-term potentiation (LTP) associated with capacitive energy storage in the phospholipid bilayer. The time scales for the physical changes associated with the LTP range between minutes and hours, and are substantially longer than previous STP studies, where stored energy dissipated after only a few seconds. STP behavior is the result of reversible changes in bilayer area and thickness. On the other hand, LTP is the result of additional molecular and structural changes to the zwitterionic lipid headgroups and the dielectric properties of the lipid bilayer that result from the buildup of an increasingly asymmetric charge distribution at the bilayer interfaces.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Disentangling Memristive and Memcapacitive Effects in Droplet Interface Bilayers Using Dynamic Impedance Spectroscopy

The underlying principles for generating intelligent behavior in living organisms are fundamentally different from those in traditional solid-state circuits. Biomimetic neuromorphic equivalents based on biological membranes offer novel implementation of tunable plasticity and diverse mechanisms to control functionality. Here, dynamic electrochemical impedance spectroscopy (dEIS) to probe diphytanoylphosphatidylcholine (DPhPC) droplet interface bilayers (DIBs) to better understand the differences in molecular level structure/dynamics that give rise to hysteretic loops and neuromorphic, memelement behaviors in lipid bilayers in response to electrical biasing is used. Importantly, this system does not have ion-conducting channels and is, therefore, not expected to show memristive behavior. Surprisingly, both memristive and memcapacitive behaviors by measuring the time-dependent complex impedance of DPhPC DIBs are detected. Furthermore, it is shown that nonlinear memristance can originate from structural changes in the bilayer, affecting its dielectric properties. This novel dEIS application allows for the simultaneous analysis of the system's changing memristive and memcapacitive properties, which originate from different molecular restructuring processes. Moreover, and importantly, access to this type of information increases the number of neuromorphic processes supported simultaneously in a single two-terminal device.

36 MATERIALS SCIENCE↗

DOE OSTI2021

Biophysical analysis of the plant-specific GIPC sphingolipids reveals multiple modes of membrane regulation

The plant plasma membrane (PM) is an essential barrier between the cell and the external environment, controlling signal perception and transmission. It consists of an asymmetrical lipid bilayer made up of three different lipid classes: sphingolipids, sterols, and phospholipids. The glycosyl inositol phosphoryl ceramides (GIPCs), representing up to 40% of total sphingolipids, are assumed to be almost exclusively in the outer leaflet of the PM. However, their biological role and properties are poorly defined. In this study, we investigated the role of GIPCs in membrane organization. Because GIPCs are not commercially available, we developed a protocol to extract and isolate GIPC-enriched fractions from eudicots (cauliflower and tobacco) and monocots (leek and rice). Lipidomic analysis confirmed the presence of trihydroxylated long chain bases and 2-hydroxylated very long-chain fatty acids up to 26 carbon atoms. The glycan head groups of the GIPCs from monocots and dicots were analyzed by gas chromatograph-mass spectrometry, revealing different sugar moieties. Multiple biophysics tools, namely Langmuir monolayer, ζ-Potential, light scattering, neutron reflectivity, solid state 2H-NMR, and molecular modeling, were used to investigate the physical properties of the GIPCs, as well as their interaction with free and conjugated phytosterols. We showed that GIPCs increase the thickness and electronegativity of model membranes, interact differentially with the different phytosterols species, and regulate the gel-to-fluid phase transition during temperature variations. These results unveil the multiple roles played by GIPCs in the plant PM.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Modeling the partitioning of amphiphilic molecules and co-solvents in biomembranes

We report amphiphilic co-solvents can have a significant impact on the structure, organization and physical properties of lipid bilayers. Describing the mutual impact of partitioning and induced structure changes is therefore a crucial consideration for a range of topics such as anesthesia and other pharmacokinetic effects, as well as microbial solvent tolerance in the production of biofuels and other fermentation products, where molecules such as ethanol, butanol or acetic acid might be generated. Small-angle neutron scattering (SANS) is a key method for studying lipid and polymer bilayer structures, with many models for extracting bilayer structure (thickness, area per lipid etc.) from scattering data in use today. However, the molecular details of co-solvent partitioning are conflated with induced changes to bilayer structure, making interpretation and modeling of the scattering curves a challenge with the existing set of models. To address this, a model of a bilayer structure is presented which invokes a two-term partition constant accounting for the localization of the co-solvent within the bilayer. This model was validated using a series of SANS measurements of lipid vesicles in the presence of the co-solvent tetrahydrofuran (THF), showing several strategies of how to deploy the two-parameter partition constant model to describe scattering data and extract both structure and partitioning information from the data. Molecular dynamics simulations are then used to evaluate assumptions of the model, provide additional molecular scale details and illustrate its complementary nature to the data fitting procedure. This approach results in estimates of the partition coefficient for THF in 1,2-dimyristoyl-sn-glycero-3-phosphocholine at 35°C, along with an estimate of the fraction of THF residing in the hydrophobic core of the membrane. The authors envision that this model will be applicable to a wide range of other bilayer/amphiphile interactions and provide the associated code needed to implement this model as a fitting algorithm for scattering data in the SasView suite.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Full scale structural, mechanical and dynamical properties of HIV-1 liposomes

Enveloped viruses are enclosed by a lipid membrane inside of which are all of the components necessary for the virus life cycle; viral proteins, the viral genome and metabolites. Viral envelopes are lipid bilayers that adopt morphologies ranging from spheres to tubes. The envelope is derived from the host cell during viral replication. Thus, the composition of the bilayer depends on the complex constitution of lipids from the host-cell’s organelle(s) where assembly and/or budding of the viral particle occurs. Here, molecular dynamics (MD) simulations of authentic, asymmetric HIV-1 liposomes are used to derive a unique level of resolution of its full-scale structure, mechanics and dynamics. Analysis of the structural properties reveal the distribution of thicknesses of the bilayers over the entire liposome as well as its global fluctuations. Moreover, full-scale mechanical analyses are employed to derive the global bending rigidity of HIV-1 liposomes. Finally, dynamical properties of the lipid molecules reveal important relationships between their 3D diffusion, the location of lipid-rafts and the asymmetrical composition of the envelope. Overall, our simulations reveal complex relationships between the rich lipid composition of the HIV-1 liposome and its structural, mechanical and dynamical properties with critical consequences to different stages of HIV-1’s life cycle.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2026

Melatonin-Induced Modulation of Cholesterol-Enriched Model Neuronal Membranes

Melatonin, a hormone primarily produced by the brain’s pineal gland, not only regulates circadian rhythms, but also influences the structural and biophysical properties of neuronal membranes. Its amphiphilic nature enables direct incorporation into lipid bilayers and preferential interactions with cholesterol-rich lipid rafts, critical hubs for cellular signaling and membrane organization. Despite increasing recognition of its membrane activity, the molecular basis of melatonin’s interactions with coexisting liquid-ordered (L o ) and liquid-disordered (L d ) phases remains unclear. Here, in this study, we combine small-angle neutron scattering (SANS) and all-atom molecular dynamics simulations to examine model neuronal membranes composed of DSPC, DOPC, POPC, and cholesterol. Our results show that melatonin preserves domain morphology while adopting distinct orientations within the bilayer and at the membrane interface, allowing both lateral and transmembrane bridging across lipid phases. These findings establish the molecular underpinnings of melatonin’s modulation of membrane heterogeneity and provide strong support for its receptor-independent actions.

atomistic simulations↗

DOE OSTI2024

Physical insights into biological memory using phospholipid membranes

Electrical signals may propagate along neuronal membranes in the brain, thus enabling communication between nerve cells. In doing so, lipid bilayers, fundamental scaffolds of all cell membranes, deform and restructure in response to such electrical activity. These changes impact the electromechanical properties of the membrane, which then physically store biological memory. This memory can exist either over a short or long period of time. Traditionally, biological memory is defined by the strengthening or weakening of transmissions between individual neurons. In this report we show that electrical stimulation may also alter the properties of the lipid membrane, thus pointing toward a novel mechanism for memory storage. Furthermore, based on the analysis of existing electrophysiological data, we study molecular mechanisms underlying the long-term potentiation in phospholipid membranes. Finally, we examine possible relationships between the memory capacitive properties of lipid membranes, neuronal learning, and memory.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

A Membrane-Associated Light-Harvesting Model is Enabled by Functionalized Assemblies of Gene-Doubled TMV Proteins

Photosynthetic light harvesting requires efficient energy transfer within dynamic networks of light-harvesting complexes embedded within phospholipid membranes. Artificial light-harvesting models are valuable tools for understanding the structural features underpinning energy absorption and transfer within chromophore arrays. Here, a method for attaching a protein-based light-harvesting model to a planar, fluid supported lipid bilayer (SLB) is developed. The protein model consists of the tobacco mosaic viral capsid proteins that are gene-doubled to create a tandem dimer (dTMV). Assemblies of dTMV break the facial symmetry of the double disk to allow for differentiation between the disk faces. A single reactive lysine residue is incorporated into the dTMV assemblies for the site-selective attachment of chromophores for light absorption. Further, on the opposing dTMV face, a cysteine residue is incorporated for the bioconjugation of a peptide containing a polyhistidine tag for association with SLBs. The dual-modified dTMV complexes show significant association with SLBs and exhibit mobility on the bilayer. The techniques used herein offer a new method for protein-surface attachment and provide a platform for evaluating excited state energy transfer events in a dynamic, fully synthetic artificial light-harvesting system.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

Electric fields near undulating dielectric membranes

Dielectric interfaces are crucial to the behavior of charged membranes, from graphene to synthetic and biological lipid bilayers. Understanding electrolyte behavior near these interfaces remains a challenge, especially in the case of rough dielectric surfaces. A lack of analytical solutions consigns this problem to numerical treatments. Here, we report an analytic method for determining electrostatic potentials near curved dielectric membranes in a two-dimensional periodic “slab” geometry using a periodic summation of Green’s functions. This method is amenable to simulating arbitrary groups of charges near surfaces with two-dimensional deformations. We concentrate on one-dimensional undulations. We show that increasing membrane undulation increases the asymmetry of interfacial charge distributions due to preferential ionic repulsion from troughs. In the limit of thick membranes, we recover results mimicking those for electrolytes near a single interface. Our work demonstrates that rough surfaces generate charge patterns in electrolytes of charged molecules or mixed-valence ions.

Chemistry↗

DOE OSTI2020

Membrane stiffness and myelin basic protein binding strength as molecular origin of multiple sclerosis

Myelin basic protein (MBP) and its interaction with lipids of the myelin sheath plays an important part in the pathology of multiple sclerosis (MS). Previous studies observed that changes in the myelin lipid composition lead to instabilities and enhanced local curvature of MBP-lipid multilayer structures. We investigated the molecular origin of the instability and found that the diseased lipid membrane has a 25% lower bending rigidity, thus destabilizing smooth >1µm curvature radius structures such as in giant unilamellar vesicles. MBP-mediated assembling of lipid bilayers proceeds in two steps, with a slow second step occurring over many days where native lipid membranes assemble into well-defined multilayer structures, whereas diseased lipid membranes form folded assemblies with high local curvature. For both native and diseased lipid mixtures we find that MBP forms dense liquid phases on top of the lipid membranes mediating attractive membrane interactions. Furthermore, we observe MBP to insert into its bilayer leaflet side in case of the diseased lipid mixture, whereas there is no insertion for the native mixture. Insertion increases the local membrane curvature, and could be caused by a decrease of the sphingomyelin content of the diseased lipid mixture. These findings can help to open a pathway to remyelination strategies.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Molecular simulations and NMR reveal how lipid fluctuations affect membrane mechanics

Lipid bilayers form the main matrix of functional cell membranes, and their dynamics underlie a host of physical and biological processes. Here we show that elastic membrane properties and collective molecular dynamics (MD) are related by the mean-square amplitudes (order parameters) and relaxation rates (correlation times) of lipid acyl chain motions. We performed all-atom MD simulations of liquid-crystalline bilayers that allow direct comparison with carbon-hydrogen (CH) bond relaxations measured with NMR spectroscopy. Previous computational and theoretical approaches have assumed isotropic relaxation, which yields inaccurate description of lipid chain dynamics and incorrect data interpretation. Instead, the new framework includes a fixed bilayer normal (director axis) and restricted anisotropic motion of the CH bonds in accord with their segmental order parameters, enabling robust validation of lipid force fields. Simulated spectral densities of thermally excited CH bond fluctuations exhibited well-defined spin-lattice (Zeeman) relaxations analogous to those in NMR measurements. Their frequency signature could be fit to a simple power-law function, indicative of nematic-like collective dynamics. Moreover, calculated relaxation rates scaled as the squared order parameters yielding an apparent K C modulus for bilayer bending. Our results show a strong correlation with K C values obtained from solid-state NMR studies of bilayers without and with cholesterol as validated by neutron spin-echo measurements of membrane elasticity. The simulations uncover a critical role of interleaflet coupling in membrane mechanics and thus provide important insights into molecular sites of emerging elastic properties within lipid bilayers.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Machine learning–driven multiscale modeling reveals lipid-dependent dynamics of RAS signaling proteins

Significance Here we present an unprecedented multiscale simulation platform that enables modeling, hypothesis generation, and discovery across biologically relevant length and time scales to predict mechanisms that can be tested experimentally. We demonstrate that our predictive simulation-experimental validation loop generates accurate insights into RAS-membrane biology. Evaluating over 100,000 correlated simulations, we show that RAS–lipid interactions are dynamic and evolving, resulting in: 1) a reordering and selection of lipid domains in realistic eight-lipid bilayers, 2) clustering of RAS into multimers correlating with specific lipid fingerprints, 3) changes in the orientation of the RAS G-domain impacting its ability to interact with effectors, and 4) demonstration that RAS–RAS G-domain interfaces are nonspecific in these putative signaling domains.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2020

The Effect of Cholesterol on Membrane Binding and Self-Assembly of Collagen Fibrils

Collagen is a skeleton of native extracellular matrix (ECM) that is known to provide mechanical and structural stability. In an attempt to develop a new connective cellular model with the surrounding ECM without further experimental complications, such as the reconstitution of ECM receptors, we designed the experiments and discovered that the fibrillogenesis of membrane-bound collagen is not spontaneous as it is in the form of free collagen in bulk solution. Furthermore, the confocal microscopic results suggest that cholesterol is a crucial component that facilitates the fibril formation on the membrane surface. In situ X-ray and neutron reflectivity on Langmuir monolayer and solid-supported lipid bilayer models, respectively, reveal two features of cholesterol effects on the collagen fibril formation. Mainly, cholesterol increases the lateral lipid headgroup separation on the membrane surface, which promotes the association degree of collagen monomers. It also enhances the elastic modulus of the membrane to impede membrane filtration by the collagen assemblies.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗