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 K02: Binding and Assembly of Proteins on MembranesFocus
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Sponsoring Units: GSNP DSOFT DBIO Chair: Ehssan Nazockdast, University of North Carolina at Chapel H; Christopher Edelmaier Room: Room 125 |
Tuesday, March 7, 2023 3:00PM - 3:36PM |
K02.00001: Surface Fluctuating Hydrodynamics Methods for the Drift-Diffusion Dynamics of Proteins and Microstructures within Curved Lipid Bilayer Membranes Invited Speaker: Paul J Atzberger We introduce surface fluctuating hydrodynamics approaches for investigating transport and fluid-structure interactions arising in cell mechanics within curved lipid bilayer membranes. We focus particularly on drift-diffusion dynamics of interacting proteins and microstructures. We show how a mesoscale stochastic description of the mechanics can be formulated (SPDEs) accounting for geometric contributions, hydrodynamic coupling, and thermal fluctuations. The underlying stochastic equations (SPDEs) pose practical challenges for use in simulations, including, (i) a need for accurate and stable discretizations of geometric terms and differential operators on curved geometries, (ii) techniques for hydrodynamics handling surface incompressibility constraints, and (iii) stiffness from rapid time-scales introduced by the thermal fluctuations. We show how practical spectral methods and meshfree computational approaches can be developed for simulations over long spatial-temporal scales. We then present results for protein and microstructure interactions within membranes and the roles played by hydrodynamic coupling and geometry. |
Tuesday, March 7, 2023 3:36PM - 3:48PM |
K02.00002: Modeling the assembly of curvature inducing proteins in SARS-CoV-2 budding at multiple scales Joseph McTiernan, Michael Colvin, Roya Zandi, Ajay Gopinathan The assembly of SARS-CoV-2 in the ER-Golgi intermediate compartment (ERGIC) is a result of the interplay between the virus' accumulated structural proteins and the ERGIC membrane. As the most abundant structural protein, the membrane (M) protein is thought to interact with the envelope (E), nucleocapsid (N), and spike (S) proteins and plays a key role in producing sufficient curvature for viral budding. Experimentally, it has been shown that M proteins phase separate with a combination of N proteins and RNA in solvent, possibly mediating the onset of budding in the presence of a membrane. This phase separation can be demonstrated analytically by modeling the coupled evolution of M protein density and membrane shape, where proper parameterization requires a microscopic understanding of the interactions and dynamics of M proteins. To help develop this understanding, we utilize a multiscale modeling approach. From mesoscale, continuum models of membrane-bound M protein dimers, we show the impact of different protein properties on the budding process. Additionally, we present estimates of parameters needed for our mesoscopic model using all-atom simulations of M protein dimers, both free and bound in the membrane. Combining the parameters determined from all-atom simulations with our mesoscopic model allows for improved understanding of the budding and assembly process for SARS-CoV-2. |
Tuesday, March 7, 2023 3:48PM - 4:00PM |
K02.00003: Curvature sensing as an emergent property of multi-scale assembly of septins Wenzheng Shi, Ehssan Nazockdast, Christopher J Edelmaier
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Tuesday, March 7, 2023 4:00PM - 4:12PM |
K02.00004: Influence of thermal fluctuations on the association and localization of proteins onto curved membranes Indrajit Badvaram, Brian A Camley Recently, we derived theoretical limits to how well a single protein could sense membrane curvatures in the presence of thermal fluctuations of the membrane. Here, we extend these results to develop models that predict single-protein association rates to membrane-adhered beads of different curvatures. Referring to experiments on the association of septin proteins, we propose two classes of predictive models: i) for proteins with a maximal association rate to a preferred membrane curvature, and ii) for proteins with enhanced association rates above a threshold curvature. This allows us to connect concepts such as fluctuation variances and sensing limits to experimentally measurable protein association rates. Because proteins may be exploiting asymmetries in lipid packing in the bilayer as a proxy for curvature, we show how an algorithm we developed for simulating lipid density fluctuations in continuum membranes can be used to study the localization of proteins to regions with their preferred lipid density deviations. We then investigate how lipid density fluctuations influence the assembly of multiple proteins on the membrane, while varying parameters such as the membrane's thickness and area compressibility modulus, and the topography of substrates underlying the membrane. |
Tuesday, March 7, 2023 4:12PM - 4:24PM |
K02.00005: A bifurcation amplifies and integrates a noisy signal from many molecular thermo-receptors Isabella R Graf, Benjamin B Machta In various biological systems information from many individually noisy molecular receptors must be integrated into a collective response. A striking example is the thermal imaging organ of pit vipers. Single neurons in the organ reliably respond to mK temperature increases, 1000 times more sensitive than single thermo-TRP ion channels, whose opening probability barely rises – by less than 0.1%. Here, we propose a mechanism for the integration of this molecular information into an amplified neural response. In our model TRP channels are embedded into the electrical dynamics of the neural membrane. Due to the channels' intrinsic voltage sensitivity, these dynamics contain a bifurcation separating a monostable regime, with regular firing of action potentials (APs), from a bistable regime, with rare and stochastic APs. Near the transition, AP frequency has a sharp dependence on temperature, naturally accounting for the 1000-fold increase in sensitivity from single channels to neuronal firing. Furthermore, near the bifurcation most of the information about temperature available in the channels' kinetics can be easily read out by the timing of APs. While tuning to such bifurcation points typically requires fine-tuning of parameters, we propose that having feedback act from the order parameter (AP frequency) onto the control parameter naturally maintains the system in the vicinity of the bifurcation. |
Tuesday, March 7, 2023 4:24PM - 4:36PM |
K02.00006: Probing surface-mediated protein aggregation via FRET-induced lifetime changes Paula-Marie E Ivey, Magaly Guzman Sosa, Arjun Krishnamoorthi, Justin A Patel, Jean-Christophe Rochet, Kevin J Webb Alpha-synuclein (aSyn) aggregation in the brain is a distinctive pathological feature of Parkinson's disease (PD). Much remains unknown about the molecular details of aSyn aggregation, namely the mechanism for its onset and propagation, and how this process leads to neuron dysfunction and ultimately death. A substantial fraction of aSyn molecules in neurons are bound to phospholipid membranes, where binding affinity is dependent on membrane polarity and curvature. Membrane-induced aSyn aggregation is hypothesized to be a pathologically relevant event in PD. Notably, lipid membrane surfaces may act as a platform upon which nucleation can occur. Surface-mediated protein aggregation can be studied via fluorescence resonance energy transfer (FRET) interactions between fluorescently labeled membrane surfaces and proteins, where the donor fluorescence lifetime is indicative of the degree of proximity. We describe progress on the detection and understanding of surface-mediated aSyn aggregation on artificial membranes made from anionic phospholipids. This is achieved through FRET-induced fluorescence lifetime changes recorded by a custom-built fluorescence lifetime imaging microscope. Additionally, the affinity of aSyn to various membranes in SY5Y neurons is explored. |
Tuesday, March 7, 2023 4:36PM - 4:48PM |
K02.00007: The mechanical basis for single amphipathic helix engagement with membranes Christopher J Edelmaier Septins are a class of cytoskeletal proteins that can sense and communicate details about micron-scale curvature based on their binding to cellular membranes. Studies show that amphipathic helix (AH) domains on the protein are indispensable for the ability of these nanoscale proteins to probe micron-scale curvatures. Yet, the underlying mechanochemical interactions that modulate this curvature sensing remains ambiguous. One barrier is the difference in time scale(s) between atomistic, coarse-grained, and continuum simulations when compared to in vivo or in vitro experiments. I will present research into how AH-domains interact with cellular membranes at the atomistic scale. Our preliminary results suggest that the folded, helical form of the AH-domain leads to stable membrane association, while the unfolded form leads to dissociation from the membrane. Additionally, our results suggest that the structure of AH-domain-membrane interface seems to be driven by electrostatic interactions. |
Tuesday, March 7, 2023 4:48PM - 5:00PM |
K02.00008: All Atom Simulations Reveal Adaptive and Multimodal Membrane Binding of Contractile Ring Anchoring Protein Mid1 Aaron R Hall, Yeol Kyo Choi, Wonpil Im, Dimitrios Vavylonis The positioning of the cytokinetic ring at the cell equator in animals and fungi depends crucially on the anillin scaffold proteins. In fission yeast, anillin-like Mid1 binds to the plasma membrane and helps establish a broad band of cytokinetic nodes near the cell center. Mid1 consists of a C terminal globular domain with two membrane binding candidate regions, the Plekstrin Homology (PH) and C2 domains, both of which prefer PIP2 lipids, and an N terminal intrinsically disordered region. The PH and C2 domains are joined by a connector domain (CNCT) and the C2 domain contains a predicted flexible region that is important for membrane binding. Previous studies have shown that both PH and C2 domains can associate with the membrane. However, it's unclear if they can simultaneously bind to the membrane in a way allowing Mid1 dimerization or oligomerization, and if one domain plays a dominant role. In order to elucidate Mid1's membrane binding mechanism, we used the available structural information of the PH, C2, and CNCT in all atom molecular dynamics simulations of Mid1 near membrane compositionally based on experimental measurements. The results indicate that Mid1 initially binds through the C2's L3 loop, and can further bind through the PH domain and C2's L1 loop. Mid1's multiple modes of binding may reflect multiple interactions with membranes and other node proteins, and ability to sustain mechanical forces. |
Tuesday, March 7, 2023 5:00PM - 5:12PM |
K02.00009: Atomic Insights into Amyloid-Induced Membrane Damage Yanxing Yang Amphipathic peptides can cause biological membranes to leak either by dissolving their lipid content via a detergent-like mechanism or by forming pores on the membrane surface. These modes of membrane damage have been related to the toxicity of amyloid peptides and to the activity of antimicrobial peptides. Here, we perform the first all-atom simulations in which membrane-bound amphipathic peptides self-assemble into β-sheets that subsequently either form stable pores inside the bilayer or drag lipids out of the membrane surface. An analysis of these simulations shows that the acyl tail of lipids interact strongly with non-polar side chains of peptides deposited on the membrane. These strong interactions enable lipids to be dragged out of the bilayer by oligomeric structures accounting for detergent-like damage. They also disturb the orientation of lipid tails in the vicinity of peptides. These distortions are minimized around pore structures. We also show that membrane-bound β-sheets become twisted with one of their extremities partially penetrating the lipid bilayer. This allows peptides on opposite leaflets to interact and form a long transmembrane β-sheet, which initiates poration. In simulations, where peptides are deposited on a single leaflet, the twist in β sheets allows them to penetrate the membrane and form pores. In addition, our simulations show that fibril-like structures produce little damage to lipid membranes, as non-polar side chains in these structures are unavailable to interact with the acyl tail of lipids. |
Tuesday, March 7, 2023 5:12PM - 5:24PM |
K02.00010: Investigation of the synergistic antimicrobial effect of Winter Flounder peptides using molecular dynamics simulations Miruna Serian With the fast-growing resistance of bacteria to antibiotics, antimicrobial peptides (AMPs) have gained attention as potential drug candidates because of their potency against a broad spectrum of bacteria. AMPs are ubiquitous in nature and their activity occurs through a wide range of mechanisms, including membrane disruption and immunomodulation. Although many AMPs have been tested in clinical trials, it has been observed that, in certain cases, the antimicrobial effect of combinations of AMPs is stronger than for each peptide alone. Analogous to combinations of drugs, combinations of AMPs could lead to more potent antibacterial agents with lower host toxicity, a delay in the evolution of drug resistance and a reduction in the dosage needed, hence causing less side effects. The use of molecular dynamics (MD) simulations has proven to be a powerful tool to investigate the molecular mechanisms which drive the antimicrobial effects of AMPs. Here we report the results of all-atom molecular dynamics simulations of the interaction of 10 different two-way combinations of Winter Flounder peptides, a family of cationic AMPs found in the epithelial mucous cells of winter flounder, against membrane models representative of gram-positive bacteria (100% POPG), gram-negative bacteria (POPE:POPG = 3:1) and red blood cells (RBC). The results of the MD simulations of the most promising WF peptides combinations in different bacterial membrane models could help shed light into the synergistic activity of AMPs and help guide the creation of effective AMPs cocktails for therapeutic use. |
Tuesday, March 7, 2023 5:24PM - 5:36PM |
K02.00011: Exploring Specific and Non-specific Membrane Binding Targets of Self-assembling Human Islet Amyloid Polypeptide Oligomers on Phase-Separated Lipid Domains Using MD Simulations Kwan H Cheng, Angela D Graf, Aakriti Acharya, Thuong L Pham Self-aggregation of human Islet Amyloid Polypeptide (hIAPP) is linked to type 2 diabetics (T2D). Recent cellular studies indicate that the small, disordered hIAPP oligomers are more membrane-active and cytotoxic than the mature, ordered hIAPP fibrils. How hIAPP oligomers interact with the phase-separated lipid bilayers, a model of plasma membranes, is still unclear. Using coarse-grained (CG) and all-atom (AA) MD simulations, hIAPP oligomers in solution were created. By mixing phosphatidylcholine, cholesterol, ganglioside (GM1), and phosphatidylserine (PS) lipids, bilayers containing ordered (Lo), disordered (Ld), and mixed (Lod) domains on both leaflets, as well as PS- or GM1-domains on one leaflet each, were also formed. Within 10 μs of CG simulations, hIAPP oligomers bound to the Lod domains in leaflets without PS or GM1, but to PS- or GM1-domains in leaflets with PS or GM1. After a CG-to-AA mapping and a 300 ns long AA simulation, protein-induced disruptions of lipid chain orientational order in all lipids, particularly saturated lipids, and extensive beta-sheet formation in oligomers bound on Lod domains were found. Since PS and GM1 are found exclusively in the inner and outer leaflets of plasma membranes, respectively, we conclude that the PS- and GM1-domains are leaflet-specific targets while the Lod domains are non-specific membrane targets in the early progression of T2D. |
Tuesday, March 7, 2023 5:36PM - 5:48PM |
K02.00012: Antibody binding regulates the dynamics of the membrane-bound prion protein Ioana M Ilie, Marco Bacci, Andreas Vitalis, Amedeo Caflisch Prion diseases are associated with the conversion of the cellular prion protein (PrPC) into a pathogenic conformer (PrPSc). A proposed therapeutic approach to avoid the pathogenic transformation is to develop monoclonal antibodies that bind to PrPC and stabilize its structure. POM1 and POM6 are two monoclonal antibodies that bind the globular domain of PrPC and have different biological responses, i.e. trigger neurotoxicity mimicking prion infections (POM1) or prevent neurotoxicity (POM6). The crystal structures of PrPC in complex with the two antibodies show similar epitopes which seems inconsistent with the opposite phenotypes. |
Tuesday, March 7, 2023 5:48PM - 6:00PM |
K02.00013: Force probing ligand-receptor interactions on cells and exosomes sakurako tani, Lina A Alhalhooly, Yongki Choi Using the single-molecule force spectroscopy method, we probed dynamic ligand-cellular receptor interactions and found important physical parameters associated with binding and unbinding thermodynamics. First, the rupture force of individual ligand-receptor bonds was unchanged for different cell types. Second, the dissociation dynamics of the binary complex were fitted to the Bell–Evans two-state transition model, in which the kinetic off-rate of multivalent bonds was substantially decreased. Third, sequential rupture events of multiple bonds revealed that the force strength for breaking up the initial bonds under multivalent interactions was weaker than that of synchronous multiple rupture events, but the last rupture events and the force strength were identical to the synchronous case, suggesting an independent parallel bond mechanism. The results provide a wealth of new information on cellular receptors' binding selectivity, affinity, and stability to their ligands. |
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