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 G11: Multi-Scale Modelling of Biological Cells: from Atoms to Whole CellsFocus
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Sponsoring Units: DBIO Chair: Margaret Cheung, Pacific Northwest National Laboratory Room: Room 203 |
Tuesday, March 7, 2023 11:30AM - 12:06PM |
G11.00001: Active transport and self-organization in living cells Invited Speaker: Michael J Shelley Efficient control of mass, energy, and information flows is critical for the robust function of large complex systems. Cities, for example, can come to a standstill when power grids, transportation, or information networks are disrupted. A living organism is another - one whose function requires the tandem operation of circulatory and nervous systems that couple disparate parts of the body, orchestrating the joint work of billions of cells. Large-scale coordination is no less essential in a single cell, especially for events leading up to cell division or the maturation of an egg. Much of that coordination is actuated through the cell's cytoskeleton, a collection of polymers, cross-linkers, and molecular motors, that organizes itself into mesoscopic active structures to perform its various tasks. Along this vein, I'll discuss how genetic material is "properly" positioned within the cell as it moves towards division, and how egg cells self-organize large-scale transport flows during growth. Both involve the collective interaction of cytoskeletal polymers with motors, and understanding them has required new experiments, new models, and new methods of simulation. As mechanics problems they are also beautiful, giving rise to novel fluid-structure problems, and new instabilities to ponder. |
Tuesday, March 7, 2023 12:06PM - 12:18PM |
G11.00002: Individual-based Biophysical Modeling of Spatial Dynamics of Chemotactic Microbial Populations Congjian Ni One important direction of synthetic biology is to establish desired spatial structures from microbial populations. Underlying this structural development process are different driving factors, among which bacterial motility and chemotaxis serve as a major force. Here, we present an individual-based, biophysical computational framework for mechanistic and multiscale simulation of the spatiotemporal dynamics of motile and chemotactic microbial populations. The framework integrates cellular movement with spatial population growth, mechanical and chemical cellular interactions, and intracellular molecular kinetics. It is validated by a statistical comparison of single-cell chemotaxis simulations with reported experiments. The framework successfully captures colony range expansion of growing isogenic populations, and also reveals chemotaxismodulated, spatial patterns of a two-species amensal community. Partial differential equation-based models subsequently validate these simulation findings. The study provides a versatile computational tool to uncover the fundamentals of microbial spatial ecology as well as to facilitate the design of synthetic consortia for desired spatial patterns. |
Tuesday, March 7, 2023 12:18PM - 12:30PM Author not Attending |
G11.00003: Combining mechanistic and statistical models to enable Nascent Chain Tracking for multiple mRNAs using a single color William S Raymond mRNA translation is the ubiquitous cellular process of reading messenger-RNA strands into functional proteins. Within the past decade, large strides in fluorescent microscopy techniques have allowed observation of mRNA translation at a single-molecule resolution for self-consistent time-series measurements in live cells. Dubbed Nascent Chain Tracking (NCT), these methods elucidate translation dynamics lost by other investigatory techniques such as ribosomal footprinting or mRNA-seq; However, NCT has been limited to the observation of one or two mRNA species at a time within the same cell partly due to limits in the number of resolvable fluorescent tags. In this work, we present a hybrid computational pipeline where detailed mechanistic simulations produce realistic NCT videos and machine learning is used to assess experimental designs for their potential to resolve multiple mRNA species sharing a single fluorescent color. With careful application, this hybrid design strategy could in principle be used to extend the number of mRNA species that could be watched simultaneously within the same cell. We present a toy example NCT experiment with 7 different mRNAs species within the same simulated cell and use our ML labeling to label these spots with a 90% accuracy. The possibilities offered by this color palette extension will allow experimentalists access to a plethora of new experimental design possibilities -- especially for investigating cell signals that affect multiple mRNAs at a time. |
Tuesday, March 7, 2023 12:30PM - 1:06PM |
G11.00004: Landscapes of Genomic Architecture Across Evolution Invited Speaker: Michele Di Pierro The human genome is composed of 46 DNA molecules — the chromosomes — with a combined length of about two meters. Chromosomes are stored in the cell nucleus in a very organized fashion that is specific to the cell type and phase of life; this three-dimensional architecture is a key element of transcriptional regulation and its disruption often leads to disease. What is the physical mechanism leading to genome architecture? If the DNA contained in every human cell is identical, where is the blueprint of such architecture stored? |
Tuesday, March 7, 2023 1:06PM - 1:18PM |
G11.00005: Stochastic Models of Cellular Survival and Evolution Christopher R Siebor, Gabor Balazsi Simple models of growing and dying cell populations could be useful for studying cellular evolution. Using an Ornstein-Uhlenbeck process, we simulate fluctuating protein levels within an initial set of agents capable of division and death, which could represent living cells. We verify that the average, standard deviation, and autocorrelation coefficient correspond to expectations for the Ornstein-Uhlenbeck process. To model cytotoxic stress, we then introduce a Heaviside Step Function as a condition to induce agent replication and agent death and analyze the number of descendants as a function of the death/replication threshold, correlation time, and standard deviation. Furthermore, we utilize this model in simulating the long-term evolution of agent populations. |
Tuesday, March 7, 2023 1:18PM - 1:30PM |
G11.00006: Oxygen delivery to tissue via a complex branched cellular network Tatyana Gavrilchenko, Pauline Hansen, Daniel Fortunato, Alex Barnett, Stanislav Y Shvartsman In the insect respiratory system, air-filled trachea permeate the animal's body, supplying the necessary oxygen for metabolic activity and removing waste carbon dioxide. The structure of a single branched tracheole acts as an efficient distribution system, ensuring that no tissue regions are left hypoxic. To understand what structural features allow for adequate supply of the system, we investigate the steady-state tissue oxygen gradient arising from a tree-like distribution network with a single point of entry. We model the 2D system with two simple transport behaviors: fast oxygen diffusion through the air-filled tracheal network and slow diffusion and absorption in the surrounding tissue. The oxygen concentrations in the tissue and within the network are coupled by a boundary condition on the plasma membrane that constitutes the interface between the network and the tissue. We apply a potential theory approach, which approximates the continuous oxygen field in the network as a series of decaying point-sources of oxygen, and solves for the strengths of these point sources. This method is efficient because it involves only discretizing the network; the oxygen field in the tissue is then evaluated by summing over the contributions across all point sources. We find that this approach works well on complex network geometries, including curved and branched networks that approximate the geometry of the tracheal cells. Modeling the tissue oxygen gradient arising from a static geometry is the first step towards a fully-contained developmental model of tracheal cell growth. Tracheal cells grow by extending branches into regions of tissue hypoxia, so adding an adaptive growth mechanism based on chemical signaling of undersupplied regions is a way to generate realistic tracheal network geometries. |
Tuesday, March 7, 2023 1:30PM - 1:42PM |
G11.00007: Multiscale Model of Antiviral Timing, Potency, and Heterogeneity Effects on an Epithelial Tissue Patch Infected by SARS-CoV-2 Juliano Ferrari Gianlupi, Tarunendu Mapder, T.J. Sego, James P Sluka, Sara K Quinney, Morgan Craig, Robert E Stratford, Jr, James A Glazier We extend our established agent-based multiscale computational model of infection of lung tissue by SARS-CoV-2 to include pharmacokinetic and pharmacodynamic models of remdesivir. We model remdesivir treatment for COVID-19; however, our methods are general to other viral infections and antiviral therapies. We investigate the effects of drug potency, drug dosing frequency, treatment initiation delay, antiviral half-life, and variability in cellular uptake and metabolism of remdesivir and its active metabolite on treatment outcomes in a simulated patch of infected epithelial tissue. Non-spatial deterministic population models which treat all cells of a given class as identical can clarify how treatment dosage and timing influence treatment efficacy. However, they do not reveal how cell-to-cell variability affects treatment outcomes. Our simulations suggest that for a given treatment regime, including cell-to-cell variation in drug uptake, permeability and metabolism increase the likelihood of uncontrolled infection as the cells with the lowest internal levels of antiviral act as super-spreaders within the tissue. The model predicts substantial variability in infection outcomes between similar tissue patches for different treatment options. In models with cellular metabolic variability, antiviral doses have to be increased significantly (>50% depending on simulation parameters) to achieve the same treatment results as with the homogeneous cellular metabolism. We believe this explains some of the ambiguity of the clinical?trials. The spatial model enables exploration of the effects of inter-cellular heterogeneous response to the antiviral. Something that a population model wouldn't be able to explore. |
Tuesday, March 7, 2023 1:42PM - 1:54PM |
G11.00008: Ab Initio investigation of bio-interfaces Deniz Cakir, Ashan Fernando Warnakulasuriya, Mark Hoffmann The interaction of amino acids with clay minerals results in the formation of novel biomaterial nanocomposite systems promising such as for bone tissue regeneration through osteogenesis. Therefore, an atomistic understanding of nano clay interaction with biologically relevant materials is of great importance. In this respect, we investigated the interaction of eleven unnatural amino acids with Fe and Mg co-doped montmorillonite clay using density functional theory calculations. Fe doping gives rise to a ferromagnetic ground state with a magnetic moment of around 4 μB/Fe. Our calculations indicated a substantial electrostatic interaction between all amino acid molecules and the clay surface. We identified the amino acids with large binding energies. Our calculations pointed out that the amino group has the dominant role in the binding of amino acids on the clay surface. An atomistic understanding of amino-acid/clay interaction will pave the way for the rational design of amino acids and help to elucidate the clay-integrin interaction. |
Tuesday, March 7, 2023 1:54PM - 2:06PM |
G11.00009: Contrasting self-assembly pathways at the membrane Margaret E Johnson Self-assembly of protein components from solution to the plasma membrane is necessary for a variety of membrane remodelling processes. For entry into and exit from the cell, the clathrin protein and the Gag polyprotein, respectively, assemble rigid lattices that help scaffold the membrane. However, these assemblies differ in how they couple to co-factors that can separately promote either protein-protein assembly or protein-membrane recruitment. We discuss similarities between these systems that can help them to efficiently assemble only on membranes, highlighting how cooperativity plays a key role in avoiding kinetic traps. We contrast the distinct routes that these systems use for effective assembly, dependent on the valency and flexibility of their interactions, the properties of their co-factors, and the production of these proteins within cells. Using theory and models that can be simulated using reaction-diffusion software, we determine regimes where these distinct systems can maintain robust assembly, and where they can be perturbed to disrupt assembly and remodelling. |
Tuesday, March 7, 2023 2:06PM - 2:18PM |
G11.00010: Enhancement of Information Transmission Efficiency via Feedback in Synapses of the Fly Early Visual System Golam M Kashef, Robert de Ruyter Metabolic efficiency and the rate of information transmission are both important factors in biological design. Producing synaptic vesicles, for example, comes at a metabolic cost, and while fidelity of synaptic transmission can be made indefinitely high by increasing the rate of vesicle release, such an adaptation will also use up an indefinite amount of energy. A driving principle in the design of the synapse is thus the optimization of the bit rate per vesicle in operational conditions. A study of the contrast power transfer spectrum and the noise power spectral density of large monopolar cells (LMCs) of the blowfly C. vicina predicts a sustained minimum rate of >105 synaptic vesicles per second per LMC. The calculation of this rate assumes that the exocytosis of vesicles occurs as an unstructured (Poisson) process. If instead, we assume that vesicle release is more structured, noise may be suppressed at the low end of the spectrum, substantially bringing down the release rate required for observed experimental results. Weckström and Laughlin (2010) show that significant electric potentials are generated in the photoreceptor-LMC extracellular space as a response to visual activity. We propose that regularization of vesicles occurs through the control of the voltage sensors responsible for vesicle release by these feedback potentials. We demonstrate signatures of synaptic control experimentally, and through modeling, the consequences of the measured extracellular responses on the bit rate per vesicle. |
Tuesday, March 7, 2023 2:18PM - 2:30PM |
G11.00011: Energetic and kinetic criteria for assembling HIV-1 Gag lattices in solution Yian Qian, Margaret E Johnson, Daniel Evans For cells infected by the HIV-1 virus, forming new virions requires self-assembly of the |
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