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Author: search.filters.author.Ni, HaoranStart date: 2020

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    Simulating membrane-bound cytoskeletal dynamics
    (2023) Ni, Haoran; Papoian, Garegin A.; Biophysics (BIPH); Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    The cell membrane defines the shape of the cell and plays an indispensable role in bridging intra- and extra-cellular environments. The membrane, consisting of a lipid bilayer and various attaching proteins, mechanochemically interacts with the active cytoskeletal network that dynamically self-organizes, playing a vital role in cellular biomechanics and mechanosensing. Comprehensive simulations of membrane-cytoskeleton dynamics can bring insight in understanding how the cell mechanochemically responds to external signals, but a computational model that captures the complex cytoskeleton-membrane with both refined details and computational efficiency is lacking. To address this, we introduce in this thesis a triangulated membrane model and incorporate it with the active biological matter simulation platform MEDYAN ("Mechanochemical Dynamics of Active Networks"). This model accurately captures the membrane physical properties, showing how the membrane rigidity, the structure of actin networks and local chemical environments regulate the membrane deformations. Then, we present a new method for simulating membrane proteins, using stochastic reaction-diffusion sampling on unstructured membrane meshes. By incorporating a surface potential energy field into the reaction-diffusion sampling, we demonstrate rich membrane protein collective behaviors such as confined diffusion, liquid-liquid phase separation and membrane curvature sensing. Finally, in order to capture stretching, bending, shearing and twisting of actin filaments which are not all available with traditional actomyosin simulations, we introduce new finite-radius filament models based off Cosserat theory of elastic rods, with efficient implementation using finite-dimensional configurational spaces. Using the new filament models, we show that the filaments' torsional compliance can induce chiral symmetry breaking in a cross-linked actin bundle. All the new models are implemented in the MEDYAN platform, shedding light on whole cell simulations, paving way for a better understanding of the membrane-cytoskeleton system and its role in cellular dynamics.
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    Simulation source code for "Myosin and α-actinin regulation of stress fiber contractility under tensile stress"
    (2023) Ni, Haoran; Ni, Qin; Papoian, Garegin A.; Trache, Andreea; Jiang, Yi; Jiang, Yi
    Stress fibers are actomyosin bundles that regulate cellular mechanosensation and force transduction. Connecting to extracellular matrix through focal adhesion complexes, stress fibers actively generate contractile forces with myosin motors and crosslinking proteins. Under external mechanical stimuli such as tensile forces, the stress fiber remodels its architectures to adapt to the external cues, displaying properties of viscoelastic materials. How the structural remodeling of stress fibers is related to the generation of contractile force is not well understood. In this work, we simulate mechanochemical dynamics and force generation of stress fibers using the molecular simulation platform MEDYAN. We model stress fiber as two connecting bipolar bundles attached at the ends to focal adhesion complexes. The simulated stress fibers generate contractile force that is regulated by myosin motors and α-actinin crosslinkers. We find that stress fibers are able to enhance contractility by reducing the distance between actin filaments to increase crosslinker binding, while this structural remodeling ability depends on the crosslinker turnover rate. Under tensile pulling, the stress fiber shows an instantaneous increase of the contractile forces followed by a slow relaxation into a new steady state. While the new steady state contractility after pulling only depends on the overlap between actin bundles, the short term contractility enhancement is sensitive to the tensile pulling distance. We further show that this mechanical response is sensitive to the crosslinker turnover rate. Our results provide insights into the stress fiber mechanics that have significant implications for understanding the cellular adaptation to mechanical signaling.
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    Data for "A tug of war between filament treadmilling and myosin induced contractility generates actin ring"
    (2022-06-23) Ni, Qin; Wagh, Kaustubh; Pathni, Aashli; Ni, Haoran; Vashisht, Vishavdeep; Upadhyaya, Arpita; Papoian, Garegin A.; Upadhyaya, Arpita; Papoian, Garegin A.
    In most eukaryotic cells, actin filaments assemble into a shell-like actin cortex under the plasma membrane, controlling cellular morphology, mechanics, and signaling. The actin cortex is highly polymorphic, adopting diverse forms such as the ring-like structures found in podosomes, axonal rings, and immune synapses. The biophysical principles that underlie the formation of actin rings and cortices remain unknown. Using a molecular simulation platform, called MEDYAN, we discovered that varying the filament treadmilling rate and myosin concentration induces a finite size phase transition in actomyosin network structures. We found that actomyosin networks condense into clusters at low treadmilling rates or high myosin concentration but form ring-like or cortex-like structures at high treadmilling rates and low myosin concentration. This mechanism is supported by our corroborating experiments on live T cells, which exhibit ring-like actin networks upon activation by stimulatory antibody. Upon disruption of filament treadmilling or enhancement of myosin activity, the pre-existing actin rings are disrupted into actin clusters or collapse towards the network center respectively. Our analyses suggest that the ring-like actin structure is a preferred state of low mechanical energy, which is, importantly, only reachable at sufficiently high treadmilling rates.
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    Data for "Membrane-MEDYAN: Simulating Deformable Vesicles Containing Complex Cytoskeletal Networks"
    (2021) Ni, Haoran; Papoian, Garegin A.; Papoian, Garegin A.
    The plasma membrane defines the shape of the cell and plays an indispensable role in bridging intra- and extra-cellular environments. Mechanochemical interactions between plasma membrane and cytoskeleton are vital for cell biomechanics and mechanosensing. A computational model that comprehensively captures the complex, cell-scale cytoskeleton-membrane dynamics is still lacking. In this work, we introduce a triangulated membrane model that accounts for membrane's elastic properties, as well as for membrane-filament steric interactions. The corresponding force-field was incorporated into the active biological matter simulation platform, MEDYAN ("Mechanochemical Dynamics of Active Networks"). Simulations using the new model shed light on how actin filament bundling affects generation of tubular membrane protrusions. In particular, we used membrane-MEDYAN simulations to investigate protrusion initiation and dynamics while varying geometries of filament bundles, membrane rigidities and local G-Actin concentrations. We found that bundles' protrusion propensities sensitively depend on the synergy between bundle thickness and inclination angle at which the bundle approaches the membrane. The new model paves the way for simulations of biological systems involving intricate membrane-cytoskeleton interactions, such as occurring at the leading edge and the cortex, eventually helping to uncover the fundamental principles underlying the active matter organization in the vicinity of the membrane.