Browsing by Author "Cheung, Margaret S."

Now showing 1 - 6 of 6
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    Assemblies of calcium/calmodulin-dependent kinase II with actin and their dynamic regulation by calmodulin in dendritic spines
    (National Academy of Sciences, 2019) Wang, Qian; Chen, Mingchen; Schafer, Nicholas P.; Bueno, Carlos; Song, Sarah S.; Hudmon, Andy; Wolynes, Peter G.; Waxham, M. Neal; Cheung, Margaret S.
    The structural dynamics of the dendritic synapse, arising from the remodeling of actin cytoskeletons, has been widely associated with memory and cognition. The remodeling is regulated by intracellular Ca2+ levels. Under low Ca2+ concentration, actin filaments are bundled by a calcium signaling protein, CaMKII. When the Ca2+ concentration is raised, CaMKII dissociates from actin and opens the window for actin remodeling. At present, the molecular details of the actin bundling and regulation are elusive. Herein we use experimental tools along with molecular simulations to construct a model of how CaMKII bundles actin and how the CaMKII–actin architecture is regulated by Ca2+ signals. In this way, our results explain how Ca2+ signals ultimately change the structure of the dendritic synapse.
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    Coarse-Grained Modeling and Molecular Dynamics Simulations of Ca2+-Calmodulin
    (Frontiers, 2021) Nde, Jules; Zhang, Pengzhi; Ezerski, Jacob C.; Lu, Wei; Knapp, Kaitlin; Wolynes, Peter G.; Cheung, Margaret S.; Center for Theoretical Biological Physics
    Calmodulin (CaM) is a calcium-binding protein that transduces signals to downstream proteins through target binding upon calcium binding in a time-dependent manner. Understanding the target binding process that tunes CaM’s affinity for the calcium ions (Ca2+), or vice versa, may provide insight into how Ca2+-CaM selects its target binding proteins. However, modeling of Ca2+-CaM in molecular simulations is challenging because of the gross structural changes in its central linker regions while the two lobes are relatively rigid due to tight binding of the Ca2+ to the calcium-binding loops where the loop forms a pentagonal bipyramidal coordination geometry with Ca2+. This feature that underlies the reciprocal relation between Ca2+ binding and target binding of CaM, however, has yet to be considered in the structural modeling. Here, we presented a coarse-grained model based on the Associative memory, Water mediated, Structure, and Energy Model (AWSEM) protein force field, to investigate the salient features of CaM. Particularly, we optimized the force field of CaM and that of Ca2+ ions by using its coordination chemistry in the calcium-binding loops to match with experimental observations. We presented a “community model” of CaM that is capable of sampling various conformations of CaM, incorporating various calcium-binding states, and carrying the memory of binding with various targets, which sets the foundation of the reciprocal relation of target binding and Ca2+ binding in future studies.
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    Molecular mechanisms of the interhead coordination by interhead tension in cytoplasmic dyneins
    (National Academy of Sciences of the United States of America, 2018) Wang, Qian; Jana, Biman; Diehl, Michael R.; Cheung, Margaret S.; Kolomeisky, Anatoly B.; Onuchic, José Nelson
    Cytoplasmic dyneins play a major role in retrograde cellular transport by moving vesicles and organelles along microtubule filaments. Dyneins are multidomain motor proteins with two heads that coordinate their motion via their interhead tension. Compared with the leading head, the trailing head has a higher detachment rate from microtubules, facilitating the movement. However, the molecular mechanism of such coordination is unknown. To elucidate this mechanism, we performed molecular dynamics simulations on a cytoplasmic dynein with a structure-based coarse-grained model that probes the effect of the interhead tension on the structure. The tension creates a torque that influences the head rotating about its stalk. The conformation of the stalk switches from the α registry to the β registry during the rotation, weakening the binding affinity to microtubules. The directions of the tension and the torque of the leading head are opposite to those of the trailing head, breaking the structural symmetry between the heads. The leading head transitions less often to the β registry than the trailing head. The former thus has a greater binding affinity to the microtubule than the latter. We measured the moment arm of the torque from a dynein structure in the simulations to develop a phenomenological model that captures the influence of the head rotating about its stalk on the differential detachment rates of the two heads. Our study provides a consistent molecular picture for interhead coordination via interhead tension.
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    Molecular origin of the weak susceptibility of kinesin velocity to loads and its relation to the collective behavior of kinesins
    (National Academy of Sciences, 2017) Wang, Qian; Diehl, Michael R.; Jana, Biman; Cheung, Margaret S.; Kolomeisky, Anatoly B.; Onuchic, José Nelson
    Motor proteins are active enzymatic molecules that support important cellular processes by transforming chemical energy into mechanical work. Although the structures and chemomechanical cycles of motor proteins have been extensively investigated, the sensitivity of a motor’s velocity in response to a force is not well-understood. For kinesin, velocity is weakly influenced by a small to midrange external force (weak susceptibility) but is steeply reduced by a large force. Here, we utilize a structure-based molecular dynamic simulation to study the molecular origin of the weak susceptibility for a single kinesin. We show that the key step in controlling the velocity of a single kinesin under an external force is the ATP release from the microtubule-bound head. Only under large loading forces can the motor head release ATP at a fast rate, which significantly reduces the velocity of kinesin. It underpins the weak susceptibility that the velocity will not change at small to midrange forces. The molecular origin of this velocity reduction is that the neck linker of a kinesin only detaches from the motor head when pulled by a large force. This prompts the ATP binding site to adopt an open state, favoring ATP release and reducing the velocity. Furthermore, we show that two load-bearing kinesins are incapable of equally sharing the load unless they are very close to each other. As a consequence of the weak susceptibility, the trailing kinesin faces the challenge of catching up to the leading one, which accounts for experimentally observed weak cooperativity of kinesins motors.
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    The role of actin-binding proteins in shaping the dynamics and structures of actomyosin networks
    (2022-12-01) Liman, James; Cheung, Margaret S.; Diehl, Michael; Wolynes, Peter G.
    Actomyosin networks give cells the ability to move and divide. These networks contract and expand while being driven by active energy-consuming processes such as motor protein walking and actin polymerization. Actin dynamics is also regulated by actin-binding proteins, such as the actin-related protein 2/3 (Arp2/3) complex and calcium/calmodulin-dependent protein kinase II (CaMKII) complex. Arp2/3 generates branched filaments while CaMKII binds and bundles actin filaments, thereby changing the overall organization and dynamics of the network. While the structures of Arp2/3 and CaMKII have been explored extensively, how these complexes change the architectural dynamics of the actomyosin network raises many questions. In this work, the spatiotemporal patterns of dynamical actin assembly accompanying reorganization caused by Arp2/3 and CaMKII were studied using both a mass action kinetic model and a computational model (mechanochemical dynamics of active networks or MEDYAN). This computational model simulates actomyosin network dynamics as a result of chemical reactions whose rates are modulated by rapid mechanical equilibration. We show that branched actomyosin networks relax significantly more slowly than do unbranched networks. Also, branched networks undergo rare convulsive movements, termed “avalanches”, that release strain in the network. These avalanches are associated with the more heterogeneous distribution of mechanically-linked filaments displayed by branched networks. These far-from equilibrium events arising from the marginal stability of growing actomyosin networks provide a possible mechanism of the “cytoquakes” recently seen in experiments. We show that the multivalent interactions between CaMKII and actin enable rich structural arrangements of actin filaments. Unlike branched networks, networks with CaMKII resemble crystalline networks due to abundant connections between CaMKII and actin filaments.
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    Understanding protein-complex assembly through grand canonical maximum entropy modeling
    (American Physical Society, 2021) Gasic, Andrei G.; Sarkar, Atrayee; Cheung, Margaret S.; Center for Theoretical Biological Physics
    Inside a cell, heterotypic proteins assemble in inhomogeneous, crowded systems where the abundance of these proteins vary with cell types. While some protein complexes form putative structures that can be visualized with imaging, there are far more protein complexes that are yet to be solved because of their dynamic associations with one another. Nevertheless, it is possible to infer these protein complexes through a physical model. However, it is often not clear to physicists what kind of data from biology is necessary for such a modeling endeavor. Here, we aim to model these clusters of coarse-grained protein assemblies from multiple subunits through the constraints of interactions among the subunits and the chemical potential of each subunit. We obtained the constraints on the interactions among subunits from the known protein structures. We inferred the chemical potential that dictates the particle number distribution of each protein subunit from the knowledge of protein abundance from experimental data. Guided by the maximum entropy principle, we formulated an inverse statistical mechanical method to infer the distribution of particle numbers from the data of protein abundance as chemical potentials for a grand canonical multicomponent mixture. Using grand canonical Monte Carlo simulations, we captured a distribution of high-order clusters in a protein complex of succinate dehydrogenase with four known subunits. The complexity of hierarchical clusters varies with the relative protein abundance of each subunit in distinctive cell types such as lung, heart, and brain. When the crowding content increases, we observed that crowding stabilizes emergent clusters that do not exist in dilute conditions. We, therefore, proposed a testable hypothesis that the hierarchical complexity of protein clusters on a molecular scale is a plausible biomarker of predicting the phenotypes of a cell.