“KMC-TDGL”—a coarse-grained methodology for simulating interfacial dynamics in complex fluids: application to protein-mediated membrane processes

Weinstein, Joshua; Radhakrishnan, Ravi

doi:10.1080/00268970600997580

Cited by 13 publications

(24 citation statements)

References 62 publications

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“…69 Here, we report our results specifically for epsins interacting with the membrane. Consistent with the experimental values of Ford et al, we assume that the intrinsic membrane curvature induced by the epsin molecules falls in the range of 10 lm )1 .…”

Section: Endocytotic Vesicle Nucleationmentioning

confidence: 86%

“…Our multiscale modeling strategy is depicted in the Flowchart 1 and Table 1, (here we provide a brief overview; detailed description is available in the supplementary information S1.1 to S1.6): our hierarchical scheme involves molecular dynamics (see also Section S1.1), free energy docking (see also Section S1.2), hybrid spatial and stochastic modeling 69 (see also Sections S1.3 and S1.4), and their integration with existing deterministic network models of EGFR-mediated signal transduction (see also Section S1.5). Model approximations and scope are discussed in S1.6.…”

Section: Overall Summary Of Methodsmentioning

confidence: 99%

“…Recently, we developed the KMC-TDGL (kinetic Monte Carlo-time-dependent Ginzburg Landau) heterogeneous multiscale approach for studying membrane dynamical processes by combining two different phenomenological theories. 69 Simulations performed using this approach yields the time evolution of the membrane undulations and deformation in response to the diffusion of membrane bound epsins and a timescale for the nucleation of an endocytotic vesicle. We calculate the timescale for epsin-induced endocytotic vesicle nucleation from our membrane simulations performed using the KMC-TDGL approach.…”

Section: Spatial Stochastic Model For Endocytotic Vesiclementioning

confidence: 99%

“…We calculate the timescale for epsin-induced endocytotic vesicle nucleation from our membrane simulations performed using the KMC-TDGL approach. 69 We combine this timescale for nucleation with the timescales for signal transduction calculated using the network simulations (Section S1.3) to estimate an overall timescale for phosphorylated receptor internalization. EGF binds reversibly to EGFR, which increases the receptor's affinity for other ligand-bound receptors (v2).…”

Section: Spatial Stochastic Model For Endocytotic Vesiclementioning

confidence: 99%

“…Panels E and F provide the corresponding spatial and orientational correlations. 69 The necessary condition for nucleation is the persistence of orientational (hexagonal) ordering of the membrane-adsorbed epsin molecules (see caption). 69 Our results have suggested an interesting mechanism for the epsin-mediated membrane invagination.…”

Section: Endocytotic Vesicle Nucleationmentioning

confidence: 99%

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A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

et al. 2007

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Abstract-We describe a hierarchical multiscale computational approach based on molecular dynamics simulations, free energy-based molecular docking simulations, deterministic network-based kinetic modeling, and hybrid discrete/ continuum stochastic dynamics protocols to study the dimermediated receptor activation characteristics of the Erb family receptors, specifically the epidermal growth factor receptor (EGFR). Through these modeling approaches, we are able to extend the prior modeling of EGF-mediated signal transduction by considering specific EGFR tyrosine kinase (EGFRTK) docking interactions mediated by differential binding and phosphorylation of different C-terminal peptide tyrosines on the RTK tail. By modeling signal flows through branching pathways of the EGFRTK resolved on a molecular basis, we are able to transcribe the effects of molecular alterations in the receptor (e.g., mutant forms of the receptor) to differing kinetic behavior and downstream signaling response. Our molecular dynamics simulations show that the drug sensitizing mutation (L834R) of EGFR stabilizes the active conformation to make the system constitutively active. Docking simulations show preferential characteristics (for wildtype vs. mutant receptors) in inhibitor binding as well as preferential enhancement of phosphorylation of particular substrate tyrosines over others. We find that in comparison to the wildtype system, the L834R mutant RTK preferentially binds the inhibitor erlotinib, as well as preferentially phosphorylates the substrate tyrosine Y1068 but not Y1173. We predict that these molecular level changes result in preferential activation of the Akt signaling pathway in comparison to the Erk signaling pathway for cells with normal EGFR expression. For cells with EGFR over expression, the mutant over activates both Erk and Akt pathways, in comparison to wildtype. These results are consistent with qualitative experimental measurements reported in the literature. We discuss these consequences in light of how the network topology and signaling characteristics of altered (mutant) cell lines are shaped differently in relationship to native cell lines.

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Section: Endocytotic Vesicle Nucleationmentioning

confidence: 86%

Section: Overall Summary Of Methodsmentioning

confidence: 99%

Section: Spatial Stochastic Model For Endocytotic Vesiclementioning

confidence: 99%

Section: Spatial Stochastic Model For Endocytotic Vesiclementioning

confidence: 99%

Section: Endocytotic Vesicle Nucleationmentioning

confidence: 99%

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A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

et al. 2007

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Quantification of Curvature Sensing Behavior of Curvature-Inducing Proteins on Model Wavy Substrates

et al. 2022

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Nonaxisymmetric Shapes of Biological Membranes from Locally Induced Curvature

Omar

Sahu

Sauer

et al. 2020

Biophysical Journal

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In various biological processes such as endocytosis and caveolae formation, the cell membrane is locally deformed into curved configurations. Previous theoretical and computational studies to understand membrane morphologies resulting from locally induced curvature are often limited to axisymmetric shapes, which severely restricts the physically admissible morphologies. Under the restriction of axisymmetry, past efforts predict that the cell membrane buds at low resting tensions and stalls at a flat pit at high resting tensions. In this work, we lift the restriction of axisymmetry by employing recent theoretical and numerical advances to understand arbitrarily curved and deforming lipid bilayers. Our non-axisymmetric morphologies reveal membrane morphologies which agree well with axisymmetric studies-however only if the resting tension of the membrane is low. When the resting tension is moderate to high, we show that (i) axisymmetric invaginations are unstable; and (ii) non-axisymmetric ridge-shaped structures are energetically favorable. We further study the dynamical effects resulting from the interplay between intramembrane viscous flow and induced curvature, and find the rate at which the locally induced curvature increases is a key determinant in the formation of ridges. In particular, we show that axisymmetric buds are favored when the induced curvature is rapidly increased, while non-axisymmetric ridges are favored when the curvature is slowly increased: The rate of change of induced curvature affects the intramembrane viscous flow of lipids, which can impede the membrane's ability to transition into ridges. We conclude that the appearance of non-axisymmetric ridges indicates that axisymmetry cannot be generally assumed when understanding processes involving locally induced curvature. Our results hold potentially relevant implications for biological processes such as endocytosis, and physical phenomena like phase separation in lipid bilayers.

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“KMC-TDGL”—a coarse-grained methodology for simulating interfacial dynamics in complex fluids: application to protein-mediated membrane processes

Cited by 13 publications

References 62 publications

A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

Quantification of Curvature Sensing Behavior of Curvature-Inducing Proteins on Model Wavy Substrates

Nonaxisymmetric Shapes of Biological Membranes from Locally Induced Curvature

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