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2. Integrin-based mechanosensing through conformational deformation

Author

Driscoll, Tristan P, Bidone, Tamara C, Ahn, Sang Joon, Yu, Alvin, Groisman, Alexander, Voth, Gregory A, and Schwartz, Martin A

Subjects
Biochemistry and Cell Biology, Biological Sciences, 1.1 Normal biological development and functioning, Underpinning research, Cell Adhesion, Integrin alphaVbeta3, Integrins, Ligands, Mechanical Phenomena, Protein Binding, Talin, Physical Sciences, Chemical Sciences, Biophysics, Biological sciences, Chemical sciences, Physical sciences
Abstract

Conversion of integrins from low to high affinity states, termed activation, is important in biological processes, including immunity, hemostasis, angiogenesis, and embryonic development. Integrin activation is regulated by large-scale conformational transitions from closed, low affinity states to open, high affinity states. Although it has been suggested that substrate stiffness shifts the conformational equilibrium of integrin and governs its unbinding, here, we address the role of integrin conformational activation in cellular mechanosensing. Comparison of wild-type versus activating mutants of integrin αVβ3 show that activating mutants shift cell spreading, focal adhesion kinase activation, traction stress, and force on talin toward high stiffness values at lower stiffness. Although all activated integrin mutants showed equivalent binding affinity for soluble ligands, the β3 S243E mutant showed the strongest shift in mechanical responses. To understand this behavior, we used coarse-grained computational models derived from molecular level information. The models predicted that wild-type integrin αVβ3 displaces under force and that activating mutations shift the required force toward lower values, with S243E showing the strongest effect. Cellular stiffness sensing thus correlates with computed effects of force on integrin conformation. Together, these data identify a role for force-induced integrin conformational deformation in cellular mechanosensing.

Published
2021

11. Application of Funnel Metadynamics to the Platelet Integrin αIIbβ3 in Complex with an RGD Peptide.

Author

Coffman, Robert E. and Bidone, Tamara C.

Subjects
*PEPTIDES, *BLOOD platelet aggregation, *INTEGRINS, *BLOOD platelets, *DEGREES of freedom, *BINDING sites, *FIBRINOGEN
Abstract

Integrin αIIbβ3 mediates platelet aggregation by binding the Arginyl-Glycyl-Aspartic acid (RGD) sequence of fibrinogen. RGD binding occurs at a site topographically proximal to the αIIb and β3 subunits, promoting the conformational activation of the receptor from bent to extended states. While several experimental approaches have characterized RGD binding to αIIbβ3 integrin, applying computational methods has been significantly more challenging due to limited sampling and the need for a priori information regarding the interactions between the RGD peptide and integrin. In this study, we employed all-atom simulations using funnel metadynamics (FM) to evaluate the interactions of an RGD peptide with the αIIb and β3 subunits of integrin. FM incorporates an external history-dependent potential on selected degrees of freedom while applying a funnel-shaped restraint potential to limit RGD exploration of the unbound state. Furthermore, it does not require a priori information about the interactions, enhancing the sampling at a low computational cost. Our FM simulations reveal significant molecular changes in the β3 subunit of integrin upon RGD binding and provide a free-energy landscape with a low-energy binding mode surrounded by higher-energy prebinding states. The strong agreement between previous experimental and computational data and our results highlights the reliability of FM as a method for studying dynamic interactions of complex systems such as integrin. [ABSTRACT FROM AUTHOR]

Published
2024
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15. On natural selection of cochlear outer hair cell electro-mechanical properties.

Author

Rabbitt, Richard D. and Bidone, Tamara C.

Subjects
*HAIR cells, *NATURAL selection, *ION channels, *IMPEDANCE matching
Abstract

The biophysical and mechanical properties of outer hair cells (OHCs) vary systematically with location along the cochlear tonotopic map following monotopic relationships that apply universally across all mammalian species studied to date. To reasonable approximation, OHCs located at a specific characteristic frequency (CF; ωcf, rad-s−1) all have roughly the same length, linear capacitance, nonlinear capacitance, basolateral conductance, axial stiffness and mechano-electrical transduction (MET) current kinetics. Such correlations do not arise in nature by chance, but in the Darwinian view arise through natural selection. We hypothesized that OHC biophysical and mechanical properties evolved to maximize OHC electro-mechanical power efficiency. To test this hypothesis, we analyzed a simple linear model consisting of an OHC working against a mechanical cochlear load. Analytical methods were used to optimize tuning and efficiency at the same time by adjusting: prestin expression (non-linear capacitance), cell length (linear capacitance), compliance (stiffness), voltage-gated ion-channel expression (basolateral conductance), and MET channel kinetics (gain and phase). Results demonstrate these factors are interrelated, and when optimized together predict key relationships between OHC properties and CF observed experimentally. To overcome viscous dissipation and optimize tuning, the MET current must have a specific magnitude and phase at CF related to prestin expression, basolateral conductance, viscous drag and OHC stiffness. To maximize efficiency at CF, the resistive-capacitive corner frequency (ωrc, rad-s−1) must be well below CF, prestin expression must yield a nonlinear capacitance roughly equal to the linear capacitance, and the OHC axial stiffness must be nearly equal to the stiffness of the cochlear load (which constrains OHC length). If any key parameters are changed, tuning and power efficiency are predicted to drop precipitously. Basolateral membrane conductance is predicted to have a much stronger effect on power output than predicted by the reduction in the voltage modulation alone, inducing the hypothesis that tonic activation of the medial olivocochlear system tunes the impedance match to maximize power output, while phasic activation disrupts the impedance match to attenuate amplification. [ABSTRACT FROM AUTHOR]

Published
2024
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39. The lamellipodium is a myosin independent mechanosensor

Author

Oakes, Patrick W., primary, Bidone, Tamara C., additional, Beckham, Yvonne, additional, Skeeters, Austin V., additional, Ramirez-San Juan, Guillermina R., additional, Winter, Stephen P., additional, Voth, Gregory A., additional, and Gardel, Margaret L., additional

Published
2017
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43. Multiscale Modelling for investigating single molecule effects on the mechanics of actin filaments

Author

Carbone Laura, Bignardi Cristina, Morbiducci Umberto, Bidone Tamara C, Deriu Marco A, and Montevecchi Franco M

Subjects
Persistence length, History, macromolecular substances, Mechanics, Computer Science Applications, Education, Protein filament, chemistry.chemical_compound, Adenosine diphosphate, Molecular dynamics, Monomer, chemistry, Molecule, Adenosine triphosphate, Actin
Abstract

This work presents a preliminary multiscale computational investigation of the effects of nucleotides and cations on the mechanics of actin filaments (F-actin). At the molecular level, Molecular Dynamics (MD) simulations are employed to characterize the rearrangements of the actin monomers (G-actin) in terms of secondary structures evolution in physiological conditions. At the mesoscale level, a coarse grain (CG) procedure is adopted where each monomer is represented by means of Elastic Network Modeling (ENM) technique. At the macroscale level, actin filaments up to hundreds of nanometers are assumed as isotropic and elastic beams and characterized via Rotation Translation Block (RTB) analysis. F-actin bound to adenosine triphosphate (ATP) shows a persistence length around 5 μm, while actin filaments bound to adenosine diphosphate (ADP) have a persistence length of about 3 μm. With magnesium bound to the high affinity binding site of G-actin, the persistence length of F-actin decreases to about 2 μm only in the ADP-bound form of the filament, while the same ion has no effects, in terms of stiffness variation, on the ATP-bound form of F-actin. The molecular mechanisms behind these changes in flexibility are herein elucidated. Thus, this study allows to analyze how the local binding of cations and nucleotides on G-actin induce molecular rearrangements that transmit to the overall F-actin, characterizing shifts of mechanical properties, that can be related with physiological and pathological cellular phenomena, as cell migration and spreading. Further, this study provides the basis for upcoming investigating of network and cellular remodelling at higher length scales.

Published
2011

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