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Csk αC Helix: A Computational Analysis of an Essential Region for Conformational Transitions

  • Raphael Vinicius Rodrigues Dias
    Raphael Vinicius Rodrigues Dias
    São Paulo State University (Unesp), Department of Physics, Institute of Biosciences, Humanities and Exact Sciences, Rua Cristóvão Colombo, 2265, São José do Rio Preto, São Paulo15054-000, Brazil
  • Carolina Tatiani Alves Ferreira
    Carolina Tatiani Alves Ferreira
    São Paulo State University (Unesp), Department of Physics, Institute of Biosciences, Humanities and Exact Sciences, Rua Cristóvão Colombo, 2265, São José do Rio Preto, São Paulo15054-000, Brazil
  • Patricia Ann Jennings
    Patricia Ann Jennings
    University of California, San Diego, 9500 Gilman Drive, Natural Science Building #3110, La Jolla, California92093, United States
  • Paul Charles Whitford
    Paul Charles Whitford
    Northeastern University, Department of Physics and Center for Theoretical Biological Physics, 360 Huntington Avenue, Boston, Massachusetts02115, United States
  • , and 
  • Leandro Cristante de Oliveira*
    Leandro Cristante de Oliveira
    São Paulo State University (Unesp), Department of Physics, Institute of Biosciences, Humanities and Exact Sciences, Rua Cristóvão Colombo, 2265, São José do Rio Preto, São Paulo15054-000, Brazil
    *E-mail: [email protected]. Phone: +55 (17)3221-2200.
Cite this: J. Phys. Chem. B 2022, 126, 50, 10587–10596
Publication Date (Web):December 13, 2022
https://doi.org/10.1021/acs.jpcb.2c05408
Copyright © 2022 American Chemical Society

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    Abstract

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    Conformational changes are an essential feature for the function of some dynamic proteins. Understanding the mechanism of such motions may allow us to identify important properties, which may be directly related to the regulatory function of a protein. Also, this knowledge may be employed for a rational design of drugs that can shift the balance between active and inactive conformations, as well as affect the kinetics of the activation process. Here, the conformational changes in carboxyl-terminal Src kinase, the major catalytic repressor to the Src family of kinases, was investigated, and it was proposed as a functionally related hypothesis. A Cα Structure-Based Model (Cα-SBM) was applied to provide a description of the overall conformational landscape and further analysis complemented by detailed molecular dynamics simulations. As a first approach to Cα-SBM simulations, reversible transitions between active (closed) and inactive (open) forms were modeled as fluctuations between these two energetic basins. It was found that, in addition to the interdomain Carboxyl-terminal SRC Kinase (Csk) correlated motions, a conformational change in the αC helix is required for a complete conformational transition. The result reveals this as an important region of transition control and domain coordination. Restrictions in the αC helix region of the Csk protein were performed, and the analyses showed a direct correlation with the global conformational changes, with this location being propitious for future studies of ligands. Also, the Src Homology 3 (SH3) and SH3 plus Src Homology 2 (SH2) domains were excluded for a direct comparison with experimental results previously published. Simulations where the SH3 was deleted presented a reduction of the transitions during the simulations, while the SH3–SH2 deletion vanishes the Csk transitions, corroborating the experimental results mentioned and linking the conformational changes with the catalytic functionality of Csk. The study was complemented by the introduction of a known kinase inhibitor close to the Csk αC helix region where its consequences for the kinetic behavior and domain displacement of Csk were verified through detailed molecular dynamics. The findings describe the mechanisms involving the Csk αC helix for the transitions and also support the dynamic correlation between SH3 and SH2 domains against the Csk lobes and how local energetic restrictions or interactions in the Csk αC helix can play an important role for long-range motions. The results also allow speculation if the Csk activity is restricted to one specific conformation or a consequence of a state transition, this point being a target for future studies. However, the αC helix is revealed as a potential region for rational drug design.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jpcb.2c05408.

    • Free energy profiles under a unique coordinate reaction to Cα-SBM dual potential, analysis of the dihedral angle torsions of the Csk αC helix during Cα-SBM simulations using dual potential, absence of conformational transitions using nonmodified Cα-SBM potentials, detailing of the Cα-SBM dual potential construction, and analysis of residue deviation, fluctuation in explicit water and ions all-atoms MD simulations, and free energy profiles using all-atoms SBM simulations (PDF)

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    Cited By

    This article is cited by 1 publications.

    1. Gongqin Sun, Marina K. Ayrapetov. Dissection of the catalytic and regulatory structure-function relationships of Csk protein tyrosine kinase. Frontiers in Cell and Developmental Biology 2023, 11 https://doi.org/10.3389/fcell.2023.1148352

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