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On the activation and deactivation pathways of the Lck kinase domain: a computational study

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Abstract

Here we report the description of the conformational pathways connecting the Lck active and inactive states by means of all-atoms molecular dynamics simulations coupled to an enhancing sampling methodology. By such an approach, we describe the major structural determinants characterizing these large conformational transitions and compare such pathways to those obtained for a similar kinase, i.e. c-Src. Our results show that both the activation and deactivation processes could follow distinct pathways, differentiated by the order by which the A-loop and the C-helix regions rearrange.

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Acknowledgements

This work was partially funded by Sapienza, University of Rome (Progetto di Ateneo 2018). The authors gratefully acknowledge NVIDIA and CINECA for computational support.

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Correspondence to Marco D’Abramo.

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Alba, J., Milanetti, E. & D’Abramo, M. On the activation and deactivation pathways of the Lck kinase domain: a computational study. J Comput Aided Mol Des 33, 597–603 (2019) doi:10.1007/s10822-019-00204-0

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Keywords

  • Molecular dynamics
  • Lck kinase
  • Src kinases
  • Activation pathways
  • Conformational equilibria