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Conserved internal hydration motifs in protein kinases.

Authors
  • Setny, Piotr1
  • 1 Centre of New Technologies, University of Warsaw, Warsaw, Poland. , (Poland)
Type
Published Article
Journal
Proteins Structure Function and Bioinformatics
Publisher
Wiley (John Wiley & Sons)
Publication Date
Dec 01, 2020
Volume
88
Issue
12
Pages
1578–1591
Identifiers
DOI: 10.1002/prot.25977
PMID: 32666522
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Crystal structures of diverse protein kinase catalytic subunits reveal a number of water molecules whose positions within the protein core are better preserved than amino acid types in many functionally important locations. It remains unknown whether they play any particular role, and whether their removal, disturbing local interaction patterns to no smaller degree than amino acid mutations, can affect kinase stability and function. In this study, we apply an array of computational approaches to characterize hydration of kinase catalytic subunits. First, we systematically screen multiple crystal structures with the use of a simplified hydration model in order to determine the distribution of internal solvent and the degree of its conservation. Second, we analyze water structure, dynamics and binding affinity to buried hydration sites in a number of kinases, also taking into account their variable functional state. We find that a large portion of buried solvent is dynamic, possibly contributing to kinase conformational changes related to the activation process. In turn, binding free energies of some of tightly bound conserved water molecules to different kinases tend to shift in a similar manner following the change of their functional state. This finding highlights the likely specific role of internal solvent in fine tuning local protein plasticity. © 2020 Wiley Periodicals LLC.

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