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Predicting the effect of disordered linkers on effective concentrations and avidity with the “Ceff calculator” app

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DOI

  • Magnus Kjaergaard
  • Juliana Glavina, Consejo Nacional de Investigaciones Científicas y Técnicas
  • ,
  • Lucia Beatriz Chemes, Consejo Nacional de Investigaciones Científicas y Técnicas

Linkers are crucial to the functions of multidomain proteins as they couple functional units to encode regulation such as auto-inhibition, enzyme targeting or tuning of interaction strength. A linker changes reactions from bimolecular to unimolecular, and the equilibrium and kinetics is thus determined by the properties of the linker rather than concentrations. We present a theoretical workflow for estimating the functional consequences of tethering by a linker. We discuss how to: (1) Identify flexible linkers from sequence. (2) Model the end-to-end distance distribution for a flexible linker using a worm-like chain. (3) Estimate the effective concentration of a ligand tethered by a flexible linker. (4) Calculate the decrease in binding affinity caused by auto-inhibition. (5) Calculate the expected avidity enhancement of a bivalent interaction from effective concentration. The worm-like chain modeling is available through a web application called the “Ceff calculator” (http://ceffapp.chemeslab.org), which will allow user-friendly prediction of experimentally inaccessible parameters.

OriginalsprogEngelsk
TitelLinkers in Biomacromolecules
RedaktørerMaarten Merkx
Antal sider27
ForlagAcademic Press
Udgivelsesårjan. 2021
Sider145-171
ISBN (trykt)9780128208182
DOI
StatusUdgivet - jan. 2021
SerietitelMethods in Enzymology
Vol/bind647
ISSN0076-6879

Bibliografisk note

Funding Information:
We thank Cesar Leonetti for developing the web deployment and server infrastructure for the “C eff Calculator” web app. JG is a postdoctoral fellow and LBC is an independent researcher from Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina. The work was supported by Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) grant #PICT 2017-1924 to LBC and grants from the “Young Investigator Program” of the Villum Foundation and PROMEMO – Center for Proteins in Memory, a Center of Excellence funded by the Danish National Research Foundation (grant number DNRF133) to MK.

Publisher Copyright:
© 2020 Elsevier Inc.

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

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