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The free energy folding penalty accompanying binding of intrinsically disordered α-helical motifs
ID
Hadži, San
(
Author
),
ID
Lah, Jurij
(
Author
)
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https://onlinelibrary.wiley.com/doi/10.1002/pro.4370
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Abstract
Intrinsically disordered proteins (IDPs) are abundant in eukaryotic proteomes and preform critical roles in many cellular processes, most often through the association with globular proteins. Despite lacking a stable three-dimensional structure by themselves, they may acquire a defined conformation upon binding globular targets. The most common type of secondary structure acquired by these binding motifs entails formation of an α-helix. It has been hypothesized that such disorder-to-order transitions are associated with a significant free energy penalty due to IDP folding, which reduces the overall IDP-target affinity. However, the exact magnitude of IDP folding penalty in α-helical binding motifs has not been systematically estimated. Here, we report the folding penalty contributions for 30 IDPs undergoing folding-upon-binding and find that the average IDP folding penalty is +2.0 kcal/mol and ranges from 0.7 to 3.5 kcal/mol. We observe that the folding penalty scales approximately linearly with the change in IDP helicity upon binding, which provides a simple empirical way to estimate folding penalty. We analyze to what extent do prestructuring and target-bound IDP dynamics (fuzziness) reduce the folding penalty and find that these effects combined, on average, reduce the folding cost by around half. Taken together, the presented analysis provides a quantitative basis for understanding the role of folding penalty in IDP-target interactions and introduces a method estimate this quantity. Estimation and reduction of IDP folding penalty may prove useful in the rational design of helix-stabilized inhibitors of IDP-target interactions.
Language:
English
Keywords:
binding motif
,
folding penalty
,
folding-upon-binding
,
fuzziness
,
intrinsically disordered proteins
,
peptide inhibitor
,
pre-folding
Work type:
Article
Typology:
1.01 - Original Scientific Article
Organization:
FKKT - Faculty of Chemistry and Chemical Technology
Publication status:
Published
Publication version:
Version of Record
Year:
2022
Number of pages:
11 str.
Numbering:
Vol. 31, iss. 7, art. e4370
PID:
20.500.12556/RUL-141972
UDC:
577.322
ISSN on article:
0961-8368
DOI:
10.1002/pro.4370
COBISS.SI-ID:
121839363
Publication date in RUL:
13.10.2022
Views:
538
Downloads:
154
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Record is a part of a journal
Title:
Protein science
Shortened title:
Protein sci.
Publisher:
The Protein Society, Wiley
ISSN:
0961-8368
COBISS.SI-ID:
15692293
Licences
License:
CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Link:
http://creativecommons.org/licenses/by-nc-nd/4.0/
Description:
The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.
Secondary language
Language:
Slovenian
Keywords:
motiv vezanja
,
neugodno zvitje
,
zvitje ob vezanju
,
kaotičnost
,
intrinzično neurejeni proteini
,
peptidni inhibitor
,
predzvitje
Projects
Funder:
ARRS - Slovenian Research Agency
Project number:
J1-1706
Name:
Stabilnost nove vrste kvadruplesov DNA (AGCGA) in njihovo prepoznavanje z nanotelesi
Funder:
ARRS - Slovenian Research Agency
Project number:
P1-0201
Name:
Fizikalna kemija
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