ǂThe ǂfree energy folding penalty accompanying binding of intrinsically disordered [alpha]-helical motifs

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.

Keywords

motiv vezanja;neugodno zvitje;zvitje ob vezanju;kaotičnost;intrinzično neurejeni proteini;peptidni inhibitor;predzvitje;binding motif;folding penalty;folding-upon-binding;fuzziness;intrinsically disordered proteins;peptide inhibitor;prefolding;

Data

Language:	English
Year of publishing:	2022
Typology:	1.01 - Original Scientific Article
Organization:	UL FKKT - Faculty of Chemistry and Chemical Technology
UDC:	577.322
COBISS:	121839363
ISSN:	0961-8368
Views:	71
Downloads:	33
Average score:	0 (0 votes)
Metadata:

Other data

Secondary language:	Slovenian
Secondary keywords:	motiv vezanja;neugodno zvitje;zvitje ob vezanju;kaotičnost;intrinzično neurejeni proteini;peptidni inhibitor;predzvitje;
Type (COBISS):	Article
Pages:	str. 1-11
Volume:	ǂVol. ǂ31
Issue:	ǂiss. ǂ7
Chronology:	Jul. 2022
DOI:	10.1002/pro.4370
ID:	16736376