Role of non-native electrostatic interactions in the coupled folding and binding of PUMA with Mcl-1.
PUMA, which belongs to the BH3-only protein family, is an intrinsically disordered protein (IDP). It binds to its cellular partner Mcl-1 through its BH3 motif, which folds upon binding into an α helix. We have applied a structure-based coarse-grained model, with an explicit Debye-Hückel charge model...
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doaj-fe7af712eba249b9857a08df6656f7732020-11-25T01:42:05ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582017-04-01134e100546810.1371/journal.pcbi.1005468Role of non-native electrostatic interactions in the coupled folding and binding of PUMA with Mcl-1.Wen-Ting ChuJane ClarkeSarah L ShammasJin WangPUMA, which belongs to the BH3-only protein family, is an intrinsically disordered protein (IDP). It binds to its cellular partner Mcl-1 through its BH3 motif, which folds upon binding into an α helix. We have applied a structure-based coarse-grained model, with an explicit Debye-Hückel charge model, to probe the importance of electrostatic interactions both in the early and the later stages of this model coupled folding and binding process. This model was carefully calibrated with the experimental data on helical content and affinity, and shown to be consistent with previously published experimental data on binding rate changes with respect to ionic strength. We find that intramolecular electrostatic interactions influence the unbound states of PUMA only marginally. Our results further suggest that intermolecular electrostatic interactions, and in particular non-native electrostatic interactions, are involved in formation of the initial encounter complex. We are able to reveal the binding mechanism in more detail than is possible using experimental data alone however, and in particular we uncover the role of non-native electrostatic interactions. We highlight the potential importance of such electrostatic interactions for describing the binding reactions of IDPs. Such approaches could be used to provide predictions for the results of mutational studies.http://europepmc.org/articles/PMC5400261?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wen-Ting Chu Jane Clarke Sarah L Shammas Jin Wang |
spellingShingle |
Wen-Ting Chu Jane Clarke Sarah L Shammas Jin Wang Role of non-native electrostatic interactions in the coupled folding and binding of PUMA with Mcl-1. PLoS Computational Biology |
author_facet |
Wen-Ting Chu Jane Clarke Sarah L Shammas Jin Wang |
author_sort |
Wen-Ting Chu |
title |
Role of non-native electrostatic interactions in the coupled folding and binding of PUMA with Mcl-1. |
title_short |
Role of non-native electrostatic interactions in the coupled folding and binding of PUMA with Mcl-1. |
title_full |
Role of non-native electrostatic interactions in the coupled folding and binding of PUMA with Mcl-1. |
title_fullStr |
Role of non-native electrostatic interactions in the coupled folding and binding of PUMA with Mcl-1. |
title_full_unstemmed |
Role of non-native electrostatic interactions in the coupled folding and binding of PUMA with Mcl-1. |
title_sort |
role of non-native electrostatic interactions in the coupled folding and binding of puma with mcl-1. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Computational Biology |
issn |
1553-734X 1553-7358 |
publishDate |
2017-04-01 |
description |
PUMA, which belongs to the BH3-only protein family, is an intrinsically disordered protein (IDP). It binds to its cellular partner Mcl-1 through its BH3 motif, which folds upon binding into an α helix. We have applied a structure-based coarse-grained model, with an explicit Debye-Hückel charge model, to probe the importance of electrostatic interactions both in the early and the later stages of this model coupled folding and binding process. This model was carefully calibrated with the experimental data on helical content and affinity, and shown to be consistent with previously published experimental data on binding rate changes with respect to ionic strength. We find that intramolecular electrostatic interactions influence the unbound states of PUMA only marginally. Our results further suggest that intermolecular electrostatic interactions, and in particular non-native electrostatic interactions, are involved in formation of the initial encounter complex. We are able to reveal the binding mechanism in more detail than is possible using experimental data alone however, and in particular we uncover the role of non-native electrostatic interactions. We highlight the potential importance of such electrostatic interactions for describing the binding reactions of IDPs. Such approaches could be used to provide predictions for the results of mutational studies. |
url |
http://europepmc.org/articles/PMC5400261?pdf=render |
work_keys_str_mv |
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1725038081170472960 |