Role of Non-Native Electrostatic Interactions in the Coupled Folding and Binding of PUMA with Mcl-1
PLoS Computational Biology
Public Library of Science (PLoS)
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Chu, W., Clarke, J., Shammas, S., & Wang, J. (2017). Role of Non-Native Electrostatic Interactions in the Coupled Folding and Binding of PUMA with Mcl-1. PLoS Computational Biology, 13 (4. e1005468)https://doi.org/10.1371/journal.pcbi.1005468
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 ion 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.
This work was supported by grants to JW from the National Science Foundation (NSF-MCB-0947767 and NSF-PHY-76066, website: www.nsf.gov/), the National Natural Science Foundation of China (91430217, website: www.nsfc.gov.cn/publish/portal1/), and Ministry of Science and Technology of China (2016YFA0203200 and 2013YQ170585, website: http://www.most.gov.cn/eng/); WTC from the National Natural Science Foundation of China (21603217, website: www.nsfc.gov.cn/publish/portal1/), and China Postdoctoral Science Foundation (2016M590268, website: jj.chinapostdoctor.org.cn/V1/Program3/Default.aspx). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Wellcome Trust (095195/Z/10/Z)
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External DOI: https://doi.org/10.1371/journal.pcbi.1005468
This record's URL: https://www.repository.cam.ac.uk/handle/1810/263619
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/