title: Role of non-native electrostatic interactions in the coupled folding and binding of PUMA with Mcl-1.
abstract: 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.
authors.affiliation: State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, China.
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Chu
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Clarke
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, United Kingdom.|Department of Biochemistry, University of Oxford, South Parks Road, Oxford, United Kingdom.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Shammas
authors.affiliation: State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, China.|Department of Chemistry & Physics, State University of New York at Stony Brook, Stony Brook, New York, United States of America.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000378:metabolism; D019295:Computational Biology; D064267:Intrinsically Disordered Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D055672:Static Electricity; D013816:Thermodynamics; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D064267:Intrinsically Disordered Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D025521:Tumor Suppressor Proteins