Mechanism of Folding and Binding of an Intrinsically Disordered Protein As Revealed by ab Initio Simulations - PubMed
- ️Wed Jan 01 2014
. 2014 Jun 10;10(6):2224-31.
doi: 10.1021/ct500287c.
Affiliations
- PMID: 26580746
- DOI: 10.1021/ct500287c
Mechanism of Folding and Binding of an Intrinsically Disordered Protein As Revealed by ab Initio Simulations
Mateusz Kurcinski et al. J Chem Theory Comput. 2014.
Abstract
A complex of the phosphorylated kinase-inducible domain (pKID) with its interacting domain (KIX) is a model system for studies of mechanisms by which intrinsically unfolded proteins perform their functions. These mechanisms are not fully understood. Using an efficient coarse-grained model, ab initio simulations were performed of the coupled folding and binding of the pKID to the KIX. The simulations start from an unbound, randomly positioned and disordered pKID structure. During the simulations the pKID chain and its position remain completely unrestricted, while the KIX backbone is limited to near-native fluctuations. Ab initio simulations of such large-scale conformational transitions, unaffected by any knowledge about the bound pKID structure, remain inaccessible to classical simulations. Our simulations recover an ensemble of transient encounter complexes in good agreement with experimental results. We find that a key folding and binding step is linked to the formation of weak native interactions between a preformed nativelike fragment of a pKID helix and KIX surface. Once that nucleus forms, the pKID chain may condense from a largely disordered encounter ensemble to a natively bound and ordered conformation. The observed mechanism is reminiscent of a nucleation-condensation model, a common scenario for folding of globular proteins.
Similar articles
-
Mechanism of pKID/KIX Association Studied by Molecular Dynamics Free Energy Simulations.
Bomblies R, Luitz MP, Zacharias M. Bomblies R, et al. J Phys Chem B. 2016 Aug 25;120(33):8186-92. doi: 10.1021/acs.jpcb.6b01792. Epub 2016 Apr 20. J Phys Chem B. 2016. PMID: 27054660
-
Explicit Characterization of the Free Energy Landscape of pKID-KIX Coupled Folding and Binding.
Chong SH, Im H, Ham S. Chong SH, et al. ACS Cent Sci. 2019 Aug 28;5(8):1342-1351. doi: 10.1021/acscentsci.9b00200. Epub 2019 Jul 15. ACS Cent Sci. 2019. PMID: 31482116 Free PMC article.
-
Arai M, Sugase K, Dyson HJ, Wright PE. Arai M, et al. Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):9614-9. doi: 10.1073/pnas.1512799112. Epub 2015 Jul 20. Proc Natl Acad Sci U S A. 2015. PMID: 26195786 Free PMC article.
-
Molecular dynamics simulation of phosphorylated KID post-translational modification.
Chen HF. Chen HF. PLoS One. 2009 Aug 5;4(8):e6516. doi: 10.1371/journal.pone.0006516. PLoS One. 2009. PMID: 19654879 Free PMC article.
-
Arai M. Arai M. Biophys Rev. 2018 Apr;10(2):163-181. doi: 10.1007/s12551-017-0346-7. Epub 2018 Jan 6. Biophys Rev. 2018. PMID: 29307002 Free PMC article. Review.
Cited by
-
Kumar N, Sood D, Tomar R, Chandra R. Kumar N, et al. ACS Omega. 2019 Dec 3;4(25):21370-21380. doi: 10.1021/acsomega.9b03035. eCollection 2019 Dec 17. ACS Omega. 2019. PMID: 31867532 Free PMC article.
-
Mechanism and rate constants of the Cdc42 GTPase binding with intrinsically disordered effectors.
Pang X, Zhou HX. Pang X, et al. Proteins. 2016 May;84(5):674-85. doi: 10.1002/prot.25018. Epub 2016 Mar 9. Proteins. 2016. PMID: 26879470 Free PMC article.
-
Kurcinski M, Jamroz M, Blaszczyk M, Kolinski A, Kmiecik S. Kurcinski M, et al. Nucleic Acids Res. 2015 Jul 1;43(W1):W419-24. doi: 10.1093/nar/gkv456. Epub 2015 May 5. Nucleic Acids Res. 2015. PMID: 25943545 Free PMC article.
-
A disordered encounter complex is central to the yeast Abp1p SH3 domain binding pathway.
Gerlach GJ, Carrock R, Stix R, Stollar EJ, Ball KA. Gerlach GJ, et al. PLoS Comput Biol. 2020 Sep 14;16(9):e1007815. doi: 10.1371/journal.pcbi.1007815. eCollection 2020 Sep. PLoS Comput Biol. 2020. PMID: 32925900 Free PMC article.
-
Sampling of the conformational landscape of small proteins with Monte Carlo methods.
Heilmann N, Wolf M, Kozlowska M, Sedghamiz E, Setzler J, Brieg M, Wenzel W. Heilmann N, et al. Sci Rep. 2020 Oct 23;10(1):18211. doi: 10.1038/s41598-020-75239-7. Sci Rep. 2020. PMID: 33097750 Free PMC article.
LinkOut - more resources
Other Literature Sources
Research Materials