title: Simulating disorder-order transitions in molecular recognition of unstructured proteins: where folding meets binding.
abstract: A microscopic study of functional disorder-order folding transitions coupled to binding is performed for the p27 protein, which derives a kinetic advantage from the intrinsically disordered unbound form on binding with the phosphorylated cyclin A-cyclin-dependent kinase 2 (Cdk2) complex. Hierarchy of structural loss during p27 coupled unfolding and unbinding is simulated by using high-temperature Monte Carlo simulations initiated from the crystal structure of the tertiary complex. Subsequent determination of the transition-state ensemble and the proposed atomic picture of the folding mechanism coupled to binding provide a microscopic rationale that reconciles the initiation recruitment of p27 at the cyclin A docking site with the kinetic benefit for a disordered alpha-helix in the unbound form of p27. The emerging structural polarization in the ensemble of unfolding/unbinding trajectories and in the computationally determined transition-state ensemble is not determined by the intrinsic folding preferences of p27 but rather is attributed to the topological requirements of the native intermolecular interface to order beta-hairpin and beta-strand of p27 that could be critical for nucleating rapid folding transition coupled to binding. In agreement with the experimental data, the disorder-order folding transition for p27 is largely determined by the functional requirement to form a specific intermolecular interface that ultimately dictates the folding mechanism and overwhelms any local folding preferences for creating a stable alpha-helix in the p27 structure before overcoming the major free energy barrier.
authors.affiliation: Pfizer Global Research and Development, La Jolla Laboratories, 10777 Science Center Drive, San Diego, CA 92121, USA. gennady.verkhivker@pfizer.com
authors.forename: Gennady M
authors.initials: GM
authors.lastname: Verkhivker
authors.forename: Djamal
authors.initials: D
authors.lastname: Bouzida
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Gehlhaar
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rejto
authors.forename: Stephan T
authors.initials: ST
authors.lastname: Freer
authors.forename: Peter W
authors.initials: PW
authors.lastname: Rose
mesh_terms: D008958:Models, Molecular; D009010:Monte Carlo Method; D011485:Protein Binding; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D011506:Proteins