A Microscopic Study of Disorder-Order Transitions in Molecular Recognition of Unstructured Proteins: Hierarchy of Structural Loss and the Transition State Determination from Monte Carlo Simulations of P27KIP1 Protein Coupled Unfolding and Unbinding

  • Gennady M. Verkhivker


A microscopic characterization of the free energy barrier suggests an atomic picture of the binding mechanism that rationalizes and reconciles the hypothesized initiation binding event with the experimental data, indicating a kinetic advantage for the intrinsically unstructured α -helix in the unbound form. Despite considerable differences between individual trajectories, the analysis of independent simulations at T=600K shows a systematic trend in the hierarchy of structural loss for p 27 Kip 1 during coupled unfolding and unbinding. The emerging structural polarization in the ensemble of unfolding/unbinding trajectories and in the computationally determined TSE are not determined by the folding topological preferences of p 27 Kip 1 , but is interpreted as a consequence of the topological requirements of the intermolecular interface to minimize free energy cost associated with ordering the β -hairpin and β -strand intermolecular contacts which are the last one to disintegrate in unfolding/unbinding and thereby could be important for nucleating rapid folding and binding. In agreement with the experimental data, it has been shown that the topology of the native intermolecular interface coupled with the localized, specific interactions formed by p 27 Kip 1 with the complex in transition state overwhelms any local folding preferences for creating a stable α -helix prior to overcoming the major free energy barrier. These results provide a structural rationale for the experimental data revealing that preorganized native-like local secondary structure in p 27 Kip 1 can result in slower binding. Hence, folding of unstructured proteins upon binding to a given template is largely determined by the requirements to form specific complex that ultimately dictates the folding mechanism. By using a protein engineering approach similar to the -value analysis developed to characterize the TS ensemble in protein folding, it should be possible to validate the predicted details of the binding mechanism by probing the kinetic consequences of mutations of every residue that makes appreciable interactions in the native state. Synergy of theoretical and experimental advances in the fields of protein folding and binding, based on the increasing amount of information in known structures and mechanisms may provide a fruitful direction for future research and allow to unify interdisciplinary efforts in resolving these key problems in molecular biology.


Root Mean Square Deviation Molecular Recognition Energy Landscape Solvation Free Energy Intermolecular Contact 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Gennady M. Verkhivker
    • 1
  1. 1.Pfizer Global Research and DevelopmentLa Jolla LaboratoriesSan DiegoUSA

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