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The deep relation between dynamics and function of proteins is now widely acknowledged. Conformational changes are commonly observed in enzymes and they are generally coupled to the interchange between their active and inactive forms, which can be triggered e.g. by substrate binding or phosphorylation. There is a growing evidence that intrinsic mobility is important also in regulating protein-protein interactions [1]. Moreover, conservation of flexibility patterns and in particular of slow, large-amplitude concerted motions has been observed in families of homologous proteins [2]. In particular, dynamical properties seem to play an important role in hub proteins. Intrinsic disorder has been claimed to be one of the peculiar features of hubs, together with low sequence complexity, larger surface and high net charge at the interface [3,4]. However, a complete consensus about the role of disorder in hubs has not yet been achieved [5]. Moreover, the possibility to classify different types of hubs on the basis of the disorder propensity is still under investigation [6]. We are investigating the possibility that 'promiscuity' of binding in hubs is favored by conformational flexibility, that is by the tendency to sample different regions of the conformational space while keeping a defined structure. Flexibility is a property that can be more easily measured than intrinsic disorder, which imply the absence of a stable structure and which is thus difficult to exactly define and directly detect. A few studies on hub proteins have indeed considered flexibility, but through indirect indexes such as the diversity of the structures found for a given protein in the Protein Data Bank (PDB) [5] or the fraction of residues in loops [3]. We present here a preliminary screening of the dynamical properties of hubs performed with molecular simulation methods. The analysis of protein motions is coupled with a description of the interfaces and in particular of the different types of binding modes that may occur in hubs. [1] Dobbins S.E., Lesk V.I., Sternberg M.J.E., Insights into protein flexibility: The relationship between normal modes and conformational change upon protein-protein docking. PNAS, 105, 10390-10395 (2008). [2] Maguid S., Fernandez-Alberti S., Echave J., Evolutionary conservation of protein vibrational dynamics. Gene, 422, 7-13 (2008). [3] Patil A., Nakamura H., Disordered domains and high surface charge confer hubs with the ability to interact with multiple proteins in interaction networks. FEBS Lett. 580, 2041-2045 (2006). [4] Zsuzsanna Dosztnyi, Jake Chen, A. Keith Dunker, Istvn Simon, and Peter Tompa Disorder and Sequence Repeats in Hub Proteins and Their Implications for Network Evolution. J. Proteome Res., 5, 2985-2995 (2006). [5] Higurashi M., Ishida T., Kinoshita K., Identification of transient hub proteins and the possible structural basis for their multiple interactions. Protein Sci., 17, 72-78 (2008). [6] Kim P. M., Sboner A., Xia Y., Gerstein M., The role of disorder in interaction networks: a structural analysis. Mol. Syst. Biol., 4, 1-7 (2008). [7] Higurashi M., Ishida T., Kinoshita K., PiSite: a database of protein interaction sites using multiple binding states in the PDB. Nucleic Acids Res., 37, D360-D364 (2009). |
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