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    On the diversity of physicochemical environments experienced by identical ligands in binding pockets of unrelated proteins

    Kahraman, A. and Morris, R.J. and Laskowski, R.A. and Favia, A.D. and Thornton, Janet M. (2010) On the diversity of physicochemical environments experienced by identical ligands in binding pockets of unrelated proteins. Proteins 78 (5), pp. 1120-1136. ISSN 1097-0134.

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    Most function prediction methods that identify cognate ligands from binding site analyses work on the assumption of molecular complementarity. These approaches build on the conjectured complementarity of geometrical and physicochemical properties between ligands and binding sites so that similar binding sites will bind similar ligands. We found that this assumption does not generally hold for protein-ligand interactions and observed that it is not the chemical composition of ligand molecules that dictates the complementarity between protein and ligand molecules, but that the ligand's share within the functional mechanism of a protein determines the degree of complementarity. Here, we present for a set of cognate ligands a descriptive analysis and comparison of the physicochemical properties that each ligand experiences in various nonhomologous binding pockets. The comparisons in each ligand set reveal large variations in their experienced physicochemical properties, suggesting that the same ligand can bind to distinct physicochemical environments. In some protein ligand complexes, the variation was found to correlate with the electrochemical characteristic of ligand molecules, whereas in others it was disclosed as a prerequisite for the biochemical function of the protein. To achieve binding, proteins were observed to engage in subtle balancing acts between electrostatic and hydrophobic interactions to generate stabilizing free energies of binding. For the presented analysis, a new method for scoring hydrophobicity from molecular environments was developed showing high correlations with experimental determined desolvation energies. The presented results highlight the complexities of molecular recognition and underline the challenges of computational structural biology in developing methods to detect these important subtleties. Proteins 2010. © 2009 Wiley-Liss, Inc.


    Item Type: Article
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Depositing User: Administrator
    Date Deposited: 04 Aug 2010 14:09
    Last Modified: 02 Aug 2023 16:49


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