Abstract
The protein MDM2 forms a complex with the tumor suppressing protein p53 and targets it for proteolysis in order to down-regulate p53 in normal cells. Inhibition of this interaction is of therapeutic importance. Molecular dynamics simulations of the association between p53 and MDM2 have revealed mutual modulation of the two surfaces. Analysis of the simulations of the two species approaching each other in solution shows how long range electrostatics steers these two proteins together. The net electrostatics is controlled largely by a few cationic residues that surround the MDM2 binding site. There is an overall separation in electrostatics of MDM2 and p53 that are mutually complementary and drive association. Upon close approach, there is significant energetic strain as the charges are occluded from water (desolvated). However, the complexation is driven by packing interactions that lead to highly favorable van der Waals interactions. Although the complementarity of the electrostatics of the two surfaces is essential for the two partners to form a complex, steric collisions of Y100 and short ranged van der Waals interactions of F19, W23, L26 of p53 determine the final steps of native complex formation. The electrostatics seem to be evolutionarily conserved, including variations in both partners.
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This work was supported by the Biomedical Research Council (Agency for Science, Technology and Research), Singapore. We thank Ivy Law of BII for technical help with Matlab.
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Dedicated to Professor Sandor Suhai on the occasion of his 65th birthday and published as part of the Suhai Festschrift Issue.
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Dastidar, S.G., Madhumalar, A., Fuentes, G. et al. Forces mediating protein–protein interactions: a computational study of p53 “approaching” MDM2. Theor Chem Acc 125, 621–635 (2010). https://doi.org/10.1007/s00214-009-0682-1
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DOI: https://doi.org/10.1007/s00214-009-0682-1