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Abstract: We study the formation of protein-protein encounter complexes with a Langevinequation approach that considers direct, steric and thermal forces. As threemodel systems with distinctly different properties we consider the pairsbarnase:barstar, cytochrome c:cytochrome c peroxidase and p53:MDM2. In eachcase, proteins are modeled either as spherical particles, as dipolar spheres oras collection of several small beads with one dipole. Spherical reactionpatches are placed on the model proteins according to the known experimentalstructures of the protein complexes. In the computer simulations, concentrationis varied by changing box size. Encounter is defined as overlap of the reactionpatches and the corresponding first passage times are recorded together withthe number of unsuccessful contacts before encounter. We find that encounterfrequency scales linearly with protein concentration, thus proving that ourmicroscopic model results in a well-defined macroscopic encounter rate. Thenumber of unsuccessful contacts before encounter decreases with increasingencounter rate and ranges from 20-9000. For all three models, encounter ratesare obtained within one order of magnitude of the experimentally measuredassociation rates. Electrostatic steering enhances association up to 50-fold.If diffusional encounter is dominant p53:MDM2 or similarly important aselectrostatic steering barnase:barstar, then encounter rate decreases withdecreasing patch radius. More detailed modeling of protein shapes decreasesencounter rates by 5-95 percent. Our study shows how generic principles ofprotein-protein association are modulated by molecular features of the systemsunder consideration. Moreover it allows us to assess different coarse-grainingstrategies for the future modelling of the dynamics of large protein complexes.

Autor: Jakob Schluttig 1 and 2, Denitsa Alamanova 3, Volkhard Helms 3, Ulrich S. Schwarz 1 and 2 1 University of Heidelberg, Bioquant, 2

Fuente: https://arxiv.org/

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