Informace o publikaci
Exploring the binding pathways of the 14-3-3 zeta : protein Structural and free-energy profiles revealed by Hamiltonian replica exchange molecular dynamics with distancefield distance restraints
| Autoři | |
|---|---|
| Rok publikování | 2017 |
| Druh | Článek v odborném periodiku |
| Časopis / Zdroj | Plos one |
| Fakulta / Pracoviště MU | |
| Citace | |
| www | http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0180633&type=printable |
| Doi | http://dx.doi.org/10.1371/journal.pone.0180633 |
| Klíčová slova | SIMULATIONS; SITES; PHOSPHOSERINE; RECOGNITION; FORCE; NMR |
| Popis | The 14-3-3 zeta protein family performs regulatory functions in eukaryotic organisms by binding to a large number of phosphorylated protein partners. Whilst the binding mode of the phosphopeptides within the primary 14-3-3 zeta binding site is well established based on the crystal structures of their complexes, little is known about the binding process itself. We present a computational study of the process by which phosphopeptides bind to the 14-3-3 zeta protein. Applying a novel scheme combining Hamiltonian replica exchange molecular dynamics and distancefield restraints allowed us to map and compare the most likely phosphopeptidebinding pathways to the 14-3-3 zeta protein. The most important structural changes to the protein and peptides involved in the binding process were identified. In order to bind phosphopeptides to the primary interaction site, the 14-3-3 zeta adopted a newly found wide-opened conformation. Based on our findings we additionally propose a secondary interaction site on the inner surface of the 14-3-3 zeta dimer, and a direct interference on the binding process by the flexible C-terminal tail. A minimalistic model was designed to allow for the efficient calculation of absolute binding affinities. Binding affinities calculated from the potential of mean force along the binding pathway are in line with the available experimental estimates for two of the studied systems. |
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