Molecular Interaction Mechanism of a 14-3-3 Protein with a Phosphorylated Peptide Elucidated by Enhanced Conformational Sampling
- 10 September 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Chemical Information and Modeling
- Vol. 60 (10), 4867-4880
- https://doi.org/10.1021/acs.jcim.0c00551
Abstract
Enhanced conformational sampling, a genetic-algorithm-guided multi-dimensional virtual-system coupled molecular dynamics, can provide equilibrated conformational distributions of a receptor protein and a flexible ligand at room temperature. The distributions provide not only the most stable but also semi-stable complex structures, and propose a ligand–receptor binding process. This method was applied to a system consisting of a receptor protein, 14-3-3ε, and a flexible peptide, phosphorylated Myeloid leukemia factor 1 (pMLF1). The results present comprehensive binding pathways of pMLF1 to 14-3-3ε. We identified four thermodynamically stable clusters of MLF1 on the 14-3-3ε surface, and free-energy barriers among some clusters. The most stable cluster includes two high-density spots connected by a narrow corridor. When pMLF1 passes the corridor, a salt-bridge relay (switching) related to the phosphorylated residue of pMLF1 occurs. Conformations in one high-density spots are similar to the experimentally determined complex structure. Three-dimensional distributions of residues in the intermolecular interface rationally explain the binding-constant changes resultant from alanine–mutation experiment for the residues. We performed a simulation of non-phosphorylated peptide and 14-3-3ε, which demonstrated that the complex structure was unstable, suggesting that phosphorylation of the peptide is crucially important for binding to 14-3-3ε.Funding Information
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science (16K05517, 16K14711, 16K18526, 24118008, JP20H03229)
- Institute for Protein Research, Osaka University (CR-19-05, CR-20-05)
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