title: Revealing the binding modes and the unbinding of 14-3-3σ proteins and inhibitors by computational methods.
abstract: The 14-3-3σ proteins are a family of ubiquitous conserved eukaryotic regulatory molecules involved in the regulation of mitogenic signal transduction, apoptotic cell death, and cell cycle control. A lot of small-molecule inhibitors have been identified for 14-3-3 protein-protein interactions (PPIs). In this work, we carried out molecular dynamics (MD) simulations combined with molecular mechanics generalized Born surface area (MM-GBSA) method to study the binding mechanism between a 14-3-3σ protein and its eight inhibitors. The ranking order of our calculated binding free energies is in agreement with the experimental results. We found that the binding free energies are mainly from interactions between the phosphate group of the inhibitors and the hydrophilic residues. To improve the binding free energy of Rx group, we designed the inhibitor R9 with group R9 = 4-hydroxypheny. However, we also found that the binding free energy of inhibitor R9 is smaller than that of inhibitor R1. By further using the steer molecular dynamics (SMD) simulations, we identified a new hydrogen bond between the inhibitor R8 and residue Arg64 in the pulling paths. The information obtained from this study may be valuable for future rational design of novel inhibitors, and provide better structural understanding of inhibitor binding to 14-3-3σ proteins.
authors.affiliation: Shandong Provincial Key Laboratory of Functional Macromolecular Biophysics and College of Physics and Electronic Information, Dezhou University, Dezhou, 253023, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Hu
authors.affiliation: Shandong Provincial Key Laboratory of Functional Macromolecular Biophysics and College of Physics and Electronic Information, Dezhou University, Dezhou, 253023, China.
authors.forename: Zanxia
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Shandong Provincial Key Laboratory of Functional Macromolecular Biophysics and College of Physics and Electronic Information, Dezhou University, Dezhou, 253023, China.
authors.forename: Shicai
authors.initials: S
authors.lastname: Xu
authors.affiliation: National Laboratory of Solid State Microstructure and Department of Physics, Nanjing University, Nanjing, 210093, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Shandong Provincial Key Laboratory of Functional Macromolecular Biophysics and College of Physics and Electronic Information, Dezhou University, Dezhou, 253023, China.
authors.forename: Jihua
authors.initials: J
authors.lastname: Wang
mesh_terms: D048948:14-3-3 Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000737:chemistry*; D005095:Exoribonucleases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D013816:Thermodynamics
chemical_list: D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D005095:Exoribonucleases; C413442:SFN protein, human