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Revealing the binding modes and the unbinding of 14-3-3σ proteins and inhibitors by computational methods.

Hu G, Cao Z, Xu S, Wang W, Wang J - Sci Rep (2015)

Bottom Line: We found that the binding free energies are mainly from interactions between the phosphate group of the inhibitors and the hydrophilic residues.However, we also found that the binding free energy of inhibitor R9 is smaller than that of inhibitor R1.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.

View Article: PubMed Central - PubMed

Affiliation: Shandong Provincial Key Laboratory of Functional Macromolecular Biophysics and College of Physics and Electronic Information, Dezhou University, Dezhou, 253023, China.

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.

No MeSH data available.


(A) Initial structure of the 14-3-3σ protein and its inhibitors. The two identical chains of the dimer are shown in red and blue color, respectively. Helices are shown as labeled cylinders. The inhibitors are shown in large ball representation. The key residues are shown in ball and stick representation. (B) Molecular structures of eight inhibitors of the 14-3-3σ protein.
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f1: (A) Initial structure of the 14-3-3σ protein and its inhibitors. The two identical chains of the dimer are shown in red and blue color, respectively. Helices are shown as labeled cylinders. The inhibitors are shown in large ball representation. The key residues are shown in ball and stick representation. (B) Molecular structures of eight inhibitors of the 14-3-3σ protein.

Mentions: Each 14-3-3 proteins consists of characteristic cup-like shape functional dimers with each monomer has nine antiparallel α-helices displaying a so-called amphipathic groove that accommodates the mostly phosphorylated interaction motifs of their partner proteins (see Fig. 1A)1112. Small-molecule regulation on PPIs is one of the most exciting but also difficult fields in drug development and chemical biology13.


Revealing the binding modes and the unbinding of 14-3-3σ proteins and inhibitors by computational methods.

Hu G, Cao Z, Xu S, Wang W, Wang J - Sci Rep (2015)

(A) Initial structure of the 14-3-3σ protein and its inhibitors. The two identical chains of the dimer are shown in red and blue color, respectively. Helices are shown as labeled cylinders. The inhibitors are shown in large ball representation. The key residues are shown in ball and stick representation. (B) Molecular structures of eight inhibitors of the 14-3-3σ protein.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4644958&req=5

f1: (A) Initial structure of the 14-3-3σ protein and its inhibitors. The two identical chains of the dimer are shown in red and blue color, respectively. Helices are shown as labeled cylinders. The inhibitors are shown in large ball representation. The key residues are shown in ball and stick representation. (B) Molecular structures of eight inhibitors of the 14-3-3σ protein.
Mentions: Each 14-3-3 proteins consists of characteristic cup-like shape functional dimers with each monomer has nine antiparallel α-helices displaying a so-called amphipathic groove that accommodates the mostly phosphorylated interaction motifs of their partner proteins (see Fig. 1A)1112. Small-molecule regulation on PPIs is one of the most exciting but also difficult fields in drug development and chemical biology13.

Bottom Line: We found that the binding free energies are mainly from interactions between the phosphate group of the inhibitors and the hydrophilic residues.However, we also found that the binding free energy of inhibitor R9 is smaller than that of inhibitor R1.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.

View Article: PubMed Central - PubMed

Affiliation: Shandong Provincial Key Laboratory of Functional Macromolecular Biophysics and College of Physics and Electronic Information, Dezhou University, Dezhou, 253023, China.

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.

No MeSH data available.