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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.


Comparison between the calculated (ΔGbind) and the experimental (ΔGexp) binding free energies.
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f4: Comparison between the calculated (ΔGbind) and the experimental (ΔGexp) binding free energies.

Mentions: We noted that 14-3-3σ would undergo conformational change caused by the binding to inhibitor. However, since we are more concerned with the ranking of the calculated binding free energies for all inhibitors with the same chemical scaffold (Fig. 1B), all the snapshots used in the MM-GBSA were extracted from the trajectories of the compounds. The binding free energies for all eight systems were calculated by using mm_pbsa program in AMBER 12 and summarized in Table 1. Though the predicted absolute free energies were larger than those of the experimental results, the ranking orders of them were in good agreement. Figure 4 shows how well the predicted free energies reproduce the experimental data. The correlation coefficient is 0.93. Besides ranking order of the binding free energies correctly, MM-GBSA method can decompose the total binding free energy into individual components, thereby enabling us to understand the complex binding process in detail31. For the eight compounds, the van der Waals interactions and the nonpolar solvation energies, which are responsible for the burial of inhibitor’s hydrophobic groups upon binding, are favorable for binding free energies. The mean value of the sum of van der Waals and hydrophobic interaction energies () is −15.65 kcal/mol with an root-mean-square deviation of 2.79 kcal/mol. For the electrostatic energy (), the mean value is −25.53 kcal/mol with an root-mean-square deviation of 6.51 kcal/mol. The mean value of entropic contribution () is 20.31 kcal/mol with a root-mean-square deviation of 0.78 kcal/mol. The correlation coefficients of the three energy terms (, , and ) with the binding free energies are 0.30, 0.92, and 0.83 in sequence. Thus it is important to add both the electrostatic and entropic contributions for the designing of potentially new inhibitor.


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)

Comparison between the calculated (ΔGbind) and the experimental (ΔGexp) binding free energies.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Comparison between the calculated (ΔGbind) and the experimental (ΔGexp) binding free energies.
Mentions: We noted that 14-3-3σ would undergo conformational change caused by the binding to inhibitor. However, since we are more concerned with the ranking of the calculated binding free energies for all inhibitors with the same chemical scaffold (Fig. 1B), all the snapshots used in the MM-GBSA were extracted from the trajectories of the compounds. The binding free energies for all eight systems were calculated by using mm_pbsa program in AMBER 12 and summarized in Table 1. Though the predicted absolute free energies were larger than those of the experimental results, the ranking orders of them were in good agreement. Figure 4 shows how well the predicted free energies reproduce the experimental data. The correlation coefficient is 0.93. Besides ranking order of the binding free energies correctly, MM-GBSA method can decompose the total binding free energy into individual components, thereby enabling us to understand the complex binding process in detail31. For the eight compounds, the van der Waals interactions and the nonpolar solvation energies, which are responsible for the burial of inhibitor’s hydrophobic groups upon binding, are favorable for binding free energies. The mean value of the sum of van der Waals and hydrophobic interaction energies () is −15.65 kcal/mol with an root-mean-square deviation of 2.79 kcal/mol. For the electrostatic energy (), the mean value is −25.53 kcal/mol with an root-mean-square deviation of 6.51 kcal/mol. The mean value of entropic contribution () is 20.31 kcal/mol with a root-mean-square deviation of 0.78 kcal/mol. The correlation coefficients of the three energy terms (, , and ) with the binding free energies are 0.30, 0.92, and 0.83 in sequence. Thus it is important to add both the electrostatic and entropic contributions for the designing of potentially new inhibitor.

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.