Limits...
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.


The decomposition of inhibitors on a per-residue basis for compounds R1 (A) and R8 (B).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4644958&req=5

f5: The decomposition of inhibitors on a per-residue basis for compounds R1 (A) and R8 (B).

Mentions: In order to find which residues make significant intermolecular interaction contributions to the binding with the inhibitors, the decomposition of the electrostatic interaction energy, van der Waals energy, and solvation free energy for all compounds were analyzed and the results are depicted in Fig. 5 for compounds R1 and R8 and in Fig. S1 for compounds R2-R7, respectively. The decomposition method with MM-GBSA can naturally be used for the energy decomposition at the atomic level for the per-atom contributions summed over all atoms of each residue to obtain the contribution of each residue. This has been successfully applied to a lot of protein-inhibitor binding systems. The major favorable energy contributions originate predominantly from seven residues (Lys53, Arg60, Lys126, Arg133, Tyr134, Leu178, and Val182) with averaged energy contribution larger than −0.5 kcal/mol in all compounds. Special attention had been paid to three residues (Arg60, Arg133 and Tyr134) with large electrostatic contribution. For example, the electrostatic contributions of residues Arg60, Arg133 and Tyr134 are −17.37, −19.04, and −5.0 kcal/mol for compound R1, respectively. The phosphate group has negative charge and residue arginine has positive charge, resulting in strong electrostatic attraction between them. The hydrogen bonds between the phosphate group and the 14-3-3σ protein were listed in Table 2, showing the occupancies and distances of hydrogen bonds in all compounds. The phosphate group forms three hydrogen bonds with both residues Arg60 and Arg133, as well as one hydrogen bond with residue Tyr134. Most of the hydrogen bonds are stable with high occupancy and similar distance in all compounds (Table 2), implying that the phosphate groups were tightly bonded in the binding pocked formed by three hydrophilic residues (Arg60, Arg133 and Tyr134). This result is in accordance with the analysis of RMSDs.


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)

The decomposition of inhibitors on a per-residue basis for compounds R1 (A) and R8 (B).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: The decomposition of inhibitors on a per-residue basis for compounds R1 (A) and R8 (B).
Mentions: In order to find which residues make significant intermolecular interaction contributions to the binding with the inhibitors, the decomposition of the electrostatic interaction energy, van der Waals energy, and solvation free energy for all compounds were analyzed and the results are depicted in Fig. 5 for compounds R1 and R8 and in Fig. S1 for compounds R2-R7, respectively. The decomposition method with MM-GBSA can naturally be used for the energy decomposition at the atomic level for the per-atom contributions summed over all atoms of each residue to obtain the contribution of each residue. This has been successfully applied to a lot of protein-inhibitor binding systems. The major favorable energy contributions originate predominantly from seven residues (Lys53, Arg60, Lys126, Arg133, Tyr134, Leu178, and Val182) with averaged energy contribution larger than −0.5 kcal/mol in all compounds. Special attention had been paid to three residues (Arg60, Arg133 and Tyr134) with large electrostatic contribution. For example, the electrostatic contributions of residues Arg60, Arg133 and Tyr134 are −17.37, −19.04, and −5.0 kcal/mol for compound R1, respectively. The phosphate group has negative charge and residue arginine has positive charge, resulting in strong electrostatic attraction between them. The hydrogen bonds between the phosphate group and the 14-3-3σ protein were listed in Table 2, showing the occupancies and distances of hydrogen bonds in all compounds. The phosphate group forms three hydrogen bonds with both residues Arg60 and Arg133, as well as one hydrogen bond with residue Tyr134. Most of the hydrogen bonds are stable with high occupancy and similar distance in all compounds (Table 2), implying that the phosphate groups were tightly bonded in the binding pocked formed by three hydrophilic residues (Arg60, Arg133 and Tyr134). This result is in accordance with the analysis of RMSDs.

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.