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.


RMSDs of the backbone atoms of the 14-3-3σ protein, heavy atoms of the binding pocket (within 5 Å), and the heavy atoms in the inhibitors as a function of the MD simulation time for: (A) the 14-3-3σ protein without the inhibitor, (B) compound R1, and (C) compound R8 as a function of the MD simulation time.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: RMSDs of the backbone atoms of the 14-3-3σ protein, heavy atoms of the binding pocket (within 5 Å), and the heavy atoms in the inhibitors as a function of the MD simulation time for: (A) the 14-3-3σ protein without the inhibitor, (B) compound R1, and (C) compound R8 as a function of the MD simulation time.

Mentions: MD simulations for eight compounds were performed for the time duration of 20 ns. The root mean square deviations (RMSDs) from the crystallographic structure, which can effectively assess the dynamics stability of compounds, were analyzed by using Ptraj54 module of AmberTools software for apo-14-3-3σ, as well as for compounds R1 and R8 (see Fig. 3). The average RMSDs of binding pocket in the last 5 ns MD simulations for apo-14-3-3σ (1.62 ± 0.16 Å) is larger than that for compound R1(1.17 ± 0.14 Å), as well as that for compound R8 (1.15 ± 0.13 Å). This indicates that the binding pocket of the 14-3-3σ protein is more stable with inhibitor than that without inhibitor. It is noted that the RMSDs for the inhibitors show large fluctuation (Fig. 3), indicating some groups of the inhibitor would not bound tightly to the proteins. To evaluate which part of the inhibitor fluctuate largely, we extracted two groups (group one: 2-hydroxyphenylphosphonic acid; and group Rxs: which names are shown in Fig. 1B) of inhibitors to calculate their RMSDs. The standard deviations of the RMSD for the inhibitors (0.33 Å and 0.55 Å) are larger than those for the group one (0.18 Å and 0.27 Å) and smaller than those for the group Rxs (0.52 Å and 0.74 Å) for compounds R1 and R8, respectively, as well as for compounds R2-R7.


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)

RMSDs of the backbone atoms of the 14-3-3σ protein, heavy atoms of the binding pocket (within 5 Å), and the heavy atoms in the inhibitors as a function of the MD simulation time for: (A) the 14-3-3σ protein without the inhibitor, (B) compound R1, and (C) compound R8 as a function of the MD simulation time.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: RMSDs of the backbone atoms of the 14-3-3σ protein, heavy atoms of the binding pocket (within 5 Å), and the heavy atoms in the inhibitors as a function of the MD simulation time for: (A) the 14-3-3σ protein without the inhibitor, (B) compound R1, and (C) compound R8 as a function of the MD simulation time.
Mentions: MD simulations for eight compounds were performed for the time duration of 20 ns. The root mean square deviations (RMSDs) from the crystallographic structure, which can effectively assess the dynamics stability of compounds, were analyzed by using Ptraj54 module of AmberTools software for apo-14-3-3σ, as well as for compounds R1 and R8 (see Fig. 3). The average RMSDs of binding pocket in the last 5 ns MD simulations for apo-14-3-3σ (1.62 ± 0.16 Å) is larger than that for compound R1(1.17 ± 0.14 Å), as well as that for compound R8 (1.15 ± 0.13 Å). This indicates that the binding pocket of the 14-3-3σ protein is more stable with inhibitor than that without inhibitor. It is noted that the RMSDs for the inhibitors show large fluctuation (Fig. 3), indicating some groups of the inhibitor would not bound tightly to the proteins. To evaluate which part of the inhibitor fluctuate largely, we extracted two groups (group one: 2-hydroxyphenylphosphonic acid; and group Rxs: which names are shown in Fig. 1B) of inhibitors to calculate their RMSDs. The standard deviations of the RMSD for the inhibitors (0.33 Å and 0.55 Å) are larger than those for the group one (0.18 Å and 0.27 Å) and smaller than those for the group Rxs (0.52 Å and 0.74 Å) for compounds R1 and R8, respectively, as well as for compounds R2-R7.

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.