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Positively-charged semi-tunnel is a structural and surface characteristic of polyphosphate-binding proteins: an in-silico study.

Wei ZZ, Vatcher G, Tin AH, Teng JL, Wang J, Cui QH, Chen JG, Yu AC - PLoS ONE (2015)

Bottom Line: We found that the PCSTs in varied proteins were folded in different secondary structure compositions.Utilizing the PCST identified in the β subunit of PPK3, we predicted the potential polyP-binding domain of PPK3.The discovery of this feature facilitates future searches for polyP-binding proteins and discovery of the mechanisms for polyP-binding activities.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Research Institute, Peking University; Department of Neurobiology, School of Basic Medical Sciences, Peking University; Key Laboratory for Neuroscience (Peking University), Ministry of Education; Key Laboratory for Neuroscience (Peking University), National Health and Family Planning Commission, Beijing 100191, China.

ABSTRACT
Phosphate is essential for all major life processes, especially energy metabolism and signal transduction. A linear phosphate polymer, polyphosphate (polyP), linked by high-energy phosphoanhydride bonds, can interact with various proteins, playing important roles as an energy source and regulatory factor. However, polyP-binding structures are largely unknown. Here we proposed a putative polyP binding site, a positively-charged semi-tunnel (PCST), identified by surface electrostatics analyses in polyP kinases (PPKs) and many other polyP-related proteins. We found that the PCSTs in varied proteins were folded in different secondary structure compositions. Molecular docking calculations revealed a significant value for binding affinity to polyP in PCST-containing proteins. Utilizing the PCST identified in the β subunit of PPK3, we predicted the potential polyP-binding domain of PPK3. The discovery of this feature facilitates future searches for polyP-binding proteins and discovery of the mechanisms for polyP-binding activities. This should greatly enhance the understanding of the many physiological functions of protein-bound polyP and the involvement of polyP and polyP-binding proteins in various human diseases.

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Related in: MedlinePlus

Binding affinities of polyP to polyP positive control proteins.PPK4 (PDB ID: 3G3Q); PPK1 (PDB ID:1XDO);PPX/GPPA (PDB ID: 1T6C); HsPLAP (PDB ID: 1EW2). PolyP ligands included Ap5 (A) and Ap6A (B). Each circle, square, or triangle represented an estimated free energy of binding from the molecular docking calculations using Ap5 or Ap6A ligand and different polyP positive control proteins.
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pone.0123713.g002: Binding affinities of polyP to polyP positive control proteins.PPK4 (PDB ID: 3G3Q); PPK1 (PDB ID:1XDO);PPX/GPPA (PDB ID: 1T6C); HsPLAP (PDB ID: 1EW2). PolyP ligands included Ap5 (A) and Ap6A (B). Each circle, square, or triangle represented an estimated free energy of binding from the molecular docking calculations using Ap5 or Ap6A ligand and different polyP positive control proteins.

Mentions: To estimate binding affinities of polyP for PCST-containing proteins, molecular docking calculations were performed. Short-chain polyP-containing ligands were used and their binding potentials were reflected by their minimum binding energies. Nucleotide ligands, distinct from short-chain polyP-containing ligands, were also used to confirm the binding of nucleotide. For most calculations, ATP, adenosine pentaphosphate (Ap5), or diadenosine hexaphosphate (Ap6A) were selected as representatives of nucleotide and polyP, respectively. We first utilized polyP-synthesizing enzymes and polyP-degrading enzymes as positive controls for molecular docking calculations. These proteins included prokaryotic PPK1, yeast PPK4, Aquifex aeolicus PPX/GPPA (Fig 1C) and human alkaline phosphatase (Fig 1D), whose structures were all revealed to contain PCST. The blind docking calculations were performed and all the calculated binding free energies were analyzed together (Fig 2). The binding affinities for the positive control proteins were high in all Ap5-based and some Ap6A (PPK1, PPX/GPPA and HsPLAP)-based dockings. We also noticed that the minimum binding free energies were lower than 100 kcal/mol for these positive controls.


Positively-charged semi-tunnel is a structural and surface characteristic of polyphosphate-binding proteins: an in-silico study.

Wei ZZ, Vatcher G, Tin AH, Teng JL, Wang J, Cui QH, Chen JG, Yu AC - PLoS ONE (2015)

Binding affinities of polyP to polyP positive control proteins.PPK4 (PDB ID: 3G3Q); PPK1 (PDB ID:1XDO);PPX/GPPA (PDB ID: 1T6C); HsPLAP (PDB ID: 1EW2). PolyP ligands included Ap5 (A) and Ap6A (B). Each circle, square, or triangle represented an estimated free energy of binding from the molecular docking calculations using Ap5 or Ap6A ligand and different polyP positive control proteins.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400040&req=5

pone.0123713.g002: Binding affinities of polyP to polyP positive control proteins.PPK4 (PDB ID: 3G3Q); PPK1 (PDB ID:1XDO);PPX/GPPA (PDB ID: 1T6C); HsPLAP (PDB ID: 1EW2). PolyP ligands included Ap5 (A) and Ap6A (B). Each circle, square, or triangle represented an estimated free energy of binding from the molecular docking calculations using Ap5 or Ap6A ligand and different polyP positive control proteins.
Mentions: To estimate binding affinities of polyP for PCST-containing proteins, molecular docking calculations were performed. Short-chain polyP-containing ligands were used and their binding potentials were reflected by their minimum binding energies. Nucleotide ligands, distinct from short-chain polyP-containing ligands, were also used to confirm the binding of nucleotide. For most calculations, ATP, adenosine pentaphosphate (Ap5), or diadenosine hexaphosphate (Ap6A) were selected as representatives of nucleotide and polyP, respectively. We first utilized polyP-synthesizing enzymes and polyP-degrading enzymes as positive controls for molecular docking calculations. These proteins included prokaryotic PPK1, yeast PPK4, Aquifex aeolicus PPX/GPPA (Fig 1C) and human alkaline phosphatase (Fig 1D), whose structures were all revealed to contain PCST. The blind docking calculations were performed and all the calculated binding free energies were analyzed together (Fig 2). The binding affinities for the positive control proteins were high in all Ap5-based and some Ap6A (PPK1, PPX/GPPA and HsPLAP)-based dockings. We also noticed that the minimum binding free energies were lower than 100 kcal/mol for these positive controls.

Bottom Line: We found that the PCSTs in varied proteins were folded in different secondary structure compositions.Utilizing the PCST identified in the β subunit of PPK3, we predicted the potential polyP-binding domain of PPK3.The discovery of this feature facilitates future searches for polyP-binding proteins and discovery of the mechanisms for polyP-binding activities.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Research Institute, Peking University; Department of Neurobiology, School of Basic Medical Sciences, Peking University; Key Laboratory for Neuroscience (Peking University), Ministry of Education; Key Laboratory for Neuroscience (Peking University), National Health and Family Planning Commission, Beijing 100191, China.

ABSTRACT
Phosphate is essential for all major life processes, especially energy metabolism and signal transduction. A linear phosphate polymer, polyphosphate (polyP), linked by high-energy phosphoanhydride bonds, can interact with various proteins, playing important roles as an energy source and regulatory factor. However, polyP-binding structures are largely unknown. Here we proposed a putative polyP binding site, a positively-charged semi-tunnel (PCST), identified by surface electrostatics analyses in polyP kinases (PPKs) and many other polyP-related proteins. We found that the PCSTs in varied proteins were folded in different secondary structure compositions. Molecular docking calculations revealed a significant value for binding affinity to polyP in PCST-containing proteins. Utilizing the PCST identified in the β subunit of PPK3, we predicted the potential polyP-binding domain of PPK3. The discovery of this feature facilitates future searches for polyP-binding proteins and discovery of the mechanisms for polyP-binding activities. This should greatly enhance the understanding of the many physiological functions of protein-bound polyP and the involvement of polyP and polyP-binding proteins in various human diseases.

Show MeSH
Related in: MedlinePlus