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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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Binding affinities of polyP to subunits of PPK3.Each circle, square, or triangle represented an estimated free energy of binding from the molecular docking calculations using Ap5 ligand and different PPK3 subunit.
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pone.0123713.g005: Binding affinities of polyP to subunits of PPK3.Each circle, square, or triangle represented an estimated free energy of binding from the molecular docking calculations using Ap5 ligand and different PPK3 subunit.

Mentions: The structures of the three PPK3 subunits (α, β and ξ) were modeled based on sequence homology and multiple alignment (Fig 4A). Superimposing modeled structures of the three subunits of PPK3 revealed great structural overlap (Fig 4B). We first performed molecular docking to compare the polyP/ATP-binding capabilities of the three subunits of PPK3. The docking results illustrated that ATP could bind to all three subunits. The α subunit bound ATP most readily, having the lowest binding free energy value of -3.37 kcal/mol compared to -2.42 kcal/mol and -1.38 kcal/mol for β and ξ. The β subunit revealed high binding affinity for polyP (Fig 5). Thus, the β subunit could be directly involved in polyP synthesis. Positive results from docking with other short-chain polyPs (Table 2) supported this notion. Two charge calculation methods, Gasteiger partial [54] and PM6 semi-empirical [55], were used individually to corroborate the data, and both showed similar values for positive results (estimated minimum binding energies less than 100 kcal/mol) and negative results (estimated minimum binding energies more than 100 kcal/mol) (Table 3).


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 subunits of PPK3.Each circle, square, or triangle represented an estimated free energy of binding from the molecular docking calculations using Ap5 ligand and different PPK3 subunit.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123713.g005: Binding affinities of polyP to subunits of PPK3.Each circle, square, or triangle represented an estimated free energy of binding from the molecular docking calculations using Ap5 ligand and different PPK3 subunit.
Mentions: The structures of the three PPK3 subunits (α, β and ξ) were modeled based on sequence homology and multiple alignment (Fig 4A). Superimposing modeled structures of the three subunits of PPK3 revealed great structural overlap (Fig 4B). We first performed molecular docking to compare the polyP/ATP-binding capabilities of the three subunits of PPK3. The docking results illustrated that ATP could bind to all three subunits. The α subunit bound ATP most readily, having the lowest binding free energy value of -3.37 kcal/mol compared to -2.42 kcal/mol and -1.38 kcal/mol for β and ξ. The β subunit revealed high binding affinity for polyP (Fig 5). Thus, the β subunit could be directly involved in polyP synthesis. Positive results from docking with other short-chain polyPs (Table 2) supported this notion. Two charge calculation methods, Gasteiger partial [54] and PM6 semi-empirical [55], were used individually to corroborate the data, and both showed similar values for positive results (estimated minimum binding energies less than 100 kcal/mol) and negative results (estimated minimum binding energies more than 100 kcal/mol) (Table 3).

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