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Quantifying water-mediated protein-ligand interactions in a glutamate receptor: a DFT study.

Sahai MA, Biggin PC - J Phys Chem B (2011)

Bottom Line: A particularly striking example of this can be found in the ionotropic glutamate receptors.Our results show (i) the energetics of a key water molecule are more favorable for the site found in the glutamate-bound mode compared to the alternative site observed in the AMPA-bound mode, (ii) polarization effects are important for glutamate but less so for AMPA, (iii) ligand-system interaction energies alone can predict the correct binding mode for glutamate, but for AMPA alternative modes of binding have similar interaction energies, and (iv) the internal energy is a significant factor for AMPA but not for glutamate.We discuss the results within the broader context of rational drug-design.

View Article: PubMed Central - PubMed

Affiliation: Structural Bioinformatics and Computational Biochemistry, University of Oxford, Oxford, United Kingdom.

ABSTRACT
It is becoming increasingly clear that careful treatment of water molecules in ligand-protein interactions is required in many cases if the correct binding pose is to be identified in molecular docking. Water can form complex bridging networks and can play a critical role in dictating the binding mode of ligands. A particularly striking example of this can be found in the ionotropic glutamate receptors. Despite possessing similar chemical moieties, crystal structures of glutamate and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) in complex with the ligand-binding core of the GluA2 ionotropic glutamate receptor revealed, contrary to all expectation, two distinct modes of binding. The difference appears to be related to the position of water molecules within the binding pocket. However, it is unclear exactly what governs the preference for water molecules to occupy a particular site in any one binding mode. In this work we use density functional theory (DFT) calculations to investigate the interaction energies and polarization effects of the various components of the binding pocket. Our results show (i) the energetics of a key water molecule are more favorable for the site found in the glutamate-bound mode compared to the alternative site observed in the AMPA-bound mode, (ii) polarization effects are important for glutamate but less so for AMPA, (iii) ligand-system interaction energies alone can predict the correct binding mode for glutamate, but for AMPA alternative modes of binding have similar interaction energies, and (iv) the internal energy is a significant factor for AMPA but not for glutamate. We discuss the results within the broader context of rational drug-design.

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Comparison of the resulting partial charge on atoms using the RESP(69) method (A) Glutamate in 1FTJ structure. (B) AMPA in the 1FTM structure. (C) Glutamate in the 1FTM structure. (D) AMPA in the 1FTJ structure.
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fig7: Comparison of the resulting partial charge on atoms using the RESP(69) method (A) Glutamate in 1FTJ structure. (B) AMPA in the 1FTM structure. (C) Glutamate in the 1FTM structure. (D) AMPA in the 1FTJ structure.

Mentions: A method commonly employed to calculate partial charges for compounds that are not already parametrized in modern force-fields is to use the restricted electrostatic potential (RESP) fitting method.(69) We performed RESP calculations on the ligands within the four models in order to assess to what extent polarization from the environment in the different binding modes might be a factor. The results are shown for the four models in Figure 7. The calculations show that there is reasonable agreement at the amino and carboxylic acid groups in all four systems (which is to be expected). The greatest variation is observed at the OE1 and OE2 atoms of Glu, which have an asymmetric charge distribution, presumably reflecting the local environment in each case (WG or WA). In contrast there is much less variation observed at the OE2 (or OE1) atoms of AMPA in 1FTM or 1FTJ.


Quantifying water-mediated protein-ligand interactions in a glutamate receptor: a DFT study.

Sahai MA, Biggin PC - J Phys Chem B (2011)

Comparison of the resulting partial charge on atoms using the RESP(69) method (A) Glutamate in 1FTJ structure. (B) AMPA in the 1FTM structure. (C) Glutamate in the 1FTM structure. (D) AMPA in the 1FTJ structure.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3102440&req=5

fig7: Comparison of the resulting partial charge on atoms using the RESP(69) method (A) Glutamate in 1FTJ structure. (B) AMPA in the 1FTM structure. (C) Glutamate in the 1FTM structure. (D) AMPA in the 1FTJ structure.
Mentions: A method commonly employed to calculate partial charges for compounds that are not already parametrized in modern force-fields is to use the restricted electrostatic potential (RESP) fitting method.(69) We performed RESP calculations on the ligands within the four models in order to assess to what extent polarization from the environment in the different binding modes might be a factor. The results are shown for the four models in Figure 7. The calculations show that there is reasonable agreement at the amino and carboxylic acid groups in all four systems (which is to be expected). The greatest variation is observed at the OE1 and OE2 atoms of Glu, which have an asymmetric charge distribution, presumably reflecting the local environment in each case (WG or WA). In contrast there is much less variation observed at the OE2 (or OE1) atoms of AMPA in 1FTM or 1FTJ.

Bottom Line: A particularly striking example of this can be found in the ionotropic glutamate receptors.Our results show (i) the energetics of a key water molecule are more favorable for the site found in the glutamate-bound mode compared to the alternative site observed in the AMPA-bound mode, (ii) polarization effects are important for glutamate but less so for AMPA, (iii) ligand-system interaction energies alone can predict the correct binding mode for glutamate, but for AMPA alternative modes of binding have similar interaction energies, and (iv) the internal energy is a significant factor for AMPA but not for glutamate.We discuss the results within the broader context of rational drug-design.

View Article: PubMed Central - PubMed

Affiliation: Structural Bioinformatics and Computational Biochemistry, University of Oxford, Oxford, United Kingdom.

ABSTRACT
It is becoming increasingly clear that careful treatment of water molecules in ligand-protein interactions is required in many cases if the correct binding pose is to be identified in molecular docking. Water can form complex bridging networks and can play a critical role in dictating the binding mode of ligands. A particularly striking example of this can be found in the ionotropic glutamate receptors. Despite possessing similar chemical moieties, crystal structures of glutamate and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) in complex with the ligand-binding core of the GluA2 ionotropic glutamate receptor revealed, contrary to all expectation, two distinct modes of binding. The difference appears to be related to the position of water molecules within the binding pocket. However, it is unclear exactly what governs the preference for water molecules to occupy a particular site in any one binding mode. In this work we use density functional theory (DFT) calculations to investigate the interaction energies and polarization effects of the various components of the binding pocket. Our results show (i) the energetics of a key water molecule are more favorable for the site found in the glutamate-bound mode compared to the alternative site observed in the AMPA-bound mode, (ii) polarization effects are important for glutamate but less so for AMPA, (iii) ligand-system interaction energies alone can predict the correct binding mode for glutamate, but for AMPA alternative modes of binding have similar interaction energies, and (iv) the internal energy is a significant factor for AMPA but not for glutamate. We discuss the results within the broader context of rational drug-design.

Show MeSH