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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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Hydrogen bond interactions for individual water molecules for the 1FTJ-Glu model system (A) WG, (B) W1, (C) W2, (D) W3, (E) W4, and (F) W5.
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fig3: Hydrogen bond interactions for individual water molecules for the 1FTJ-Glu model system (A) WG, (B) W1, (C) W2, (D) W3, (E) W4, and (F) W5.

Mentions: Figures 3–4 describe the water interactions in the four models. We first discuss what we refer to above as the “pharmacophoric water”, which is the water that appears to act as a surrogate part of the ligand in either the glutamate (WG, see Figure 2, panels A and D) or AMPA (WA, see Figure 2, panels B and C) complexes. Before an in depth analysis, one might expect that the interaction energy of WG or WA would be more favorable in the poses adopted in the crystal. However, the interaction energy of the pharmacophoric water with the remainder of the system (WA-WsLP and WG-WsLP cells in Table 2) presents a different perspective of what is observed in the crystal structures. We find that regardless of the ligand bound WA appears to be iso-energetic with a 0.67 kcal mol–1 difference between the glutamate bound (−5.59 kcal mol–1) mode and the AMPA bound (−6.26 kcal mol–1) mode. In the 1FTJ-based models, WG appears to also be iso-energetic albeit with a slight preference of 1.88 kcal mol–1 for the AMPA bound (−9.75 kcal mol–1) mode than the glutamate bound (−7.87 kcal mol–1) mode. One might expect these to be exactly isoenergetic, but the optimizations are done in the presence of ligands and thus there will be some small effects on the final positions of the protein atoms dictated by the ligand. In the 1FTJ-based models, WG forms hydrogen bonds (Figures 3A and 5A) with the backbone NH group of Glu705, the water W2 and an oxygen atom from the ligand (one of the carboxylate oxygens for Glu, and the ring oxygen for AMPA). In the 1FTM-based models, WA forms hydrogen bonds (Figures 5A and 6A) with the OH group of Ser 654, the backbone NH of Thr 655, W5 and two oxygen atoms from the ligand in each case.


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

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

Hydrogen bond interactions for individual water molecules for the 1FTJ-Glu model system (A) WG, (B) W1, (C) W2, (D) W3, (E) W4, and (F) W5.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Hydrogen bond interactions for individual water molecules for the 1FTJ-Glu model system (A) WG, (B) W1, (C) W2, (D) W3, (E) W4, and (F) W5.
Mentions: Figures 3–4 describe the water interactions in the four models. We first discuss what we refer to above as the “pharmacophoric water”, which is the water that appears to act as a surrogate part of the ligand in either the glutamate (WG, see Figure 2, panels A and D) or AMPA (WA, see Figure 2, panels B and C) complexes. Before an in depth analysis, one might expect that the interaction energy of WG or WA would be more favorable in the poses adopted in the crystal. However, the interaction energy of the pharmacophoric water with the remainder of the system (WA-WsLP and WG-WsLP cells in Table 2) presents a different perspective of what is observed in the crystal structures. We find that regardless of the ligand bound WA appears to be iso-energetic with a 0.67 kcal mol–1 difference between the glutamate bound (−5.59 kcal mol–1) mode and the AMPA bound (−6.26 kcal mol–1) mode. In the 1FTJ-based models, WG appears to also be iso-energetic albeit with a slight preference of 1.88 kcal mol–1 for the AMPA bound (−9.75 kcal mol–1) mode than the glutamate bound (−7.87 kcal mol–1) mode. One might expect these to be exactly isoenergetic, but the optimizations are done in the presence of ligands and thus there will be some small effects on the final positions of the protein atoms dictated by the ligand. In the 1FTJ-based models, WG forms hydrogen bonds (Figures 3A and 5A) with the backbone NH group of Glu705, the water W2 and an oxygen atom from the ligand (one of the carboxylate oxygens for Glu, and the ring oxygen for AMPA). In the 1FTM-based models, WA forms hydrogen bonds (Figures 5A and 6A) with the OH group of Ser 654, the backbone NH of Thr 655, W5 and two oxygen atoms from the ligand in each case.

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