Dataset Information

Hydration Site Thermodynamics Explain SARs for Triazolylpurines Analogues Binding to the A2A Receptor.

ABSTRACT: A series of triazolylpurine analogues show interesting and unintuitive structure-activity relationships against the A2A adenosine receptor. As the 2-substituted aliphatic group is initially increased to methyl and isopropyl, there is a decrease in potency; however, extending the substituent to n-butyl and n-pentyl results in a significant gain in potency. This trend cannot be readily explained by ligand-receptor interactions, steric effects, or differences in ligand desolvation. Here, we show that a novel method for characterizing solvent thermodynamics in protein binding sites correctly predicts the trend in binding affinity for this series based on the differential water displacement patterns. In brief, small unfavorable substituents occupy a region in the A2A adenosine receptor binding site predicted to contain stable waters, while the longer favorable substituents extend to a region that contains several unstable waters. The predicted binding energies associated with displacing water within these hydration sites correlate well with the experimental activities.

SUBMITTER: Higgs C

PROVIDER: S-EPMC4007955 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Hydration Site Thermodynamics Explain SARs for Triazolylpurines Analogues Binding to the A2A Receptor.

Higgs Christopher C Beuming Thijs T Sherman Woody W

ACS medicinal chemistry letters 20100510 4

A series of triazolylpurine analogues show interesting and unintuitive structure-activity relationships against the A2A adenosine receptor. As the 2-substituted aliphatic group is initially increased to methyl and isopropyl, there is a decrease in potency; however, extending the substituent to n-butyl and n-pentyl results in a significant gain in potency. This trend cannot be readily explained by ligand-receptor interactions, steric effects, or differences in ligand desolvation. Here, we show th ...[more]

PMID: 24900189

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Project description:Actomyosin is an important molecular motor, and the binding of actin and myosin is an essential research target in biophysics. Nevertheless, the physical factors driving or opposing the binding are still unclear. Here, we investigate the role of water in actin-myosin binding using the most reliable statistical-mechanical method currently available for assessing biomolecules immersed in water. This method is characterized as follows: water is treated not as a dielectric continuum but as an ensemble of molecules; the polyatomic structures of proteins are taken into consideration; and the binding free energy is decomposed into physically insightful entropic and energetic components by accounting for the hydration effect to its full extent. We find that the actin-myosin binding brings large gains of electrostatic and Lennard-Jones attractive interactions. However, these gains are accompanied by even larger losses of actin-water and myosin-water electrostatic and LJ attractive interactions. Although roughly half of the energy increase due to the losses is cancelled out by the energy decrease arising from structural reorganization of the water released upon binding, the remaining energy increase is still larger than the energy decrease brought by the gains mentioned above. Hence, the net change in system energy is positive, which opposes binding. Importantly, the binding is driven by a large gain of configurational entropy of water, which surpasses the positive change in system energy and the conformational entropy loss occurring for actin and myosin. The principal physical origin of the large water-entropy gain is as follows: the actin-myosin interface is closely packed with the achievement of high shape complementarity on the atomic level, leading to a large increase in the total volume available to the translational displacement of water molecules in the system and a resultant reduction of water crowding (i.e., entropic correlations among water molecules).

Dataset Information

Hydration Site Thermodynamics Explain SARs for Triazolylpurines Analogues Binding to the A2A Receptor.

Publications

Hydration Site Thermodynamics Explain SARs for Triazolylpurines Analogues Binding to the A2A Receptor.

Similar Datasets

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