Water Matters: Role of Water in the Binding Selectivity of β-Blockers to Human β-Adrenergic Receptors

Abstract

This work investigates the problem of selective binding of the chosen β-blockers towards human β1 and β2-adrenergic receptors (βARs). The selective blockade of the cardiac β1 has important medical applications. However, the current understanding of this prominent medical problem is still very limited. The recently published crystal structures of β1 and the β2 [1,2] offer an opportunity to understand the mechanism of β1-selective binding with atomic accuracy. Numerous computational studies have explored the binding pockets or conformational properties of these receptors through homology modeling, structure-based modeling, fragment-based screening and molecular dynamics simulations [3-5]. Yet, as far as the authors know, thus far there have been no computational studies focusing exclusively on the problem of the selective blockade of the β1 subtype. The computations carried out and reported here fill this gap. Surprisingly, our simulations show that water plays a fundamental role in the binding site of both βARs, being particularly important in determining the selectivity of binding.1. T. Warne et al., (2008) Structure of a beta1-adrenergic G-protein-coupled receptor. Nature 454, 486-91.2. V. Cherezov et al., (2007) High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 318, 1258-65.3. K. Kaszuba et al., (2010) Molecular dynamics simulations reveal fundamental role of water as factor determining affinity of binding of beta-blocker nebivolol to beta(2)-adrenergic receptor. J. Phys. Chem. B. B 114, 8374-86.4. A. Ivetacet et al., (2010) Mapping the druggable allosteric space of g-protein coupled receptors: a fragment-based molecular dynamics approach. CB&DD 76, 201-17.5. S. Vanni et al., (2011) Predicting Novel Binding Modes of Agonists to β Adrenergic Receptors using All-Atom Molecular Dynamics Simulations. Plos Comput Biol 7, 1, ee1001053.