Water matters : role of water in the binding selectivity of β-blockers to human β-adrenergic receptors

This work investigates the problem of selective binding of the chosen ß-blockers towards human ß1 and ß2-adrenergic receptors (ßARs). The selective blockade of the cardiac ß1 has important medical applications. However, the current understanding of this prominent medical problem is still very limited. The recently published crystal structures of ß1 and the ß2 [1,2] offer an opportunity to understand the mechanism of ß1-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 ß1 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 ßARs, being particularly important in determining the selectivity of binding.