Physical basis of structural and catalytic Zn-binding sites in proteins

Zn2+, an element that is essential to all life forms, can play a catalytic or a solely structural role. Previous works have shown that Zn2+ binds preferentially to water molecules and His in catalytic sites, but to Cys(-) instructural sites, but the molecular basis for the observed ligand preference is unclear. Here, we show that the different Zn roles are also reflected in the different bond distances to Zn2+ in structural and catalytic sites. We reveal the physical basis for the observed differences between structural and catalytic Zn sites: In most catalytic sites, water is found bound to Zn2+ as it transfers the least charge to Zn2+ and is less bulky compared to the protein ligands, enabling Zn2+ to serve as a Lewis acid in catalysis. In most structural sites, however, >= 2 Cys- are found bound to Zn2+, as Cys- transfers the most charge to Zn2+ and reduces the Zn charge to such an extent that Zn2+ can no longer act as a Lewis acid; furthermore, steric repulsion among the bulky Cys (S-) prevents Zn2+ from accommodating another ligand. Based on the observed ligand preference and Zn-ligand distance differences between structural and catalytic Zn sites, we present a simple method for distinguishing the two types of sites and for verifying the catalytic role of Zn2+. Finally, we discuss how the physical bases revealed aid in designing potential drug molecules that target Zn proteins. (c) 2008 Elsevier Ltd. All rights reserved.