Physical Basis of Structural and Catalytic Zn-Binding Sites in Proteins

Abstract

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 Zn2+ 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.