Metal-Binding Residues are Distinguished by their Lower Mobilities and Efficient Signal Propagation Properties

Abstract

Metal-binding proteins are associated with a variety of functions. Understanding the fundamental functional mechanism of these proteins entails a thorough characterization of the structural and dynamic properties of their metal-binding sites. Recent studies have shown that proteins at equilibrium undergo collective changes in conformation, which facilitate their function, and such intrinsic protein dynamics can be characterized using elastic network models in conjunction with normal mode analysis methods.1 The usefulness of the Gaussian Network Model (GNM) in capturing the unique architecture-induced properties of a protein has been shown in analyzing the dynamics of catalytic sites for a series of enzymes where functional sites were inferred from structural dynamics. In this study, we analyzed the equilibrium dynamics of metal-binding proteins as seen in the lowest frequency modes predicted by the GNM, to see whether any dynamic role is assumed by the metal-binding sites, in addition to their chemical role of coordinating the ligand. We also examined the communication properties of these sites using an information theoretic spectral method of signal propagation.2 Our results demonstrate that metal-binding residues are predisposed towards having relatively smaller-scale fluctuations than other residues. Intuitively, a flexible residue would be entropically more unfavorable for binding purposes and the inherent small-scale fluctuations imply lesser loss of conformational entropy upon metal binding. Our study further shows that metal-binding residues efficiently communicate signals, suggesting that their particular locations in the structure have been evolutionarily optimized to achieve most efficient allosteric function. These properties provide insights into the functional design of metal-binding proteins.