Analysis of First and Second Shell Interactions in Phosphate-Binding Proteins

Abstract

The phosphate anion is involved a wide range of processes ranging from cell signaling to energy storage in cells1. It can interact with proteins in different modes, where its interactions range from being covalently bound to the protein to coordinating metal sites in enzymes2. The motif for coordinating or binding the phosphate depends on its functional usage and e.g., in ATP or GTP binding proteins a structural motif named the P loop is often found3. Only few of these structural motifs have been studied in great detail where quantum mechanical computations will give an elaborate description of the interactions. In this work, we survey phosphate-binding proteins with emphasis on the molecular recognition of the first- and second-shell interactions between anion and amino acid residues. To characterize the binding sites, we optimize the geometries by using density functional theory calculations. From the optimized geometries, we calculate the charge transfer and force constants between the first shell interactions and the phosphate moiety as well as the interaction between the first- and second shell of the protein. The results describe the strength of the first shell interaction with the anion and the importance of the second shell to support the binding motif. This knowledge is of importance in understanding phosphate binding proteins and in the development of biomimetic sustainable phosphate biosensors.1 Bowler, M. W., Cliff, M. J., Waltho, J. P. & Blackburn, G. M. in New J. Chem. 34: 784-794 (2010).2 Hirsch, A., Fischer, F. R. & Diederich, F. in Angewandte Chemie-International Edition 46: 338-353 (2007).3 Saraste, M., Sibbald, P. R. & Wittinghofer, A. in Trends in biochemical sciences 15: 430-434 (1990).