Role of water-bridged interactions in metal ion coupled protein allostery

Allosteric communication between distant parts of proteins controls many cellular functions, in which metal ions are widely utilized as effectors to trigger the allosteric cascade. Due to the involvement of strong coordination interactions, the energy landscape dictating the metal ion binding is intrinsically rugged. How metal ions achieve fast binding by overcoming the landscape ruggedness and thereby efficiently mediate protein allostery is elusive. By performing molecular dynamics simulations for the Ca2+ binding mediated allostery of the calmodulin (CaM) domains, each containing two Ca2+ binding helix-loop-helix motifs (EF-hands), we revealed the key role of water-bridged interactions in Ca2+ binding and protein allostery. The bridging water molecules between Ca2+ and binding residue reduces the ruggedness of ligand exchange landscape by acting as a lubricant, facilitating the Ca2+ coupled protein allostery. Calcium-induced rotation of the helices in the EF-hands, with the hydrophobic core serving as the pivot, leads to exposure of hydrophobic sites for target binding. Intriguingly, despite being structurally similar, the response of the two symmetrically arranged EF-hands upon Ca2+ binding is asymmetric. Breakage of symmetry is needed for efficient allosteric communication between the EF-hands. The key roles that water molecules play in driving allosteric transitions are likely to be general in other metal ion mediated protein allostery. Author summary Natural proteins often utilize allostery in executing a variety of functions. Metal ions are typical cofactors to trigger the allosteric cascade. In this work, using the Ca2+ sensor protein calmodulin as the model system, we revealed crucial roles of water-bridged interactions in the metal ion coupled protein allostery. The coordination of the Ca2+ to the binding site involves an intermediate in which the water molecule bridges the Ca2+ and the liganding residue. The bridging water reduces the free energy barrier height of ligand exchange, therefore facilitating the ligand exchange and allosteric coupling by acting as a lubricant. We also showed that the response of the two symmetrically arranged EF-hand motifs of CaM domains upon Ca2+ binding is asymmetric, which is directly attributed to the differing dehydration process of the Ca2+ ions and is needed for efficient allosteric communication.

Automated summary

This study reveals the crucial role of water-bridged interactions in metal ion coupled protein allostery, which reduces the ruggedness of ligand exchange landscape and facilitates allosteric communication. The asymmetric response of symmetrically arranged EF-hands upon Ca2+ binding is also highlighted as essential for efficient allosteric communication.