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Protein Grabs a Ligand by Extending Anchor Residues: Molecular Simulation for Ca²⁺ Binding to Calmodulin Loop

Department of Chemistry, Faculty of Science, Kobe University, and CREST, Japan Science and Technology Corporation, Rokkodai, Nada, Kobe 657-8501, Japan

Correspondence: Address reprint requests to Shoji Takada, E-mail: stakada{at}kobe-u.ac.jp.

The structural difference in proteins between unbound and bound forms directly suggests the importance of the conformational plasticity of proteins. However, pathways that connect two-end structures and how they are coupled to the binding reaction are not well understood at atomic resolution. Here, we analyzed the free-energy landscape, explicitly taking into account coupling between binding and conformational change by performing atomistic molecular dynamics simulations for Ca²⁺ binding to a calmodulin loop. Using the AMBER force field with explicit water solvent, we conducted umbrella sampling for the free-energy surface and steered molecular dynamics for the pathway search. We found that, at an early stage of binding, some key residue side chains extend their "arms" to catch Ca²⁺ and, after catching, they carry the Ca²⁺ to the center of the binding pocket. This grabbing motion resulted in smooth and stepwise exchange in coordination partners of Ca²⁺ from water oxygen to atoms in the calmodulin loop. The key residue that first caught the ion was one of the two acidic residues, which are highly conserved. In the pathway simulations, different pathways were observed between binding and dissociation reactions: The former was more diverse than the latter.