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      Energy landscape views for interplays among folding, binding, and allostery of calmodulin domains.

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          Abstract

          Ligand binding modulates the energy landscape of proteins, thus altering their folding and allosteric conformational dynamics. To investigate such interplay, calmodulin has been a model protein. Despite much attention, fully resolved mechanisms of calmodulin folding/binding have not been elucidated. Here, by constructing a computational model that can integrate folding, binding, and allosteric motions, we studied in-depth folding of isolated calmodulin domains coupled with binding of two calcium ions and associated allosteric conformational changes. First, mechanically pulled simulations revealed coexistence of three distinct conformational states: the unfolded, the closed, and the open states, which is in accord with and augments structural understanding of recent single-molecule experiments. Second, near the denaturation temperature, we found the same three conformational states as well as three distinct binding states: zero, one, and two calcium ion bound states, leading to as many as nine states. Third, in terms of the nine-state representation, we found multiroute folding/binding pathways and shifts in their probabilities with the calcium concentration. At a lower calcium concentration, "combined spontaneous folding and induced fit" occurs, whereas at a higher concentration, "binding-induced folding" dominates. Even without calcium binding, we observed that the folding pathway of calmodulin domains can be modulated by the presence of metastable states. Finally, full-length calmodulin also exhibited an intriguing coupling between two domains when applying tension.

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          Author and article information

          Journal
          Proc. Natl. Acad. Sci. U.S.A.
          Proceedings of the National Academy of Sciences of the United States of America
          1091-6490
          0027-8424
          Jul 22 2014
          : 111
          : 29
          Affiliations
          [1 ] National Laboratory of Solid State Microstructure and Department of Physics, Nanjing University, Nanjing 210093, China; and.
          [2 ] National Laboratory of Solid State Microstructure and Department of Physics, Nanjing University, Nanjing 210093, China; and takada@biophys.kyoto-u.ac.jp wangwei@nju.edu.cn.
          [3 ] Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan takada@biophys.kyoto-u.ac.jp wangwei@nju.edu.cn.
          Article
          1402768111
          10.1073/pnas.1402768111
          4115553
          25002491

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