Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 29, Pages 10550-10555Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1402768111
Keywords
metal; coarse grained; molecular dynamics; multiscale simulations; force
Categories
Funding
- Natural Science Foundation of China [11174134, 11334004, 81121062]
- Natural Science Foundation of Jiangsu Province [BK2011546]
- Program for New Century Excellent Talents in University
- High Performance Computing Center of Nanjing University
- Grants-in-Aid for Scientific Research [25251019, 26104517] Funding Source: KAKEN
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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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