Fig. 2: Conformational changes at calcium and ATP-binding sites along the functional path.

Ryanodine receptor 1 (RyR1) conformational changes at calcium and ATP-binding sites along the functional trajectory of Fig. 1a, augmented with excursions from the minimum-energy points along CC1. These excursions are in the increasing CC1 direction on the no-ligand landscape, and in the decreasing CC1 direction on the with-ligand landscape. Top: The general region and the specific sites examined in detail. Distance variations between two amino acid backbones on the opposite side of the ATP and calcium are shown. The amino acids used for measurement are represented as sticks, the rest of the molecule in blue ribbon for the model corresponding to “START” in Fig. 1a, and in green ribbon for model corresponding to “FINISH”. Bottom: Distance variations between carbon-alpha backbone atoms of two opposing residues at each of the calcium and ATP binding sites for 50 structures along the functional and interpolated trajectories. For the latter, 50 structures were extracted from a morph between a model of RyR1 without ligands (PDB: 5TB4) and a model of RyR1 with calcium, ATP, and caffeine (PDB: 5T9V). To analyze the functional route, six published models (PDB: 5TB4, 5T9R, 5TAP, 5T9V, 5TAL, 5TAQ) were each fitted and refined into the maps along the trajectory. Error bars represent the full scatter (not standard deviation) of the results obtained with different starting models.