Conformational Effects of the C-terminal Tail on the Human Neuronal Calcium Sensor-1 Protein: An Atomistic Simulation Study

Abstract

Functional neuronal calcium sensor-1 protein plays multiple neuronal functions and binds partners mostly through a largely exposed hydrophobic crevice (HC). The C-terminal tail (loop L3, spanning residues D176∼V190) binds directly to the HC pocket and regulates its conformational stability in the absence of a ligand. A NMR experimental study demonstrated that L3 deletion resulted in global structure destabilization. However, the influence of C-terminal deletion on the conformations of NCS-1 protein is unclear at atomic level. In order to delineate the role of L3 in human NCS-1 protein, we investigated the structural properties and the conformational dynamics of wild type (WT) NCS-1 and the L3 truncation variant by extensive all-atom molecular dynamics simulations. Our multiple simulations starting from two different initial structures demonstrated that the secondary structure content of WT NCS-1 was closely similar to that of the L3 truncation variant, consistent with a recent NMR experimental study. The structural flexibilities of the C-domain and the N-domain distal to C-terminal tail were increased, indicating local and global perturbations of C-terminal tail on the conformation of NCS-1 protein. The global structure and HC were simultaneously expanded, inducing the HC to be fully exposed to the solvent. The salt-bridges, especially in the C-domain, were significantly disrupted. The community network analysis illustrated that the L3 truncation weakened the inter-domain correlation and altered the residue-residue connections. These results reveal that L3 plays a critical role in the conformation dynamics and these structural changes caused by the variant may affect the regulation of target interactions. Our study provides atomic details for the conformational dynamics effects of the C-terminal tail on human wild type NCS-1.