Neuronal calcium sensor-1 (NCS-1) protein has been implicated in multiple neuronal functions by binding partners mostly through a largely exposed hydrophobic crevice (HC). In the absence of a ligand, the C-terminal tail (loop L3, residues D176 to V190) binds directly to the HC pocket as a ligand mimetic, occupying the HC and regulating its conformational stability. A recent experimental study reported that L3 deletion resulted in global structure destabilization. However, the influence of C-terminal tail on the conformations of NCS-1 protein is unclear at the atomic level. In this study, we investigated the structural properties and the conformational dynamics of wild type NCS-1 and L3 truncation variant by extensive all-atom molecular dynamics (MD) simulations. Our cumulative 2 μs MD simulations demonstrated that L3 deletion increased the structural flexibility of the C-domain and the distant N-domain. The community network analysis illustrated that C-terminal tail truncation weakened the interdomain correlation. Moreover, our data showed that the variant significantly disrupted the salt bridges network and expanded simultaneously the global structure and HC. These conformational changes caused by C-terminal tail truncation may affect the regulation of target interactions. Our study provides atomic details of the conformational dynamics effects of the C-terminal tail on human wild type NCS-1.