The goal of the current study is to utilize molecular dynamic (MD) simulations to investigate the dynamic behavior of 16S rRNA in the presence and absence of S15 and to identify the binding interactions between these two molecules. The simulations show that: (i) 16S rRNA remains in a highly folded structure when it is bound to S15; (ii) in the absence of S15, 16S rRNA significantly alters its conformation and transiently forms conformations that are similar to the bound structure that make it available for binding with S15; (iii) the unbound rRNA spends the majority of its time in extended conformations. The formation of the extended conformations is a result of the molecule reaching a lower electrostatic energy and the formation of the highly folded, crystal-like conformation is a result of achieving a lower solvation energy. In addition, our MD simulations show that 16S rRNA and S15 bind across the major groove of helix 22 (H22) via electrostatic interactions. The negatively charged phosphate groups of G658, U740, G741 and G742 bind to the positively charged S15 residues Lys7, Arg34 and Arg37. The current study provides a dynamic view of the binding of 16S rRNA with S15.