The RMSD of the backbone for both the systems for the polymerase domains (thumb, fingers and palm) reveal stability of the systems over 500 ns of simulations (Figs. and). However, when investigating per residue fluctuations of both systems, it was noticed that the system with Mn 2+ shows higher flexibility in most of the protein, other than regions in the spacer and exo domains (Figures and). These regions are seen to have Mn 2+ ions around them for most of the simulation time, which helps explain the reduced fluctuations compared with the Mg 2+ system. The dynamic cross-correlation analysis suggests specific differences in the dynamics of the two systems (Figure ). It is seen that the exo domain shows higher correlated motion to the fingers domain and the palm domain in the system with Mn 2+ ions (encircled in black), whereas the N-terminus domain shows higher correlation with fingers domain in the system with Mg 2+ ions (encircled in purple). The fingers and thumb domains show higher anti-correlated movement with respect to each other in the system with Mn 2+ , whereas the palm domain shows higher anti-correlation with fingers in the system with Mg 2+ ions (encircled in green). Normal Mode Analysis shows that the mode with highest contribution to the motion represents a breathing motion, while the second highest contribution shows a rocking motion (Videos in SI). showing correlated movement (left) and anti-correlated movement (right). Regions in red showing higher correlation/anti-correlation in the system with Mg 2+ ions and regions in blue show higher correlation/anticorrelation in the system with Mn 2+ ions.