Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the global spread of the coronavirus disease (COVID-19), which has caused great loss of life and property worldwide. We investigated the regulatory mechanism with the antibody targeting the N-terminal domain (NTD) of the S protein by molecular dynamic simulation. It was found that the structure of the S1-4A8 complex experienced the largest change when the receptor binding domain (RBD) of S1 was in the Up state. By calculating the angle between domains of S1 in the Down and Up states, we found that the RBD angle changed more in the Up state. We further performed binding free energy calculations for S1-4A8 complexes in both Up and Down states, and the results showed that 4A8 has a stronger affinity with NTD in the Up state. These results indicate that 4A8 plays a stronger regulatory role in the RBD Up state. The N3 and N5 loops on the NTD are the main antigen-antibody binding sites, and residues on the antibody complementarity determining region 3 (CDR3) in the Up state can penetrate deeper into the hydrophobic pocket at the bottom of the N5 loop to form a tighter binding. Through the tICA method, we found that except the residues at the binding interface, distant residues including A609, V610, G652, and A653 at the linker region of subdomain 2, and residues S359 and N360 near the bottom of RBD are able to influence the regulatory effect in the long-range. This work provides new insights into the neutralization mechanism of targeting NTD antibodies in SARS-CoV-2.