Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is mainly mediated through the interaction between the spike protein (S-pro) of the virus and the host angiotensin-converting enzyme II (ACE2). The attachment of heparan sulfate (HS) to S-pro is necessary for its binding to ACE2. In this study, the binding process of the receptor-binding domain (RBD) of S-pro to ACE2 was explored by enhanced sampling simulations. The free-energy landscape was characterized to elucidate the binding mechanism of S-pro to ACE2 with and without HS fragment DP4. We found that the stability of the T470-F490 loop and the hydrophobic interactions contributed from F486/Y489 in the T470-F490 loop of S-pro are quite crucial for the binding, which is enhanced by the presence of DP4. Our study provides valuable insights for rational drug design to prevent the invasion of SARS-CoV-2.