Computational simulations reveal the binding dynamics between human ACE2 and the receptor binding domain of SARS-CoV-2 spike protein

Cecylia S. Lupala; Xuanxuan Li; Jian Lei; Hong Chen; Jianxun Qi; Haiguang Liu; Xiao-dong Su

In terms of collective conformational changes, the CoV2-RBD/ACE2 complex showed two interesting movements: (1) the loop (L 67 ) between β 6 and β 7 (residues between S477 and G485 in particular) of CoV2-RBD was found to expand its interactions with the Nterminal helix (the helix-1) of the ACE2 (Figure 2a) , while it pointed away from the helix-1 in the predicted and the crystal structures (Figure 2d, left) ; (2) a tilting movement of the RBD relative to the ACE2 was observed, which can be depicted as a swinging motion with the binding interface as the pivot (see Figure 4 for an illustration). In both predicted and the crystal structures of the CoV2-RBD/ACE2 complex, the L 67 does not form close contacts with the ACE2. The analysis of the crystal packing revealed that this loop participated in the interaction with another asymmetric unit (see Figure S3 ). Interestingly, the simulation data suggested that the L 67 could move towards the ACE2 and form contacts with the helix-1. This can potentially enhance the binding, as reflected in the change of interaction energies. In the crystal structure, the C480 and C488 of the RBD are crosslinked via a disulfide bond that reduces the flexibility of the L 67 region, limiting its access to the ACE2. On the other hand, it has been reported that the binding of SARS-RBD to ACE2 is insensitive to the redox states of the cysteines to a high extend 26 . Based on the simulation results, we hypothesize that the reduced form of C480 and C488 can also exist during the virus invasion to host cells, and the reduced cysteines can potentially enhance the binding to ACE2. In the other two simulation trajectories, we found that the L 67 . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.24.005561 doi: bioRxiv preprint remained in conformations similar to that in the crystal structure and the cysteines (C480 and C488) were close enough for disulfide bond formation.