Modeling the SARS-CoV-2 receptor ACE2 indicates that protein-bound Zn affects distant protein stability and interactions

Abstract Molecular Dynamics (MD) is a widely used drug design tool capable of rapidly screening the binding capacity many candidate inhibitors in cost-effective manner. This approach has been leveraged to search for molecules that can bind angiotensin converting enzyme 2 (ACE2) and prevent SARS-CoV-2 viral entry host cells. However, ACE2 difficult model due an embedded zinc ion (Zn), which introduces complex charge transfer polarization. Since Zn distant from site binding, groups have assumed does not impact protein interactions excluded while modeling ACE2. Here, we evaluated by performing MD simulations Zn-bound Zn-free versions ACE2-spike (S1) ACE2-monoclonal antibody (mAb) systems . We found excluding had significant effect on total stability interacting residues, indicating sites. Additionally, discovered including protein-bound improved free energy both −3.26 −14.8 kcal/mol ACE2-S1 ACE2-mAb systems, respectively. These data suggest may alter inhibitor selection decisions should be included accurate modeling. Interestingly, particularly sensitive changes receptor structure, likely reflecting its generation against vivo Collectively, our demonstrates significantly impacts simulation outcomes inform selection, when receptor-mAb complexes.