Molecular insights and optimization strategies for the competitive binding of engineered ACE2 proteins: a multiple replica molecular dynamics study
Jiahao Sun, Xinguo Liu, Shaolong Zhang, Meng Li, Qinggang Zhang, Jianzhong Chen
Abstract
, WT and BA.1 RBD), but also faces immune escape as the virus evolves. Moreover, by modifying residue types near the binding interface, engineered ACE2 alters the electrostatic potential distribution and reconfigures the hydrogen bonding network, which results in modified binding to the RBD. However, this structural rearrangement does not occur in all RBD variants. In addition, we identified potentially engineerable beneficial residues and potentially engineerable detrimental residues in both ACE2 and RBD. Functional conservation can thus enable the optimization of these residues and improve the binding competitiveness of engineered ACE2, which therefore provides additional immune escape prevention. Finally, we conclude that these findings have implications for understanding the mechanisms responsible for engineered ACE2 and can help us to develop engineered ACE2 proteins that show superior performance.