Self-Association of ACE-2 with Different RBD Amounts: A Dynamic Simulation Perspective on SARS-CoV-2 Infection

Transmissibility of SARS-CoV-2 initiallyrelies on its trimericSpike-RBDs to tether the ACE-2 on host cells, and enhanced self-associationof ACE-2 engaged with Spike facilitates the viral infection. Two primarypacking modes of Spike-ACE2 heteroproteins exist potentially due todiscrepant amounts of RBDs loading on ACE-2, but the resultant self-associationdifference is inherently unclear. We used extensive coarse-graineddynamic simulations to characterize the self-association efficiency,the conformation relevance, and the molecular mechanism of ACE-2 withdifferent RBD amounts. It was revealed that the ACE-2 hanging two/fullRBDs (Mode-A) rapidly dimerized into the heteroprotein complex ina compact "linear" conformation, while the bare ACE-2showed weakened self-association and a protein complex. The RBD-tetheredectodomains of ACE-2 presented a more upright conformation relativeto the membrane, and the intermolecular ectodomains were predominantlypacked by the neck domains, which was obligated to the rapid proteinself-association in a compact pattern. Noted is the fact that theACE-2 tethered by a single RBD (Mode-B) retained considerable self-associationefficiency and clustering capability, which unravels the interrelationof ACE-2 colocalization and protein cross-linkage. The molecular perspectivesin this study expound the self-association potency of ACE-2 with differentRBD amounts and the viral activity implications, which can greatlyenhance our comprehension of SARS-CoV-2 infection details.