In silico study of intrinsic dynamics of full-length apo-ACE2 and RBD-ACE2 complex

The key step for SARS-CoV-2 to infect human cells is the membrane fusion triggered by the binding of the viral extracellular Spike protein to the human extracellular receptor, the angiotensin-converting enzyme 2 (ACE2). Although the Cryo-electron microscopy (Cryo-EM) uncovered the static atomic details of ACE2 homodimers, there is still a lack of research on the kinetic and thermodynamic properties of these full-length structures. This information is helpful to understand and interpret the role of ACE2 in the cell entry of SARS-CoV-2. In order to obtain this information, we performed microsecond-scale conventional and accelerated molecular dynamics (MD) simulations of full-length all-atomic systems of the RBD-ACE2 complex, the normal and torsional conformations of the apo-ACE2 homodimer. The comparative analysis of these systems showed that there were differences in their allosteric signal pathways and motion trends. These results may be helpful to further explore the cell entry mechanism of SARS-CoV-2. Moreover, the binding free energy and hydrogen bond distribution analysis of RBD-ACE2 binding interface provided the binding motifs that may be critical to allosteric signal transmission and RBD binding. These multi-conformational binding motifs can be used as targets or templates for the inhibitor design of the cell entry of SARS-CoV-2.