Abstract
The coronavirus disease 2019 (COVID-19) pandemic has swept over the world in the past months, causing significant loss of life and consequences to human health. Although numerous drug and vaccine development efforts are underway, there are many outstanding questions on the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral association to angiotensin-converting enzyme 2 (ACE2), its main host receptor, and host cell entry. Structural and biophysical studies indicate some degree of flexibility in the viral extracellular spike glycoprotein and at the receptor-binding domain (RBD)-receptor interface, suggesting a role in infection. Here, we perform explicitly solvated, all-atom, molecular dynamics simulations of the glycosylated, full-length, membrane-bound ACE2 receptor in both an apo and spike RBD-bound state to probe the intrinsic dynamics of the ACE2 receptor in the context of the cell surface. A large degree of fluctuation in the full-length structure is observed, indicating hinge bending motions at the linker region connecting the head to the transmembrane helix while still not disrupting the ACE2 homodimer or ACE2-RBD interfaces. This flexibility translates into an ensemble of ACE2 homodimer conformations that could sterically accommodate binding of the spike trimer to more than one ACE2 homodimer and suggests a mechanical contribution of the host receptor toward the large spike conformational changes required for cell fusion. This work presents further structural and functional insights into the role of ACE2 in viral infection that can potentially be exploited for the rational design of effective SARS-CoV-2 therapeutics.
Highlights
Angiotensin-converting enzyme 2 (ACE2) acts as the extracellular receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1,2,3], the virus responsible for the COVID-19 pandemic that has catastrophically affected the world since its first identification in December 2019 [4,5,6,7]
Simulations of receptor-binding domain (RBD)-bound and apo ACE2 evidenced a striking degree of flexibility in the ACE2 homodimer
With respect to the fairly vertical, extended conformation of the initial cryogenic electron microscopy (cryoEM) structure [16], the most striking fluctuation observed during the simulations is characterized by a tilt of the head relative to the long axis of the respective monomer’s transmembrane helix
Summary
Angiotensin-converting enzyme 2 (ACE2) acts as the extracellular receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1,2,3], the virus responsible for the COVID-19 pandemic that has catastrophically affected the world since its first identification in December 2019 [4,5,6,7]. ACE2 is a homodimer with a large claw-like extracellular head domain, a small transmembrane domain, and a short intracellular segment [8]. The head can be further subdivided into the catalytic zinc-binding peptidase domain (PD; residues 19–615) [15] and the smaller neck domain (residues 616–726), which is where the majority of the homodimer interactions seems to lie [16]. ACE2 can function as a membrane-trafficking chaperone for B0AT1, an amino acid transporter [17], and it was only in complex
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