The flexibility of ACE2 in the context of SARS-CoV-2 infection

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.

Molecular recognition of SARS-CoV-2 spike glycoprotein: quantum chemical hot spot and epitope analyses

“…Thus, it will be necessary to discuss not only one X-ray crystal structure but also other X-ray crystal structures and structural fluctuations by MD simulations. The flexibility of sugar chains on the SARS-CoV-2 S-protein and the ACE2 was already investigated by several MD simulations [22][23][24][25][26] . One of the results that the sugar chain on N90ACE2 works favorably for molecular recognition of the S-protein was reported as follows: The sugar chain on N90ACE2…”

“…conducted to better understand their association. [20][21][22][23][24][25][26] Approaches for drug/neutralizing antibody design targeting S-protein have been reported, such as a de novo design peptide inhibitors for SARS-CoV-2 27,28 , a virtual screening of antiviral compounds for the SARS-CoV-2 29 and sequence-based epitope analysis for the SARS-CoV-2, among others 30 . These previous studies have been based on the molecular recognition of S-protein and ACE2/antibody and were highly beneficial.…”

Ca2+-dependent mechanism of membrane insertion and destabilization by the SARS-CoV-2 fusion peptide

“…Even less is known at the needed molecular level about the mechanism by which the FPs in the spearhead are involved in the fusion of the cell and virus membranes, despite the wealth of information that has recently accumulated from molecular dynamics (MD) simulations on SARS-CoV-2 models (e.g., see Refs. [24][25][26][27][28][29] ).…”

Predicting Potential SARS-COV-2 Drugs—In Depth Drug Database Screening Using Deep Neural Network Framework SSnet, Classical Virtual Screening and Docking

“…Recently, Yan et al [ 14 ] has published the structure of ACE2 in three conformations: an open conformation, a closed conformation, and a closed conformation in complex with a fragment of the viral S protein ( Figure 1 ). The ACE2 open and closed conformations differ from each other by the degree of opening of the catalytic site cleft of the peptidase domain ( Figure 1 b) [ 14 , 15 ]. This causes a distortion of the ACE2:S1 binding interface [ 15 ].…”

“…The ACE2 open and closed conformations differ from each other by the degree of opening of the catalytic site cleft of the peptidase domain ( Figure 1 b) [ 14 , 15 ]. This causes a distortion of the ACE2:S1 binding interface [ 15 ]. Moreover, ligand binding studies have identified a closing motion associated with ligand binding, suggesting that the closed conformation represents the catalytically active state of the enzyme [ 16 ].…”