Molecular dynamics analysis of a flexible loop at the binding interface of the SARS-CoV-2 spike protein receptor-binding domain
Jonathan K. Williams
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA
Search for more papers by this authorBaifan Wang
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA
Search for more papers by this authorAndrew Sam
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA
Search for more papers by this authorCody L. Hoop
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA
Search for more papers by this authorDavid A. Case
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA
Institute for Quantitative Biomedicine, Rutgers University, Piscataway, New Jersey, USA
Search for more papers by this authorCorresponding Author
Jean Baum
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA
Correspondence
Jean Baum, Department of Chemistry and Chemical Biology, Rutgers University, 123 Bevier Rd., Piscataway, NJ 08854, USA.
Email: [email protected]
Search for more papers by this authorJonathan K. Williams
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA
Search for more papers by this authorBaifan Wang
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA
Search for more papers by this authorAndrew Sam
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA
Search for more papers by this authorCody L. Hoop
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA
Search for more papers by this authorDavid A. Case
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA
Institute for Quantitative Biomedicine, Rutgers University, Piscataway, New Jersey, USA
Search for more papers by this authorCorresponding Author
Jean Baum
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA
Correspondence
Jean Baum, Department of Chemistry and Chemical Biology, Rutgers University, 123 Bevier Rd., Piscataway, NJ 08854, USA.
Email: [email protected]
Search for more papers by this authorFunding information: Rutgers University Center for COVID-19 Response and Pandemic Preparedness, Grant/Award Number: CCRP2; National Institutes of Health Grant, Grant/Award Number: GM136431
Abstract
Since the identification of the SARS-CoV-2 virus as the causative agent of the current COVID-19 pandemic, considerable effort has been spent characterizing the interaction between the Spike protein receptor-binding domain (RBD) and the human angiotensin converting enzyme 2 (ACE2) receptor. This has provided a detailed picture of the end point structure of the RBD-ACE2 binding event, but what remains to be elucidated is the conformation and dynamics of the RBD prior to its interaction with ACE2. In this work, we utilize molecular dynamics simulations to probe the flexibility and conformational ensemble of the unbound state of the receptor-binding domain from SARS-CoV-2 and SARS-CoV. We have found that the unbound RBD has a localized region of dynamic flexibility in Loop 3 and that mutations identified during the COVID-19 pandemic in Loop 3 do not affect this flexibility. We use a loop-modeling protocol to generate and simulate novel conformations of the CoV2-RBD Loop 3 region that sample conformational space beyond the ACE2 bound crystal structure. This has allowed for the identification of interesting substates of the unbound RBD that are lower energy than the ACE2-bound conformation, and that block key residues along the ACE2 binding interface. These novel unbound substates may represent new targets for therapeutic design.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
All data and protocols are available upon reasonable request to the corresponding author.
Supporting Information
| Filename | Description |
|---|---|
| prot26208-sup-0001-Figures.pdfPDF document, 2.5 MB | Figure S1 Antibody-Bound Structures of the CoV2-RBD in the PDB. (A) Overlay of structures deposited into the PDB with antibodies that contact Loop 3 of the CoV2-RBD (PDB: 6xc2, 6xc3, 6xc4, 6xc7, 6xe1, 6xkq, 7bz5, 7cdi, 7cdj, 7ch4, 7ch5, 7chb, 7che, 7chf, 7cjf, 7jmo, 7k9z, 7k45). (B) Overlay of structures deposited into the PDB with antibodies that bind to the RBD at locations other than Loop 3 (PDB: 6w41, 6xkp, 6yla, 6ym0, 6zdg, 6zer, 6zfo, 7cah, 7jmw, 7jva, 7jx3). In both panels, structures were aligned to the RBD domain of the CoV2-RBD bound to ACE2 (PDB: 6m0j). The Loop 3 region is highlighted in red, while the remainder of the RBD is in pink. The antibodies in each panel are shown in gray. Figure S2. Root-mean-square deviation (RMSD) of the backbone (N, CA, and C) atoms relative to the starting structures. The left column is the RMSD of the full RBD, the center column is the RMSD excluding the residues of Loop 3, and the right column in the RMDS considering only the residues of Loop 3. RMSD of conformations sampled from: (A) MD simulations of SARS-CoV RBD (black) and SARS-CoV2 RBD (red); from (B) MD simulations of CoV2-RBD mutants G476S (green), S477N (purple), T478I (red), and V483A (blue); from (C) MD simulations of different loop models of CoV2-RBD; and from (D) MD simulations of different loop models of CoV-RBD. The colors used in the RMSD plots match to the same colored structures and RMSF plots of the main text. Figure S3. Per-residue root-mean-square fluctuations (RMSF) of the backbone C, CA, and N of different loop models. (a) RMSF plots from the 5 different CoV-RBD loop models. (b) RMSF plots from the 5 different CoV2-RBD loop models. The colors used here match with the models used in Figure 4 of the main text. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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