Modeling Substrate Coordination to Zn-Bound Angiotensin Converting Enzyme 2

  1. Peter R. Fatouros
  2. Urmi Roy
  3. Shantanu Sur

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Abstract

The spike protein in the envelope of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts with the receptor Angiotensin Converting Enzyme 2 (ACE2) on the host cell to facilitate the viral uptake. Angiotensin II (Ang II) peptide, which has a naturally high affinity for ACE2, may be useful in inhibiting this interaction. In this study, we computationally designed several Ang II mutants to find a strong binding sequence to ACE2 receptor and examined the role of ligand substitution in the docking of native as well as mutant Ang II to the ACE2 receptor. The peptide in the ACE2-peptide complex was coordinated to zinc in the ACE2 cleft. Exploratory molecular dynamics (MD) simulations were used to measure the time-based stability of the native and mutant peptides and their receptor complexes. The MD-generated root-mean-square deviation (RMSD) values are mostly similar between the native and seven mutant peptides considered in this work, although the values for free peptides demonstrated higher variation, and often were higher in amplitude than peptides associated with the ACE2 complex. An observed lack of a strong secondary structure in the short peptides is attributed to the latter’s greater flexibility and movement. The strongest binding energies within the ACE2-peptide complexes were observed in the native Ang II and only one of its mutant variants, suggesting ACE2 cleft is designed to provide optimal binding to the native sequence. An examination of the S1 binding site on ACE2 suggests that complex formation alone with these peptides may not be sufficient to allosterically inhibit the binding of SARS-CoV-2 spike proteins. However, it opens up the potential for utilizing AngII-ACE2 binding in the future design of molecular and supramolecular structures to prevent spike protein interaction with the receptor through creation of steric hindrance.

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  1. ScreenIT

    SciScore for 10.1101/2021.03.27.437352: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Zinc Parameterization: To prepare structures for parameterization, structural files were first converted from CHARMM to Amber format with Bio3D45 which includes the removal of all hydrogen atoms.
    CHARMM
    suggested: (CHARMM, RRID:SCR_014892)
    NAMD is used to calculate the gas phase free energy while APBS and VMD calculate the polar and nonpolar solvation energies, respectively.
    NAMD
    suggested: (NAMD, RRID:SCR_014894)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    One potential limitation and a source of variability could be from the lack of entropy calculations in MM/PBSA protocol. However, these errors tend to be quite small, even with flexible ligands, and therefore, it is highly unlikely to make a major contribution to the differences found in our observations55,56. The potential role of kinetics also cannot be excluded as it plays a critical role in computing large binding free energies. It is possible that while these states are thermodynamically favorable, the kinetics presents a large activation energy barrier, preventing the formation of these final states. The impact of kinetics, which requires more computationally expensive techniques, however, is beyond the scope of the current work. During the production run, the S1 binding region generated a similar RMSD to the rest of the protein complex, ruling out any increased movement in this region. Additionally, the secondary structure of this binding region remains largely unchanged except for the two residues at 82M and 355D. Both findings suggest very few structural changes in the S1 binding region in response to Ang II binding. Thus, a relatively little impact on the S1 binding region following ACE2-peptide interaction suggests that these peptides alone are less likely to allosterically inhibit the binding of SARS-CoV-2. Identifying a peptide sequence that provides a strong binding at the Ang II binding cleft on ACE2 could still be an important step toward developing novel ther...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2021.03.27.437352 on bioRxiv