Biology subjects

Fatouros, P. R.

Publications and source records attributed to Fatouros, P. R..

2 recordsLinked to original sources

bioRxiv2022

Implications of Spike Protein Interactions with Zn-bound form of ACE2: A Computational Structural Study

The COVID-19 pandemic has generated a major interest in designing inhibitors to prevent SARS-CoV-2 binding on host cells to protect against infection. One promising approach to such research utilizes molecular dynamics (MD) to identify potential inhibitors that can prevent the interaction between spike (S) protein on the virus and angiotensin converting enzyme 2 (ACE2) receptor on the host cells. In these studies, many groups have chosen to exclude a zinc (Zn) ion bound to the ACE2 molecule which is critical for enzymatic activity. While the relatively distant location of Zn ion from the S protein binding site (S1 domain), combined with the difficulties in modeling this ion have motivated the decision of exclusion, Zn can potentially contribute to the structural stability of the entire protein, and thus, may have implications on spike protein interaction. In this study, we explored the effects of excluding Zn on the structural stability and binding free energy of the ACE2-S1 protein complex. We generated two versions of an experimentally-derived structure of the ACE2-S1 protein complex: one with Zn and one without. Examining the differences between these two complexes during MD simulation, we found that the Zn-bound complex exhibited greater instability at nearly all residues except for the interacting residues, which were more stable in the Zn-bound complex. Additionally, the Zn-bound complex had a stronger binding free energy at all internal dielectric constants greater than one. Since binding free energy is often used to score inhibitors performances, excluding Zn could potentially have implications on inhibitor selection and performance, both in the ACE2-S1 protein system and other protein complexes that include the Zn ion.

biophysics↗

bioRxiv2021

Modeling Substrate Coordination to Zn-Bound Angiotensin Converting Enzyme 2

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 latters 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.

biophysics↗