Designing peptides predicted to bind to the omicron variant better than ACE2 via computational protein design and molecular dynamics

• Published in: PloS one 2023-10, Vol.18 (10), p.e0292589-e0292589
• Main Authors: Sitthiyotha, Thassanai, Treewattanawong, Wantanee, Chunsrivirot, Surasak
• Format: Article
• Language: English
• Subjects: ACE2; Analysis; Angiotensin; Angiotensin converting enzyme; Angiotensin-converting enzyme 2; Binders; Binding; Biology and life sciences; Cells; Computer applications; Coronaviruses; COVID-19; Design; Energy; Enzymes; Health aspects; Medicine and Health Sciences; Molecular dynamics; Mutation; Pandemics; Peptides; Peptidyl-dipeptidase A; Physical Sciences; Proteins; Receptors; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Viral diseases
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0292589

Brought about by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease (COVID-19) pandemic has resulted in large numbers of worldwide deaths and cases. Several SARS-CoV-2 variants have evolved, and Omicron (B.1.1.529) was one of the important variants of concern. It gets inside human cells by using its S1 subunit's receptor-binding domain (SARS-CoV-2-RBD) to bind to Angiotensin-converting enzyme 2 receptor's peptidase domain (ACE2-PD). Using peptides to inhibit binding interactions (BIs) between ACE2-PD and SARS-CoV-2-RBD is one of promising COVID-19 therapies. Employing computational protein design (CPD) as well as molecular dynamics (MD), this study used ACE2-PD's [alpha]1 helix to generate novel 25-mer peptide binders (SPB25) of Omicron RBD that have predicted binding affinities ([DELTA]G.sub.bind (MM-GBSA)) better than ACE2 by increasing favorable BIs between SPB25 and the conserved residues of RBD. Results from MD and the MM-GBSA method identified two best designed peptides (SPB25.sub.T7L/K11A and SPB25.sub.T7L/K11L with [DELTA]G.sub.bind (MM-GBSA) of -92.4 ± 0.4 and -95.7 ± 0.5 kcal/mol, respectively) that have better [DELTA]G.sub.bind (MM-GBSA) to Omicron RBD than ACE2 (-87.9 ± 0.5 kcal/mol) and SPB25 (-71.6 ± 0.5 kcal/mol). Additionally, they were predicted to have slightly higher stabilities, based on their percent helicities in water, than SBP1 (the experimentally proven inhibitor of SARS-CoV-2-RBD). Our two best designed SPB25s are promising candidates as omicron variant inhibitors.