Abstract

S309 is a monoclonal antibody (mAb) that potentially neutralizes the SARS-CoV-2 virus, a respiratory coronavirus, which was the cause of the COVID-19 pandemic. Monoclonal antibodies differ from vaccines in that they are a treatment and do not confer long-term immunity. Due to the conserved structure across SARS-COV variants, an understanding of monoclonal antibody-mediated immune response and the interactions that lead to it offer a pathway to developing future treatments for novel vaccine resistant variants.

The spike protein--a transmembrane protein that mediates entry into a host cell-- was shown to be highly conserved across both SARS-COV and SARS-COV2, which happens to make this monoclonal antibody cross-reactive for both. The S309 mAb binds noncompetitively to a conserved glycan (sugar) on the spike protein as opposed to the ACE-2 receptor binding motif. Along with the glycan, S309 recognizes several amino acid residues within the epitope, binding and subsequently neutralizing the virus. Although the specific conformational change that leads to neutralization is unknown.

Using Jmol, we were able to identify significant intramolecular interactions by isolating amino acid residues that were involved in the binding of the antibody to the spike protein. An amino acid's significant interaction was defined as being within a proximity of 5 Å to other binding residues and its type was determined by the strongest attraction. Of the major interactions: 2 hydrophobic pockets, 1 ionic bond, 2 hydrogen bonds and 3 dipole-dipole interactions were considered integral components of the S309-spike protein binding.

S309 Antibody

S309 is a monoclonal antibody (mAb) that potentially neutralizes the SARS-CoV-2 virus, a respiratory coronavirus, which was the cause of the COVID-19 pandemic. Monoclonal antibodies differ from vaccines in that they are a treatment and do not confer long-term immunity. Due to the conserved structure across SARS-COV variants, an understanding of monoclonal antibody-mediated immune response and the interactions that lead to it offer a pathway to developing future treatments for novel vaccine resistant variants.

Spike Protein and Glycans

The spike protein of SARS-CoV-2 binds to the ACE-2 receptor on cells. Our project focuses on the recognition of the glycans on the surface of the spike protein (CPK with cyan carbon) by the S309 human monoclonal antibody fab (red and light orange).

The glycan is an oligosaccharide that is conserved across SARS-CoV and SARS-CoV-2 and is the primary target for the S309 antibody.

Identified Interactions

We identified several major interactions needed to for the docking of the antibody to the spike protein. There were 2 hydrophobic pockets, 1 ionic bond, 2 hydrogen bonds and 3 dipole dipole interactions.

The first hydrophobic pocket shown consists of 3 amino acid residues (from left to right): Tryptophan, proline and phenylalanine.

The second hydrophobic pocket shown also consists of 3 amino acid residues (from left to right):Threonine, Leucine and Isoleucine.

The ionic bond is formed between two amino acids, a Lysine on the spike protein and a Glutamic Acid on the heavy chain of the antibody.

3 Dipole-Dipole interactions were identified. The first two (in order of appearance) glutamic Acid and tyrosine on the the heavy chain form dipole interactions with a hydroxyl group on the glycan and the carboxamide group on the linking amino acid Asparagine. The last dipole interaction is between a glutamic acid on the spike protein and a nitrogen on the backbone of the heavy chain.

2 Hydrogen bonds were identified. The first identified (left) is between a hydroxyl group of the glycan and an N-H group on the backbone of the light chain. The second (right) was a hydrogen bond between a hydroxyl group of the glycan and the N-H2 group of arginine.

2 major LDF interactions were identified, which are believed to aid in stabilizing the position of the glycan due to their position under it and close proximity (<5 Angstroms).