Differential Antibody Recognition by Novel SARS-CoV-2 and SARS-CoV Spike Protein Receptor Binding Domains: Mechanistic Insights and Implications for the Design of Diagnostics and Therapeutics

Ilda D’Annessa; Filippo Marchetti; Giorgio Colombo

Here, we carry out a comparative analysis of the spike protein RBDs from SARS-CoV-2 and SARS-CoV to reveal the key properties of their surfaces that can be reconnected to observed differences in antibody (Ab) and receptor binding. Starting from the atomic resolution information available from the solved structures of the two proteins, the MLCE (Matrix of Low Coupling Energies) method is applied to identify the subsets of surface residues that can be defined as "interacting". MLCE analysis of protein energetics accounts for the interactions that each residue establishes with all other residues of the protein it belongs to. The correlation of this parameter with the structural properties of the protein thus highlights which substructures are (pre)organized to interact with a potential partner (a cell receptor or an antibody). MLCE analyzes the interaction energies of all of the amino acids in a protein. In particular, it computes the nonbonded part of the potential (van der Waals, electrostatic interactions, solvent effects) via an MM/GBSA calculation, obtaining, for a protein composed by N residues, an N × N symmetric interaction matrix Mij. Eigenvalue decomposition of the matrix highlights the regions of strongest and weakest couplings: the fragments that are on the surface, contiguous in space and weakly coupled to the protein core, define the potential interaction regions. In other words, the putative interacting patches are assumed to be characterized by frustrated intramolecular interactions. The actual interaction with a partner will actually occur if favorable interactions determine a lower free energy for the bound than the unbound state [3] [4] . Indeed, Minimal energetic coupling with the rest of the protein allows these substructures to undergo conformational changes, to be recognized by a binding partner (Antibodies, Receptors). All these properties are hallmarks of Antibody binding epitopes and PPI substructures.