Towards an optimal monoclonal antibody with higher binding affinity to the receptor-binding domain of SARS-CoV-2 spike proteins from different variants

Abstract

A highly efficient and robust multiple scales in silico protocol, consisting of atomistic constant charge Molecular Dynamics (MD), constant-charge coarse-grain (CG) MD and constant-pH CG Monte Carlo (MC), has been used to study the binding affinities, the free energy of complexation of selected antigen-binding fragments of the monoclonal antibody (mAbs) CR3022 (originally derived from SARS-CoV-1 patients almost two decades ago) and 11 SARS-CoV-2 variants including the wild type. CR3022 binds strongly to the receptor-binding domain (RBD) of SARS-CoV-2 spike protein, but chooses a different site rather than the receptor-binding motif (RBM) of RBD, allowing its combined use with other mAbs against new emerging virus variants. Totally 235,000 mAbs structures were generated using the RosettaAntibodyDesign software, resulting in top 10 scored CR3022-RBD complexes with critical mutations and compared to the native one, all having the potential to block virus-host cell interaction. Of these 10 finalists, two candidates were further identified in the CG simulations to be clearly best against all virus variants, and surprisingly, all 10 candidates and the native CR3022 did exhibit a higher affinity for the Omicron variant with its highest number of mutations (15) of them all considered in this study. The multiscale protocol gives us a powerful rational tool to design efficient mAbs. The electrostatic interactions play a crucial role and appear to be controlling the affinity and complex building. Clearly, mAbs carrying a lower net charge show a higher affinity. Structural determinants could be identified in atomistic simulations and their roles are discussed in detail to further hint at a strategy towards designing the best RBD binder. Although the SARS-CoV-2 was specifically targeted in this work, our approach is generally suitable for many diseases and viral and bacterial pathogens, leukemia, cancer, multiple sclerosis, rheumatoid, arthritis, lupus, and more.

Differences between Omicron SARS-CoV-2 RBD and other variants in their ability to interact with cell receptors and monoclonal antibodies

“…In our simulation model also the hydrophobic effect, van der Waals interactions, and excluded volume repulsion, through an LJ term between the residues are included. We have previously applied this methodology successfully in several biomolecular systems (Barroso da Silva et al, 2018; Delboni & Barroso da Silva, 2016; Mendonça et al, 2019; Persson et al, 2010) and to investigate the flaviviruses (Poveda-Cuevas et al, 2018, 2020) and coronavirus (Giron et al, 2020, 2021; Neamtu et al, 2022).…”

“…After recent updates, the method is named FORTE ( F ast c O arse-grained p R otein-pro T ein mod E l) (Neamtu et al, 2022). Unlike docking, the FORTE approach provides derivatives of the free energy, e.g., the interaction free energy as a function of separation distances but not limited to a specific separation/orientation between the macromolecules.…”

“…This coarse-grained (CG) model combines translational and rotational motions of two rigid macromolecules in a cylindrical simulation box with the “Fast Proton Titration Scheme” (FPTS) (Barroso da Silva & MacKernan, 2017). Solving this CG model in an MC simulation, the free energy of interactions for the complexation can be estimated for different pairs of macromolecules at different physical-chemical conditions at lower CPU costs in comparison with other models (Neamtu et al, 2022). Two pairs of macromolecules were investigated: a ) RBD from different variants with ACE2 with sequences from key polymorphisms (RBD x -ACE2 x where x is either the wildtype [wt] or a mutated form), and b ) RBD from different variants with several known mAbs (RBD x -mAb y where y is one of the 33 studied binders -see the list below).…”

“…This methodology has been successfully applied in several biomolecular systems from food proteins to septins (Barroso da Silva et al, 2018; Delboni & Barroso da Silva, 2016; Mendonça et al, 2019; Persson et al, 2010). It has also been used to investigate the flaviviruses (Poveda-Cuevas et al, 2018, 2020) and coronavirus (Giron et al, 2020, 2021; Neamtu et al, 2022). Recently, this theoretical approach was named FORTE (Fast cOarse-grained pRotein-proTein modEl) (Neamtu et al, 2022).…”

“…Promising therapeutic binders found in Caós study against Omicron were S309 and CR3022. Theoretical studies also suggested that CR3022, the engineered CR3022-like mAb, P1, and P1’’’ seem to be good candidates for Omicron (Neamtu et al, 2022). Another experimental group has shown that S309 was minimally affected by the multitude of mutations found in Omicron (VanBlargan et al, 2021).…”