Electrostatic Interactions Explain the Higher Binding Affinity of the CR3022 Antibody for SARS-CoV-2 than the 4A8 Antibody

Abstract

A structural understanding of the mechanism by which antibodies bind SARS-CoV-2 at the atomic level is highly desirable as it can tell the development of more effective antibodies to treat Covid-19. Here, we use steered molecular dynamics (SMD) and coarse-grained simulations to estimate the binding affinity of the monoclonal antibodies CR3022 and 4A8 to the SARS-CoV-2 receptor-binding domain (RBD) and SARS-CoV-2 N-terminal domain (NTD). Consistent with experiments, our SMD and coarse-grained simulations both indicate that CR3022 has a higher affinity for SARS-CoV-2 RBD than 4A8 for the NTD, and the coarse-grained simulations indicate the former binds three times stronger to its respective epitope. This finding shows that CR3022 is a candidate for Covid-19 therapy and is likely a better choice than 4A8. Energetic decomposition of the interaction energies between these two complexes reveals that electrostatic interactions explain the difference in the observed binding affinity between the two complexes. This result could lead to a new approach for developing anti-Covid-19 antibodies in which good candidates must contain charged amino acids in the area of contact with the virus.

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

“…Moreover, attention has recently been turned again to the CR3022 antibody as a promising candidate for COVID-19 treatment and prevention as new experimental and computational evidence became available. The experimental study of Tian et al (Tian et al, 2020) and the computational study of Nguyen et al (Nguyen et al, 2021) showed that CR3022 binds RBD of SARS-CoV-2 with high affinity (KD ~6.3 to 3 nM) in contrast with the results of Yuan et al (Yuan et al, 2020) which gave a much lower affinity of binding (KD ~115 nM). Other theoretical works showed similar binding affinities with a tendency for stronger complexes formed with RBD SARS-CoV-1 (Corrêa Giron et al, 2020).…”

“…Their results suggest combining these three mAbs for higher neutralization activity. Nguyen et al (Nguyen et al, 2021) also found electrostatic interactions explaining the higher binding affinity of CR3022 for SARS-CoV-2 than the 4A8 antibody in their all-atom and CG MD simulations (including steered MD). They used the Jarzynski equality to estimate the non-equilibrium binding free energy.…”

“…As mentioned above, CR3022 has been suggested as a promising therapeutic option to neutralize SARS-CoV-2 (Barnes et al, 2020;Tian et al, 2020;Wu et al, 2020;Yuan et al, 2020), and is often explored in theoretical studies (Corrêa Giron et al, 2020;Ding et al, 2021;Nguyen et al, 2021;Shariatifar and Farasat, 2021). In a pioneer computational study at the very beginning of the pandemic, using constant-pH MC simulations, Giron, Laaksonen, and Barroso da Silva showed that CR3022 known to bind to SARS-CoV-1 RBD could also bind to SARS-CoV-2 RBD.…”

“…This approach is aimed to capture only the main features of the complexation phenomena with a clear emphasis on the electrostatic interactions. Different studies have highlighted the importance of these interactions for the host-pathogen and antigenspecific antibody interfaces (Bai and Warshel, 2020;Corrêa Giron et al, 2020;Nguyen et al, 2021Nguyen et al, , 2020Poveda-Cuevas et al, 2020, 2018Xie et al, 2021). Successful applications of this simplified model to several biomolecular systems have been previously reported in the literature including viruses proteins and the SARS-CoV-2 RBD-mAb interactions (Barroso da Corrêa Giron et al, 2020;Delboni and Barroso da Silva, 2016;Kurut et al, 2012;Lund et al, 2008;Mendonça et al, 2019;Persson et al, 2010).…”

Polyreactivity and polyspecificity in therapeutic antibody development: risk factors for failure in preclinical and clinical development campaigns

“…The iterative selection process that underpins display technologies is likely to be more susceptible to excessive charge build up in antibody complementarity-determining regions (CDRs) during engineering given the powerful influence of electrostatic interactions on affinity. 19 , 20 This phenomenon has recently been explored during optimization of an anti-IL21R antibody, where the epitope on IL21R represented a negatively charged patch. 21 Despite the application of multiple different selection strategies, the incorporation of aggressive deselection pressures using negatively charged molecules and the design of a variety of mutational libraries, the buildup of excessive positive charge in CDR loops could not be avoided.…”