Structure–Function Analysis of Resistance to Bamlanivimab by SARS-CoV-2 Variants Kappa, Delta, and Lambda

Abstract

The newly emerging Kappa, Delta, and Lambda SARS-CoV-2 variants are worrisome, characterized with the double mutations E484Q/L452R, T478K/L452R, and F490S/L452Q, respectively, in their receptor binding domains (RBDs) of the spike proteins. As revealed in crystal structures, most of these residues (e.g., 452 and 484 in RBDs) are not in direct contact with interfacial residues in the angiotensin-converting enzyme 2 (ACE2). This suggests that albeit there are some possibly nonlocal effects, these mutations might not significantly affect RBD’s binding with ACE2, which is an important step for viral entry into host cells. Thus, without knowing the molecular mechanism, these successful mutations (from the point of view of SARS-CoV-2) may be hypothesized to evade human antibodies. Using all-atom molecular dynamics (MD) simulation, here, we show that the E484Q/L452R mutations significantly reduce the binding affinity between the RBD of the Kappa variant and the antibody LY-CoV555 (also named as Bamlanivimab), which was efficacious for neutralizing the wild-type SARS-CoV-2. To verify simulation results, we further carried out experiments with both pseudovirions- and live virus-based neutralization assays and demonstrated that LY-CoV555 completely lost neutralizing activity against the L452R/E484Q mutant. Similarly, we show that mutations in the Delta and Lambda variants can also destabilize the RBD’s binding with LY-CoV555. With the revealed molecular mechanism on how these variants evade LY-CoV555, we expect that more specific therapeutic antibodies can be accordingly designed and/or a precise mixing of antibodies can be achieved as a cocktail treatment for patients infected with these variants.

Molecular insights into the differential dynamics of SARS-CoV-2 variants of concern

“…We also checked for the difference in the H-bond interactions among the residues calculated over the last 10ns of the trajectory. Results show that most of the H-bond interactions reported in earlier studies [ 46 , 47 ] were conserved in WT. ACE2 residue Tyr83 interacts with Asn487 of RBD across all the systems.…”

Molecular Insights into the Differential Dynamics of SARS-CoV-2 Variants of Concern (VOC)

“…We also checked for the difference in the H-bond interactions among the residues calculated over the last 10ns of the trajectory. Results show that most of the H-bond interactions reported in earlier studies [46,47] were conserved in WT. ACE2 residue Y83 interacts with N487 of RBD across all the systems.…”

“…Results show that most of the H-bond interactions reported in earlier studies 44,45 were conserved in WT. ACE2 residue Tyr83 interacts with Asn487 of RBD across all the systems.…”

Omicron (B.1.1.529) - A new heavily mutated variant: Mapped location and probable properties of its mutations with an emphasis on S-glycoprotein

“…This mutation boost up the viral fitness to amplify replication and transmission property of SARS-CoV-2 virus. [85] , [87] , [90] , [91] 2. E484A Crucial role in the advancement of viral infectivity, transmissibility, and/or antigenicity.…”