posted on 2021-10-14, 16:35authored byShufeng Liu, Tien Huynh, Charles B. Stauft, Tony T. Wang, Binquan Luan
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.