AMINO ACID HYDROPHOBICITY AFFECTS RBD-hACE2 BINDING AFFINITY
In the spike glycoprotein RBD positions at 452 and 486, the amino acids
in the wild-type Wuhan-Hu-01 are leucine and phenylalanine, which are
substituted by less hydrophobic amino acids methionine and proline in
XBC.1, respectively. These mutations in XBC.1, indicate, that a
selection pressure might be working towards acquiring the amino acids
that are relatively less hydrophobic in spike glycoprotein. Kyte and
Doolittle hydrophobicity index is considered for understanding the
relative hydrophobicity.8
Hydrophobic interactions have a major role in stabilising the SARS-CoV-2
spike protein.9 When a neutral and hydrophobic amino
acid such as phenylalanine is substituted by a neutral and lesser
hydrophobic amino acid such as proline at the position 486, this
particular substitution might increase the RBD-hACE2 binding affinity.
In addition, another substitution at the 452 position where a neutral
and hydrophobic amino acid such as leucine is replaced by a neutral and
lesser hydrophobic amino acid such as methionine may alter the RBD-hACE2
binding affinity.10 Methionine substitution in XBC.1
spike glycoprotein at position 452 is predicted to increase the
RBD-hACE2 binding affinity.11 A general trend of
increasing RBD-hACE2 binding affinity is observed when a neutral and
less hydrophobic amino acid is incorporated. In contrast, there is a
reduction in the binding affinity of RBD-hACE2 when a negatively charged
and less hydrophobic amino acid is incorporated.
ZOONOTIC ORIGIN OF L452M IN XBC.1
The mutation L452M has been noticed in SARS-CoV-2 sequences collected
from minks; and has been linked to zoonotic transmissions between humans
and minks. However, the zoonotic transmissions were observed only when
the L452M mutation co-occurred with F486L.12 The
binding affinity studies show that the co-occurring mutations L452M and
F486L reduced the binding affinity between human ACE2 and RBD but
resulted in increased binding between the mink ACE2 receptor and RBD of
the spike glycoprotein.13 In the case of XBC.1, the
mutation L452M co-occurs with F486P, which might affect the RBD-hACE2
binding affinity. The cumulative effect of L452M and F486P on RBD-hACE2
binding affinity warrants further studies.