Mutations in the SARS-CoV-2 spike RBD are responsible for stronger ACE2 binding and poor anti-SARS-CoV mAbs cross-neutralization.

Computational and Structural Biotechnology Journal
Masaud ShahHyun Goo Woo

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), is a novel beta coronavirus. SARS-CoV-2 uses spike glycoprotein to interact with host angiotensin-converting enzyme 2 (ACE2) and ensure cell recognition. High infectivity of SARS-CoV-2 raises questions on spike-ACE2 binding affinity and its neutralization by anti-SARS-CoV monoclonal antibodies (mAbs). Here, we observed Val-to-Lys417 mutation in the receptor-binding domains (RBD) of SARS-CoV-2, which established a Lys-Asp electrostatic interaction enhancing its ACE2-binding. Pro-to-Ala475 substitution and Gly482 insertion in the AGSTPCNGV-loop of RBD possibly hinders neutralization of SARS-CoV-2 by anti-SARS-CoV mAbs. In addition, we identified unique and structurally conserved conformational-epitopes on RBDs, which can be potential therapeutic targets. Collectively, we provide new insights into the mechanisms underlying the high infectivity of SARS-CoV-2 and development of effective neutralizing agents.

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Citations

Jul 6, 2021·World Journal of Clinical Cases·Reza TaherkhaniFatemeh Farshadpour
Aug 25, 2021·Computational and Structural Biotechnology Journal·Zhonglei WangXian-En Zhao
Aug 28, 2021·International Journal of Molecular Sciences·Kwang-Eun ChoiNam Sook Kang
Aug 28, 2021·Future Virology·Abhishesh Kumar MehataMadaswamy S Muthu
Oct 24, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Stephen BoultonCarolina S Ilkow

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Methods Mentioned

BETA
electron microscopy
X-ray
bio-layer interferometry
enzymatic cleavage

Software Mentioned

CHARMM37
GROMACS
AMBER
SAbPred
MOE
Cryo
Epipred
Molecular Operating Environment ( MOE )
EM
APBSA

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