Title:Mechanistic Insights to the Binding of Antibody CR3022 Against RBD from SARS-CoV and HCoV-19/SARS-CoV-2: A Computational Study
Volume: 24
Issue: 7
Author(s): Wei Yu, Xiaomin Wu, Jiayi Ren, Xiaochun Zhang, Yueming Wang, Chengming Li, Wenwen Xu, Jason Li, Gang Li, Weihong Zheng, Huaxin Liao*Xiaohui Yuan*
Affiliation:
- Institute of Biomedicine, Jinan University, Guangzhou, 510632,China
- Institute of Biomedicine, Jinan University, Guangzhou, 510632,China
Keywords:
Human Coronavirus 2019 (HCoV-19/SARS-CoV-2), Coronavirus Disease 2019 (COVID-19), Receptor Binding
Domain (RBD), Molecular Dynamics (MD) Simulation, Molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA),
Computational Alanine scanning (CAS).
Abstract:
Aims & Objective: Coronavirus Disease 2019 (COVID-19) caused by the human
coronavirus 2019 (HCoV-19, also known as SARS-CoV-2) infection is currently in a global
outbreak. COVID-19 has posed a huge threat to public health and economic stability worldwide.
CR3022, a human monoclonal neutralizing antibody isolated from a Severe Acute Respiratory
Syndrome (SARS) recovery patient, was confirmed to be able to bind the S protein of HCoV-19
with a certain degree of neutralizing activity. Crystal structural information indicated that CR3022
could bind to the epitope on the receptor binding domain (RBD) of HCoV-19, whose epitope
consists of 28 amino acids, and 24 of them are conserved in SARS-CoV of SARS. However, the
crystal structure is only a static conformation at a certain moment in time, and it cannot provide
dynamic details of the interaction between antigen and antibody.
Methods: In this study, molecular dynamics (MD) simulation combined with MM/PBSA and CAS
methods were performed to investigate the mechanism of binding of CR3022 against SARS-CoVRBD
and HCoV-19-RBD in order to determine their holographic dynamic information.
Results: It was found that the CR3022-SARS-CoV-RBD complex was more stable during 100ns
MD run than that of the CR3022-HCoV-19-RBD system. There were common conservative amino
acids on the β2 sheet of RBD, including Tyr369, Phe377, Lys378, Tyr380, Gly381, Lys386,
Leu390 and others. These conservative amino acids play significant roles in the binding process of
CR3022 antibody against SARS-CoV-RBD and HCoV-19-RBD. It was also found that the binding
mode of CR3022 to its native target SARS-CoV-RBD is more comprehensive and uniform.
Moreover, the β2 sheet residue Thr385 and non-β2 sheet residues Arg408 and Asp428 of the
CR3022-SARS-CoV-RBD system were found to be crucial for their binding affinities, thus
forming a special conformational epitope. However, these key amino acids are not present in the
CR3022-HCoV-19-RBD system. The binding mode of CR3022 and HCoV-19-RBD is similar to
that of SARS-CoV-RBD, but the deficiency of crucial hydrogen-bonds and salt-bridges. Therefore,
the binding of CR3022 and HCoV-19-RBD only draws on the partial mode of the binding of
CR3022 and SARS-CoV-RBD, so there is a loss of affinity.
Conclusion: Thus, in order to better fight the epidemic of COVID-19 with the CR3022 antibody,
this antibody needs to further improve the neutralization efficiency of HCoV-19 through mutation
of it’s CDR region.
