N439K Variant in Spike Protein Alter the Infection Efficiency and Antigenicity of SARS-CoV-2 Based on Molecular Dynamics Simulation

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing an outbreak of coronavirus disease 2019 (COVID-19), has been undergoing various mutations. The analysis of the structural and energetic effects of mutations on protein-protein interactions between the receptor binding domain (RBD) of SARS-CoV-2 and angiotensin converting enzyme 2 (ACE2) or neutralizing monoclonal antibodies will be beneficial for epidemic surveillance, diagnosis, and optimization of neutralizing agents. According to the molecular dynamics simulation, a key mutation N439K in the SARS-CoV-2 RBD region created a new salt bridge with Glu329 of hACE2, which resulted in greater electrostatic complementarity, and created a weak salt bridge with Asp442 of RBD. Furthermore, the N439K-mutated RBD bound hACE2 with a higher affinity than wild-type, which may lead to more infectious. In addition, the N439K-mutated RBD was markedly resistant to the SARS-CoV-2 neutralizing antibody REGN10987, which may lead to the failure of neutralization. The results show consistent with the previous experimental conclusion and clarify the structural mechanism under affinity changes. Our methods will offer guidance on the assessment of the infection efficiency and antigenicity effect of continuing mutations in SARS-CoV-2.

The dynamics of circulating SARS-CoV-2 lineages in Bogor and surrounding areas reflect variant shifting during the first and second waves of COVID-19 in Indonesia

“…The S_N439K mutation has been associated with a similar level of fitness and virulence to the wild-type virus, whilst potentially conferring a stronger binding affinity to human ACE2 receptor and allowing immune escape from antibody-mediated immunity ( Thomson et al, 2021 ). A study employing molecular dynamic simulation further confirmed those attributes and also provided potential mechanisms by which the stronger hACE2 binding affinity and the reduction in efficacy of neutralizing antibodies occur ( Zhou et al, 2021 ). A distinctive feature of the Delta variant, the S_P681R mutation within the S protein has been correlated to higher fusogenicity, which in turn led to viruses that exhibit enhanced pathogenicity in vivo and greater resistance to neutralizing antibodies compared to the parental virus without this mutation ( Saito et al, 2021 ).…”

Structural and functional insights into the spike protein mutations of emerging SARS-CoV-2 variants

“…In contrast, the shorter Asn439 residue in the wild-type protein is positioned distantly and cannot form hydrogen-bonded interactions. N439K mutation has also been associated with resistance towards REGN10987 antibodies [82,[85][86][87][88].…”

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

“…However, the underlying mechanism of how gilteritinib overcomes lorlatinib resistance to the double mutant I1171N/F1174I is incapable of elucidating directly based on the structural comparison of ALK–lorlatinib and ALK–gilteritinib complexes. To address this issue, MD simulations that consider conformational dynamics of proteins were performed to illuminate the effect of double mutations I1171N/F1174I on the conformational plasticity of ALK–lorlatinib and ALK–gilteritinib complexes ( Sora et al, 2020 ; Wang, et al, 2020 ; Zhou et al, 2021 ; Li et al, 2021b ; Ni et al, 2021b ).…”