Dataset Information

Computational modelling of potentially emerging SARS-CoV-2 spike protein RBDs mutations with higher binding affinity towards ACE2: A structural modelling study.

ABSTRACT: The spike protein of SARS-CoV-2 and the host ACE2 receptor plays a vital role in the entry to the cell. Among which the hotspot residue 501 is continuously subjected to positive selection pressure and induces unusual virulence. Keeping in view the importance of the hot spot residue 501, we predicted the potentially emerging structural variants of 501 residue. We analyzed the binding pattern of wild type and mutants (Spike RBD) to the ACE2 receptor by deciphering variations in the amino acids' interaction networks by graph kernels along with evolutionary, network metrics, and energetic information. Our analysis revealed that N501I, N501T, and N501V increase the binding affinity and alter the intra and inter-residue bonding networks. The N501T has shown strong positive selection and fitness in other animals. Docking results and repeated simulations (three times) confirmed the structural stability and tighter binding of these three variants, correlated with the previous results following the global stability trend. Consequently, we reported three variants N501I, N501T, and N501V could worsen the situation further if they emerged. The relations between the viral fitness and binding affinity is a complicated game thus the emergence of high affinity mutations in the SARS-CoV-2 RBD brings up the question of whether or not positive selection favours these mutations or not?

SUBMITTER: Khan A

PROVIDER: S-EPMC8716154 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Computational modelling of potentially emerging SARS-CoV-2 spike protein RBDs mutations with higher binding affinity towards ACE2: A structural modelling study.

Khan Abbas A Hussain Sarfaraz S Ahmad Sajjad S Suleman Muhammad M Bukhari Imrana I Khan Taimoor T Rashid Farooq F Azad Abul Kalam AK Waseem Muhammad M Khan Wajid W Hussain Zahid Z Khan Asghar A Ali Syed Shujait SS Qin Qiyao Q Wei Dong-Qing DQ

Computers in biology and medicine 20211230

The spike protein of SARS-CoV-2 and the host ACE2 receptor plays a vital role in the entry to the cell. Among which the hotspot residue 501 is continuously subjected to positive selection pressure and induces unusual virulence. Keeping in view the importance of the hot spot residue 501, we predicted the potentially emerging structural variants of 501 residue. We analyzed the binding pattern of wild type and mutants (Spike RBD) to the ACE2 receptor by deciphering variations in the amino acids' in ...[more]

PMID: 34979405

Similar Datasets

Project description:Pet golden hamsters were first identified being infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delta variant of concern (VOC) and transmitted the virus back to humans in Hong Kong in January 2022. Here, we studied the binding of two hamster (golden hamster and Chinese hamster) angiotensin-converting enzyme 2 (ACE2) proteins to the spike protein receptor-binding domains (RBDs) of SARS-CoV-2 prototype and eight variants, including alpha, beta, gamma, delta, and four omicron sub-variants (BA.1, BA.2, BA.3, and BA.4/BA.5). We found that the two hamster ACE2s present slightly lower affinity for the RBDs of all nine SARS-CoV-2 viruses tested than human ACE2 (hACE2). Furthermore, the similar infectivity to host cells expressing hamster ACE2s and hACE2 was confirmed with the nine pseudotyped SARS-CoV-2 viruses. Additionally, we determined two cryo-electron microscopy (EM) complex structures of golden hamster ACE2 (ghACE2)/delta RBD and ghACE2/omicron BA.3 RBD. The residues Q34 and N82, which exist in many rodent ACE2s, are responsible for the lower binding affinity of ghACE2 compared to hACE2. These findings suggest that all SARS-CoV-2 VOCs may infect hamsters, highlighting the necessity of further surveillance of SARS-CoV-2 in these animals.IMPORTANCESARS-CoV-2 can infect many domestic animals, including hamsters. There is an urgent need to understand the binding mechanism of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants to hamster receptors. Herein, we showed that two hamster angiotensin-converting enzyme 2s (ACE2s) (golden hamster ACE2 and Chinese hamster ACE2) can bind to the spike protein receptor-binding domains (RBDs) of SARS-CoV-2 prototype and eight variants and that pseudotyped SARS-CoV-2 viruses can infect hamster ACE2-expressing cells. The binding pattern of golden hamster ACE2 to SARS-CoV-2 RBDs is similar to that of Chinese hamster ACE2. The two hamster ACE2s present slightly lower affinity for the RBDs of all nine SARS-CoV-2 viruses tested than human ACE2. We solved the cryo-electron microscopy (EM) structures of golden hamster ACE2 in complex with delta RBD and omicron BA.3 RBD and found that residues Q34 and N82 are responsible for the lower binding affinity of ghACE2 compared to hACE2. Our work provides valuable information for understanding the cross-species transmission mechanism of SARS-CoV-2.

Dataset Information

Computational modelling of potentially emerging SARS-CoV-2 spike protein RBDs mutations with higher binding affinity towards ACE2: A structural modelling study.

Publications

Computational modelling of potentially emerging SARS-CoV-2 spike protein RBDs mutations with higher binding affinity towards ACE2: A structural modelling study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets