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Published on: December 21, 2019
Molecular Dynamics Simulations to Decipher the Role of Phosphorylation of SARS-CoV-2 Nonstructural Proteins (nsps) in
Lamya Alomair1,2, Sabeena Mustafa1, Mohsin Saleet Jafri2,3
1King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia.
Abstract:
Protein phosphorylation is a post-translational modification that enables various cellular activities and plays essential roles in protein interactions. Phosphorylation is an important process for the replication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). To shed more light on the effects of phosphorylation, we used an ensemble of neural networks to predict potential kinases that might phosphorylate SARS-CoV-2 nonstructural proteins (nsps) and molecular dynamics (MD) simulations to investigate the effects of phosphorylation on nsps structure, which could be a potential inhibitory target to attenuate viral replication. Eight target candidate sites were found as top-ranked phosphorylation sites of SARS-CoV-2. During the process of molecular dynamics (MD) simulation, the root-mean-square deviation (RMSD) analysis was used to measure conformational changes in each nsps. Root-mean-square fluctuation (RMSF) was employed to measure the fluctuation in each residue of 36 systems considered, allowing us to evaluate the most flexible regions. These analysis shows that there are significant structural deviations in the residues namely nsp1 THR 72, nsp2 THR 73, nsp3 SER 64, nsp4 SER 81, nsp4 SER 455, nsp5 SER284, nsp6 THR 238, and nsp16 SER 132. The identified list of residues suggests how phosphorylation affects SARS-CoV-2 nsps function and stability. This research also suggests that kinase inhibitors could be a possible component for evaluating drug binding studies, which are crucial in therapeutic discovery research.
Insights
This study identifies key phosphorylation sites on SARS-CoV-2 nonstructural proteins (nsps) using neural networks and molecular dynamics. These findings reveal how phosphorylation impacts viral protein structure and stability, suggesting potential therapeutic targets for inhibiting viral replication.
Area of Science:
- Virology
- Structural Biology
- Computational Biology
Background:
- Protein phosphorylation is a critical post-translational modification regulating cellular functions and protein interactions.
- Phosphorylation plays a significant role in the replication cycle of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).
Purpose of the Study:
- To identify potential kinase targets for SARS-CoV-2 nonstructural proteins (nsps).
- To investigate the structural impact of phosphorylation on SARS-CoV-2 nsps using molecular dynamics simulations.
- To explore phosphorylation as a potential inhibitory target to attenuate viral replication.
Main Methods:
- Ensemble of neural networks used for predicting potential kinase phosphorylation sites on SARS-CoV-2 nsps.
- Molecular dynamics (MD) simulations employed to analyze conformational changes and residue fluctuations.
- Root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) analyses conducted on 36 systems.
Main Results:
- Eight top-ranked candidate phosphorylation sites on SARS-CoV-2 nsps were identified.
- Significant structural deviations were observed in specific residues (e.g., nsp1 THR 72, nsp2 THR 73, nsp3 SER 64) upon phosphorylation.
- Phosphorylation was shown to affect the function and stability of SARS-CoV-2 nsps.
Conclusions:
- The study provides insights into how phosphorylation influences SARS-CoV-2 nsps structure and function.
- Identified phosphorylation sites and structural changes offer potential targets for therapeutic intervention.
- Kinase inhibitors may serve as a basis for drug discovery to combat SARS-CoV-2 infection.
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