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Molecular dynamic study of SARS-CoV-2 with various S protein mutations and their effect on thermodynamic properties.

ABSTRACT: Studying the structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein is important to understand the infection process. The S protein is necessary in completing the virus life cycle and is responsible for the appearance of new variants and drug and vaccine resistance. Understanding the structure and dynamics of biological macromolecules is essential for understanding how they function. In this work, we investigated the effects of mutations on S protein stability and solubility through molecular dynamic (MD) simulation in a 100 ns (ns) period. We screened four variants in addition to the wild type (WT). Results show that changes on MD simulation parameters of S protein indicate fluctuations and changes in the conformation, especially in the area between 300 and 600 amino acids (aa). This provides us an image of how the virus protein can reshape itself to adapt to any changes that occur in human angiotensin-converting enzyme 2 or drugs that can target the protein region. Our results also show that the Brazil variant has high fluctuations and unstable folding at some stages compared with other variants.

SUBMITTER: Abdalla M

PROVIDER: S-EPMC8576119 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Molecular dynamic study of SARS-CoV-2 with various S protein mutations and their effect on thermodynamic properties.

Abdalla Mohnad M Eltayb Wafa Ali WA El-Arabey Amr Ahmed AA Singh Kamal K Jiang Xinyi X

Computers in biology and medicine 20211109

Studying the structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein is important to understand the infection process. The S protein is necessary in completing the virus life cycle and is responsible for the appearance of new variants and drug and vaccine resistance. Understanding the structure and dynamics of biological macromolecules is essential for understanding how they function. In this work, we investigated the effects of mutations on S protein stabilit ...[more]

PMID: 34772510

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Project description:The emergence of novel coronavirus mutants is a main factor behind the deterioration of the epidemic situation. Further studies into the pathogenicity of these mutants are thus urgently needed. Binding of the spinous protein receptor binding domain (RBD) of SARS-CoV-2 to the angiotensin-converting enzyme 2 (ACE2) receptor was shown to initiate coronavirus entry into host cells and lead to their infection. The receptor-binding motif (RBM, 438-506) is a region that directly interacts with ACE2 receptor in the RBD and plays a crucial role in determining affinity. To unravel how mutations in the non-RBM regions impact the interaction between RBD and ACE2, we selected three non-RBM mutant systems (N354D, D364Y, and V367F) from the documented clinical cases, and the Q498A mutant system located in the RBM region served as the control. Molecular dynamics simulation was conducted on the mutant systems and the wild-type (WT) system, and verified experiments also performed. Non-RBM mutations have been shown not only to change conformation of the RBM region but also to significantly influence its hydrogen bonding and hydrophobic interactions. In particular, the D364Y and V367F systems showed a higher affinity for ACE2 owing to their electrostatic interactions and polar solvation energy changes. In addition, although the binding free energy at this point increased after the mutation of N354D, the conformation of the random coil (Pro384-Asp389) was looser than that of other systems, and the combined effect weakened the binding free energy between RBD and ACE2. Interestingly, we also found a random coil (Ala475-Gly485). This random coil is very sensitive to mutations, and both types of mutations increase the binding free energy of residues in this region. We found that the binding loop (Tyr495-Tyr505) in the RBD domain strongly binds to Lys353, an important residue of the ACE2 domain previously identified. The binding free energy of the non-RBM mutant group at the binding loop had positive and negative changes, and these changes were more obvious than that of the Q498A system. The results of this study elucidate the effect of non-RBM mutation on ACE2-RBD binding, and provide new insights for SARS-CoV-2 mutation research.

Dataset Information

Molecular dynamic study of SARS-CoV-2 with various S protein mutations and their effect on thermodynamic properties.

Publications

Molecular dynamic study of SARS-CoV-2 with various S protein mutations and their effect on thermodynamic properties.

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