Computational Insights Reveal Molnupiravir’s Binding Dynamics Against Omicron Subvariants

Advanced Computational Analysis of Antiviral Efficacy

Recent computational research provides crucial insights into how molnupiravir interacts with emerging SARS-CoV-2 Omicron subvariants BA.5 and BQ.1.1. Using sophisticated molecular modeling techniques, scientists have uncovered detailed binding mechanisms that could inform future therapeutic strategies against evolving coronavirus strains.

Advanced Computational Analysis of Antiviral Efficacy
Binding Energy Calculations and Methodology
Protein Domain Architecture and Conservation
Molecular Docking Reveals Variant-Specific Binding Patterns
Molecular Dynamics Simulations Uncover Stability Profiles
Structural Insights from Simulation Trajectories
Flexibility Analysis and Functional Implications
Interaction Persistence and Binding Sustainability
Functional Domain Analysis
Implications for Antiviral Development

Binding Energy Calculations and Methodology

The investigation employed MM-GBSA (Molecular Mechanics, Generalized Born model, and Solvent Accessibility) analysis to determine free binding energies of protein-ligand complexes. Researchers utilized Schrödinger software with the VSGB 2.0 model, incorporating the OPLS-AA force field alongside an implicit solvent model. The system included physics-based modifications accounting for π-π interactions, hydrophobic interactions, and hydrogen bonding self-contact interactions, providing a comprehensive assessment of molecular interactions.

Protein Domain Architecture and Conservation

Analysis of functional domains revealed significant structural insights. The target protein demonstrated high conservation with reference beta coronavirus spike proteins, containing 1268 base pairs with 16 domain sites and 8 homologous superfamily regions. This conservation suggests maintained functional architecture despite variant evolution, which is crucial for understanding drug binding potential across different viral strains.

Molecular Docking Reveals Variant-Specific Binding Patterns

Molecular docking using PyRx software demonstrated distinct binding affinities between variants. The BA.5 complex showed a binding affinity of -5.70 kcal/mol, while BQ.1.1 exhibited -5.30 kcal/mol. Detailed interaction analysis revealed that molnupiravir formed stable hydrogen bonds with key spike protein residues in both variants, though with different interaction patterns.

For BA.5, strong hydrogen bonds formed with Gly1042 and Gly1044, supplemented by van der Waals contacts, carbon hydrogen bonds, and π-alkyl interactions with Tyr1045 and Val1038. The BQ.1.1 variant displayed more extensive conventional hydrogen bonding with Tyr394, Arg353, Ser512, Thr428, and Asp426, engaging both oxygen and nitrogen atoms of the ligand. This higher interaction density in BQ.1.1 correlates with its more favorable docking score., according to emerging trends

Molecular Dynamics Simulations Uncover Stability Profiles

Extended molecular dynamics simulations provided critical data on complex stability through RMSD (Root Mean Square Deviation) and RMSF (Root Mean Square Fluctuation) analyses over 100-nanosecond trajectories.

BA.5 Complex Stability: The system reached equilibrium with protein RMSD of 10.46 Å and ligand RMSD of approximately 8.0 Å. Despite transient fluctuations between 40-75 ns, the system stabilized from 80 ns onward. Maximum average RMSD (15.84 Å) occurred in residues 465-504 during 45-60 ns, reflecting localized flexibility near the C-terminal region where ligand repositioning occurred. Throughout these adjustments, molnupiravir maintained continuous interactions with adjacent residues.

BQ.1.1 Dynamic Behavior: This complex exhibited different stability characteristics, with receptor RMSD averaging 13.0 Å and ligand RMSD reaching 18.72 Å. The higher ligand deviation indicates significant conformational shifting between 25-57 ns as molnupiravir transitioned toward the β-core sheet region near the N-terminal site. This movement represents an adaptive search for energetically favorable conformations while maintaining receptor association throughout the trajectory., as previous analysis

Structural Insights from Simulation Trajectories

Detailed analysis of simulation trajectories revealed distinct binding pocket characteristics between variants. The BA.5 spike protein featured ligand-binding near the C-terminal domain, with residues ASP1039, TYR1045, and SER1035 contributing to firm encapsulation through hydrogen bonds and hydrophobic contacts.

In contrast, BQ.1.1’s binding pocket positioned nearer the N-terminal region, with ASP426 and ARG353 playing key stabilization roles through hydrogen bonding and van der Waals interactions. Additional dynamic aspects involved side chain flexibility in residues HIS513 and GLU427, influencing local binding environment and contributing to the higher ligand RMSD observed in MD analysis.

Flexibility Analysis and Functional Implications

RMSF calculations provided insights into regional flexibility across protein structures. The BA.5 complex showed average RMSF of 1.7 Å (range: 0.7-5.2 Å), while BQ.1.1 averaged 1.61 Å with peaks reaching 4.2 Å. Pronounced fluctuations occurred primarily in loop regions, including residues 76, 103, 203-279, and terminal regions 518 and 599.

Ligand flexibility analysis revealed mean RMSF values of 5.38 Å for BA.5 and 4.34 Å for BQ.1.1. The significant proportion of flexible loops in core, N-like domain, catalytic binding domain, and C-terminal domain regions compelled dynamic behavior, potentially representing an inherent mechanism to facilitate proper ligand accommodation and catalytic function.

Interaction Persistence and Binding Sustainability

Comprehensive interaction analysis demonstrated molnupiravir’s ability to maintain key molecular contacts despite conformational flexibility. In BA.5 complexes, conventional hydrogen bonds and water-bridged interactions predominated, with key participating residues including Arg1037, Asp1039, Cys1041, Gly1042, Lys1043, Gly1044, and Gln1069.

The BQ.1.1 complex featured strong hydrogen bond interactions with Gly379, Asp426, Thr428, Ser512, Leu515, Thr545, Arg565, and Ala568, supported by hydrophobic interactions and water-mediated contacts. Interestingly, BQ.1.1 exhibited temporary interaction disruption as molnupiravir relocated deeper into an alternative binding cavity, establishing new interactions primarily through hydrophobic contacts and water bridges with Thr545, Arg565, and Ala568.

Functional Domain Analysis

Detailed examination of functional domains was conducted using InterPro database analysis, confirming the protein’s classification within coronavirus spike protein families and providing context for understanding binding site evolution across variants.

Implications for Antiviral Development

These computational findings provide valuable insights for ongoing antiviral development efforts. The demonstrated binding capabilities across Omicron subvariants suggest molnupiravir maintains efficacy against evolving strains, though variant-specific binding characteristics may influence optimal dosing strategies. The dynamic binding behavior observed, particularly in BQ.1.1, highlights the importance of considering conformational flexibility in drug design against rapidly mutating viral targets.

The research methodology establishes a robust framework for computational assessment of antiviral compounds against emerging variants, potentially accelerating therapeutic development for future pandemic preparedness.