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<p>The Japanese encephalitis virus (JEV) RNA-dependent RNA polymerase (RdRp) requires divalent metal cofactors for catalysis, where Mg²⁺ and Mn²⁺ confer distinct functional roles in replication fidelity and catalytic activity. By employing classical molecular dynamics (MD) and polarised MD simulations, this work has elucidated the molecular determinants for RdRp ion selectivity. Classical MD and polarised MD simulations of RdRp complexed using Mg²⁺ and Mn²⁺ at the catalytic triad (Asp536, Asp668, and Asp669) showed stable tri-dentate coordination that was also confirmed by classical MD. Protein backbone RMSD stabilised at 0.4–0.5&#xa0;nm, while marginally increased fluctuations by Mn²⁺ were observed, while ion RMSDs (0.1–0.3&#xa0;nm) indicated strong positional stability for both cofactors. Binding free energy calculations (MM/PBSA) estimated a higher binding free energy for Mg²⁺ (− 210.20&#xa0;kcal/mol vs. −155.58&#xa0;kcal/mol for Mn²⁺), mainly due to electrostatic contributions. Polarized MD simulations further complemented mechanistic insights by featuring lower RMSD deviations (0.18–0.20&#xa0;nm) and reduced flexibility for residues induced by Mn²⁺, while stable residence at slightly higher RMSD (0.25–0.30&#xa0;nm) and broader RMSF distributions, suggestive of conformational adaptability, was observed for Mg²⁺. Radial distribution functions indicated a higher density hydration sphere for Mn²⁺ (g(r) = 9.5) vs. Mg²⁺ (g(r) = 4.2). Binding energy profile panels indicated higher Coulombic stabilisation effected by Mg²⁺ (− 135,800&#xa0;kcal/mol vs. −133,900&#xa0;kcal/mol for Mn²⁺). Ion positional dynamics revealed that Mn²⁺ explored a multitude of microenvironments before convergence, whereas stable localization by virtue of hydrogen-bond-assisted structure was observed for Mg²⁺. Overall, these data suggest that the flaviviral RdRp employs divalent ions as catalytic modulators, enabling fast catalysis by Mn²⁺ and ensuring replication fidelity by Mg²⁺. This dualism is characteristic of an evolutionary mechanism optimising efficiency and accuracy during the synthesis of JEV genome.</p> Graphical abstract <p></p>

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Molecular insights into divalent ion modulation of Japanese encephalitis virus RNA polymerase: a comparative dynamics study of Mg²⁺ and Mn²⁺

  • 期刊论文

  • 发表日期：

    2026年1月6日

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  • Shatha Alzahrani,
  • Hayaa M. Alhuthali,
  • Amani A. Alrehaili,
  • Maha M. Bakhuraysah,
  • Maram Jameel Hulbah,
  • Abdullah R. Alzahrani,
  • Zia Ur Rehman,
  • Mohd Imran

摘要

The Japanese encephalitis virus (JEV) RNA-dependent RNA polymerase (RdRp) requires divalent metal cofactors for catalysis, where Mg²⁺ and Mn²⁺ confer distinct functional roles in replication fidelity and catalytic activity. By employing classical molecular dynamics (MD) and polarised MD simulations, this work has elucidated the molecular determinants for RdRp ion selectivity. Classical MD and polarised MD simulations of RdRp complexed using Mg²⁺ and Mn²⁺ at the catalytic triad (Asp536, Asp668, and Asp669) showed stable tri-dentate coordination that was also confirmed by classical MD. Protein backbone RMSD stabilised at 0.4–0.5 nm, while marginally increased fluctuations by Mn²⁺ were observed, while ion RMSDs (0.1–0.3 nm) indicated strong positional stability for both cofactors. Binding free energy calculations (MM/PBSA) estimated a higher binding free energy for Mg²⁺ (− 210.20 kcal/mol vs. −155.58 kcal/mol for Mn²⁺), mainly due to electrostatic contributions. Polarized MD simulations further complemented mechanistic insights by featuring lower RMSD deviations (0.18–0.20 nm) and reduced flexibility for residues induced by Mn²⁺, while stable residence at slightly higher RMSD (0.25–0.30 nm) and broader RMSF distributions, suggestive of conformational adaptability, was observed for Mg²⁺. Radial distribution functions indicated a higher density hydration sphere for Mn²⁺ (g(r) = 9.5) vs. Mg²⁺ (g(r) = 4.2). Binding energy profile panels indicated higher Coulombic stabilisation effected by Mg²⁺ (− 135,800 kcal/mol vs. −133,900 kcal/mol for Mn²⁺). Ion positional dynamics revealed that Mn²⁺ explored a multitude of microenvironments before convergence, whereas stable localization by virtue of hydrogen-bond-assisted structure was observed for Mg²⁺. Overall, these data suggest that the flaviviral RdRp employs divalent ions as catalytic modulators, enabling fast catalysis by Mn²⁺ and ensuring replication fidelity by Mg²⁺. This dualism is characteristic of an evolutionary mechanism optimising efficiency and accuracy during the synthesis of JEV genome.

Graphical abstract