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Mutations in the WFYY motif alter human PrimPol activity: structural insights from atomistic MD simulations
Sruthi Sudhakar1, Vipin Kumar Mishra1, S Harikrishna1
1Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India. sruthisudhakarraji@gmail.com.
Physical Chemistry Chemical Physics : PCCP
|June 26, 2026
Summary
Mutations in the WFYY motif of human PrimPol (hPrimPol) disrupt DNA replication by altering enzyme structure and dNTP binding. These findings explain disease links and suggest targeting hPrimPol for drug development.
Area of Science:
- Molecular Biology
- Biochemistry
- Structural Biology
Background:
- Human PrimPol (hPrimPol) is crucial for DNA replication reinitiation at stalled forks.
- hPrimPol mutations are associated with ophthalmoplegia and mitochondriopathies.
- The WFYY motif stabilizes incoming deoxynucleotide triphosphates (dNTPs).
Purpose of the Study:
- To investigate the structural basis of polymerase activity loss in hPrimPol mutants.
- To elucidate the role of the WFYY motif in hPrimPol function and regulation.
Main Methods:
- Microsecond molecular dynamics simulations of wild-type and mutant hPrimPol complexes.
- Analysis of structural parameters, residue interaction networks, and community dynamics.
- Focus on mutations W87G and Y90D, which abolish polymerase activity.
Main Results:
- Mutations W87G and Y90D caused significant structural and dynamic changes in hPrimPol.
- Disorientation of incoming dCTP and altered ModC module motion observed in inactive mutants.
- Disrupted intra-module communication between ModN and ModC affected dCTP binding affinity.
Conclusions:
- Structural alterations in the WFYY motif directly impair hPrimPol polymerase activity.
- These findings rationalize experimental data and provide mechanistic insights into hPrimPol dysfunction.
- The WFYY motif represents a potential allosteric target for therapeutic drug development.
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