Molecular dynamics simulations reveal R399Q mutation disrupts XRCC1-polβ interaction, potentially impairing DNA base...

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Mutations in XRCC1 disrupt DNA base excision repair (BER), a critical pathway for maintaining genomic stability.
• Defects in BER are linked to increased cancer risk and genomic instability.
• The R399Q mutation is of particular interest due to its potential impact on XRCC1 function.

Purpose of the Study:

• To investigate the structural and functional effects of the R399Q mutation on XRCC1 interactions with DNA ligase IIIα and DNA polymerase β.
• To provide atomic-level insights into mutation-induced alterations in DNA repair protein dynamics.
• To reconcile conflicting experimental data on XRCC1 mutation effects.

Main Methods:

• Large-scale molecular dynamics (MD) simulations were employed to model XRCC1 interactions.
• Analysis of protein-protein interactions and hydrogen bond rearrangements.
• Free energy calculations to quantify binding affinity changes.

Main Results:

• The R399Q mutation caused subtle rearrangements in XRCC1's interaction with DNA ligase IIIα.
• Binding of XRCC1 to DNA polymerase β was significantly destabilized by the R399Q mutation.
• Free energy calculations indicated a substantial reduction in binding affinity to DNA polymerase β.

Conclusions:

• The R399Q mutation impairs XRCC1's role in DNA repair by disrupting its interaction with DNA polymerase β.
• MD simulations offer dynamic, atomic-level insights into mutation effects, complementing biochemical studies.
• These findings provide a computational framework for understanding mutation-driven DNA repair defects and their link to cancer risk.