Proliferating cell nuclear antigen loaded onto double-stranded DNA: dynamics, minor groove interactions and...

Area of Science:

• Molecular Biology
• Biochemistry
• Computational Biology

Background:

• Proliferating cell nuclear antigen (PCNA) is a crucial processivity factor in DNA replication and repair.
• PCNA forms a sliding clamp around DNA, facilitating interactions with key enzymes like polymerase, flap endonuclease-1 (FEN-1), and ligase.

Purpose of the Study:

• To computationally characterize the interactions between human and Archaeoglobus fulgidus PCNA trimers and double-stranded DNA (dsDNA).
• To elucidate the dynamic motions and binding orientations of PCNA during DNA processing.

Main Methods:

• Multi-nanosecond classical molecular dynamics simulations were employed.
• Covariance matrix analysis and principal component analysis were used to study PCNA dynamics and subunit correlations.

Main Results:

• Detailed interactions of dsDNA passing through the PCNA trimeric ring were revealed, including DNA tilting due to electrostatic interactions with PCNA's inner surface.
• Correlated motions within PCNA subunits and low-frequency global motions suitable for DNA translocation were identified.
• Specific interactions between PCNA and the DNA minor groove were computationally characterized.

Conclusions:

• The study provides novel computational insights into the dynamic interactions and motions of PCNA with dsDNA.
• These findings offer a mechanistic basis for PCNA's role in coordinating enzyme handoffs during DNA replication and repair.
• The results highlight the importance of PCNA's structure and dynamics in ensuring efficient DNA processing.