Domain Mobility in the ORF2p Complex Revealed by Molecular Dynamics Simulations and Big Data Analysis

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• ORF2p (open reading frame 2 protein) is a key enzyme in cancer pathophysiology, possessing reverse transcriptase and endonuclease activities.
• Recent structural studies revealed "open" and "closed" ring conformations of the seven-domain ORF2p complex.
• The structural diversity of ORF2p may extend beyond these observed conformations.

Purpose of the Study:

• To investigate the dynamic behavior of the entire ORF2p complex using molecular dynamics simulations.
• To explore potential structural variations not captured by experimental methods.

Main Methods:

• All-atom molecular dynamics simulations of the ORF2p complex were performed for sub-microsecond timescales.
• Dimension reduction and clustering techniques (principal component analysis) were applied to analyze simulation trajectories.
• Analysis focused on domain movements, interactions, and conformational changes.

Main Results:

• Simulations revealed complex dynamics in domains beyond the rigid fingers-palm-thumb core.
• The endonuclease (EN) and carboxy-terminal (CTD) domains exhibited significant translations and rotations.
• The CTD domain's interaction with the tower domain varied, independent of the overall ring conformation, and could obstruct the active site.

Conclusions:

• Molecular dynamics simulations provide valuable insights into the complex and dynamic nature of ORF2p.
• The study highlights that domain movements, particularly of CTD and EN, contribute to structural diversity beyond static experimental structures.
• These findings enhance our understanding of ORF2p's functional mechanisms and its role in cancer, offering avenues for future research.