Mechanisms of DNA hybridization: Transition path analysis of a simulation-informed Markov model

Area of Science:

• Biophysics
• Computational Biology
• Molecular Biology

Background:

• Complementary deoxyribonucleic acid (DNA) strands in solution hybridize to form stable duplexes.
• Understanding the kinetics and mechanisms of DNA hybridization is crucial for molecular biology applications.

Purpose of the Study:

• To investigate the kinetics and mechanisms of DNA hybridization.
• To identify the dominant pathway for two isolated DNA strands forming a double helix.

Main Methods:

• Utilized Brownian dynamics simulations with the oxDNA2 model.
• Constructed a Markov state model based on inter-strand hydrogen bonding.
• Applied transition path theory to analyze thermodynamic and dynamic properties.

Main Results:

• Identified a dominant hybridization mechanism involving sequential base pairing in a zipper-like fashion.
• Found that initial base pairing typically occurs near the ends of the nascent double helix.
• Demonstrated that the number of formed base pairs is insufficient to characterize the transition state.

Conclusions:

• The DNA hybridization process follows a predominant zipper-like mechanism.
• The transition state of hybridization is more complex than just the number of base pairs formed.
• Computational modeling provides quantitative insights into DNA duplex formation.