Target search on DNA by interacting molecules: First-passage approach

Area of Science:

• Molecular Biology
• Biophysics
• Computational Biology

Background:

• Gene regulation is a fundamental cellular process involving proteins binding to DNA.
• The dynamics of protein search for DNA targets are well-studied, but intermolecular interactions' role is less clear.
• Gene activation/repression relies on multi-protein complexes forming at specific DNA sites.

Purpose of the Study:

• To model and analyze the target search dynamics of two interacting protein molecules.
• To investigate how intermolecular interactions and residence times affect gene regulation.
• To quantify the role of molecular complex formation in DNA target search.

Main Methods:

• Developed a one-dimensional model for two interacting molecules forming a dimer.
• Incorporated finite residence times for proteins on target sites.
• Utilized first-passage analytical calculations and Monte Carlo simulations.

Main Results:

• Search dynamics show complex behavior influenced by interaction strength and residence times.
• Search time exhibits non-monotonic behavior with respect to the dimer dissociation rate.
• Intermolecular interactions significantly impact the efficiency of gene activation/repression.

Conclusions:

• Molecular interactions are crucial for efficient gene regulation by multiple transcription factors.
• The formation of molecular complexes can alter DNA search dynamics.
• Theoretical modeling provides insights into the physical-chemical basis of gene regulation.