The Effect of Obstacles in Multi-Site Protein Target Search with DNA Looping

TL;DR

This paper presents a theoretical model analyzing how obstacles on DNA affect the search process of multi-site proteins, revealing that obstacle effects depend on DNA loop lifetime and relative positioning, with implications for understanding protein-DNA complex formation.

Contribution

The study introduces a discrete-state stochastic model to evaluate obstacle effects on multi-site protein target search involving DNA looping, incorporating simulations and physical-chemical analysis.

Findings

Obstacles slow down search when DNA loops are long-lived.

Short-lived DNA loops are minimally affected by obstacles.

Obstacle position influences search kinetics and noise levels.

Abstract

Many fundamental biological processes are regulated by protein-DNA complexes called {\it synaptosomes}, which possess multiple interaction sites. Despite the critical importance of synaptosomes, the mechanisms of their formation remain not well understood. Because of the multi-site nature of participating proteins, it is widely believed that their search for specific sites on DNA involves the formation and breaking of DNA loops and sliding in the looped configurations. In reality, DNA in live cells is densely covered by other biological molecules that might interfere with the formation of synaptosomes. In this work, we developed a theoretical approach to evaluate the role of obstacles in the target search of multi-site proteins when the formation of DNA loops and the sliding in looped configurations are possible. Our theoretical method is based on analysis of a discrete-state stochastic model that uses a master equations approach and extensive computer simulations. It is found that the obstacle slows down the search dynamics in the system when DNA loops are long-lived, but the effect is minimal for short-lived DNA loops. In addition, the relative positions of the target and the obstacle strongly influence the target search kinetics. Furthermore, the presence of the obstacle might increase the noise in the system. These observations are discussed using physical-chemical arguments. Our theoretical approach clarifies the molecular mechanisms of formation of protein-DNA complexes with multiple interactions sites.