Mechanisms of Protein Search for Targets on DNA: Theoretical Insights

Alexey Shvets,Anatoly Kolomeisky,Maria Kochugaeva

doi:10.3390/molecules23092106

Abstract

Protein-DNA interactions are critical for the successful functioning of all natural systems. The key role in these interactions is played by processes of protein search for specific sites on DNA. Although it has been studied for many years, only recently microscopic aspects of these processes became more clear. In this work, we present a review on current theoretical understanding of the molecular mechanisms of the protein target search. A comprehensive discrete-state stochastic method to explain the dynamics of the protein search phenomena is introduced and explained. Our theoretical approach utilizes a first-passage analysis and it takes into account the most relevant physical-chemical processes. It is able to describe many fascinating features of the protein search, including unusually high effective association rates, high selectivity and specificity, and the robustness in the presence of crowders and sequence heterogeneity.

Highlights

Dynamical nature of underlying processes is what distinguishes the living systems from other processes [1,2]
To understand the dynamic aspects of protein-DNA interactions, we developed a discrete-state stochastic framework to take into account the most relevant physical-chemical processes in the system
Protein search for targets on DNA is a very complex phenomenon that involves multiple biochemical and biophysical processes, significant advances in our understanding of the underlying molecular mechanisms have been achieved in recent years

Summary

Introduction

Dynamical nature of underlying processes is what distinguishes the living systems from other processes [1,2]. The first-passage ideas have been already widely utilized in studies of various complex processes in Chemistry, Physics and Biology [4,5] We employ these ideas in developing a discrete-state stochastic framework for analyzing the dynamics of protein search for specific targets on DNA. (two orders of magnitude faster than the diffusion limit!) [6], and many other experimentally determined protein-DNA association rates were astonishingly high in comparison to typical biological binding rates This is known as a facilitated diffusion. Our goal is not to cover all studies and all existing views but to present a clear theoretical picture of these processes as we understand it

Simplest Discrete-State Stochastic Model of the Protein Target Search

The Effect of Multiple Targets and Traps

Targets

Sequence Heterogeneity

The Effect of Crowding on DNA in the Protein Target Search

Conclusions and Future Directions