Non-specific DNA-protein interaction: Why proteins can diffuse along DNA

TL;DR

This paper investigates how proteins diffuse along DNA via non-specific interactions, revealing that electrostatic repulsion and osmotic pressure create a favorable sliding path, facilitating target search and recognition.

Contribution

It demonstrates that electrostatic repulsion and osmotic effects enable proteins to slide along DNA without nonspecific binding, a novel insight into DNA-protein interaction mechanisms.

Findings

Proteins experience a repulsive force from DNA due to osmotic pressure.

A free energy minimum exists at a certain distance from DNA, allowing sliding.

Sequence recognition occurs when specific interactions counter osmotic barriers.

Abstract

The structure of DNA Binding Proteins enables a strong interaction with their specific target site on DNA. However, recent single molecule experiment reported that proteins can diffuse on DNA. This suggests that the interactions between proteins and DNA play a role during the target search even far from the specific site. It is unclear how these non-specific interactions optimize the search process, and how the protein structure comes into play. Each nucleotide being negatively charged, one may think that the positive surface of DNA-BPs should electrostatically collapse onto DNA. Here we show by means of Monte Carlo simulations and analytical calculations that a counter-intuitive repulsion between the two oppositely charged macromolecules exists at a nanometer range. We also show that this repulsion is due to a local increase of the osmotic pressure exerted by the ions which are trapped at the interface. For the concave shape of DNA-BPs, and for realistic protein charge densities, we find that the repulsion pushes the protein in a free energy minimum at a distance from DNA. As a consequence, a favourable path exists along which proteins can slide without interacting with the DNA bases. When a protein encounters its target, the osmotic barrier is completely counter-balanced by the H-bond interaction, thus enabling the sequence recognition.