Facilitated Target Location in Biological Systems

TLDR

The rapid location of DNA targets by macromolecules has intrigued physicists, chemists, and biologists, prompting investigations into mechanisms that surpass three‑dimensional diffusion limits. This minireview aims to examine how transcription‑factor regulators find their DNA targets at rates exceeding diffusion control. The authors survey recent theoretical and experimental progress on accelerated target search, focusing on protein regulators of gene expression. The review cites Riggs et al.

Abstract

In 1970 Riggs et al. (1) reported that Escherichia coli lac repressor binding to λ DNA in vitro seemed to find its target (operator) site on the DNA at a rate as much as 1000-fold faster than the upper limit estimated for a diffusion-controlled process involving macromolecules of this size. This observation startled and intrigued many physically oriented molecular biologists and biochemists and initiated a flurry of theoretical and experimental papers seeking to offer an explanation. However, scrutiny of the older literature reveals that scientists, ranging from mathematicians to biologists, had long been concerned with how systems of various sorts might transcend the rate limits set by three-dimensional diffusion control (2). Such problems are now of interest at many different levels. The pure physical chemist feels that an understanding of such phenomena might provide new insight into what happens when molecules meet and rearrange in the course of forming and passing through the transition state complex. The enzyme mechanician hopes that the secrets of some of the astonishing increases in rates achieved in enzyme-catalyzed reactions may be revealed by a study of these rate accelerations. And the cell biologist who studies macromolecular interactions and assembly processes is intrigued by the possibility that these systems may reveal opportunities for acceleration of intracellular rates beyond the limits set by the relatively slow diffusion of macromolecules in the cytoplasm. In this minireview we propose to touch on recent progress in all of these areas but will focus primarily on a problem that has engaged our attention over the past few years, i.e. how do protein regulators of gene expression at the transcriptional level find their regulatory DNA targets at speeds that appear to be faster than diffusion controlled?