Abstract

DNA-binding proteins (DBPs) rapidly search and specifically bind to their target sites on genomic DNA in order to trigger many cellular regulatory processes. It has been suggested that the facilitation of search dynamics is achieved by combining 3D diffusion with one-dimensional sliding and hopping dynamics of interacting proteins. Although, recent studies have advanced the knowledge of molecular determinants that affect one-dimensional search efficiency, the role of DNA molecule is poorly understood. In this study, by using coarse-grained simulations, we propose that dynamics of DNA molecule and its degree of confinement due to cellular crowding concertedly regulate its groove geometry and modulate the inter-communication with DBPs. Under weak confinement, DNA dynamics promotes many short, rotation-decoupled sliding events interspersed by hopping dynamics. While this results in faster 1D diffusion, associated probability of missing targets by jumping over them increases. In contrast, strong confinement favours rotation-coupled sliding to locate targets but lacks structural flexibility to achieve desired specificity. By testing under physiological crowding, our study provides a plausible mechanism on how DNA molecule may help in maintaining an optimal balance between fast hopping and rotation-coupled sliding dynamics, to locate target sites rapidly and form specific complexes precisely.

Highlights

  • Many in vivo enzymatic processes such as transcription, repression, activation etc. are triggered by specific binding of proteins to their respective target sites on DNA

  • We propose that DNA dynamics, together with its degree of confinement, modulates groove geometry and protein–DNA inter-communications, which in turn regulates the target search mechanism and efficiency of DNA binding proteins (DBPs)

  • In order to investigate how DNA dynamics under various degree of confinement modulates target search dynamics and kinetics of DBPs, we performed coarse-grained molecular dynamics simulations of Sap-1 with a randomly selected 200 bp DNA molecule that was encapsulated in a cylinder (Figure 1A)

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Summary

Introduction

Many in vivo enzymatic processes such as transcription, repression, activation etc. are triggered by specific binding of proteins to their respective target sites on DNA. A plausible mechanism of ‘facilitated diffusion’ [6,7] was proposed in which DBPs were assumed to speed up their target search process by lowering their search dimension [8,9] They bind nonspecifically to a random DNA site and perform onedimensional (1D) diffusion such as sliding, hopping along the DNA contour to reach target sites rapidly. The details of this multifaceted search mechanism were thoroughly investigated by both experimental and in silico simulation techniques at various levels of complexity [10,11,12,13,14,15]. The interacting DBPs sense these modulations to select search mode

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