Toward a Detailed Description of the Thermally Induced Dynamics of the Core Promoter

Abstract

Establishing the general and promoter-specific mechanistic features of gene transcription initiation requires improved understanding of the sequence-dependent structural/dynamic features of promoter DNA. Experimental data suggest that a spontaneous dsDNA strand separation at the transcriptional start site is likely to be a requirement for transcription initiation in several promoters. Here, we use Langevin molecular dynamic simulations based on the Peyrard-Bishop-Dauxois nonlinear model of DNA (PBD LMD) to analyze the strand separation (bubble) dynamics of 80-bp-long promoter DNA sequences. We derive three dynamic criteria, bubble probability, bubble lifetime, and average strand separation, to characterize bubble formation at the transcriptional start sites of eight mammalian gene promoters. We observe that the most stable dsDNA openings do not necessarily coincide with the most probable openings and the highest average strand displacement, underscoring the advantages of proper molecular dynamic simulations. The dynamic profiles of the tested mammalian promoters differ significantly in overall profile and bubble probability, but the transcriptional start site is often distinguished by large (longer than 10 bp) and long-lived transient openings in the double helix. In support of these results are our experimental transcription data demonstrating that an artificial bubble-containing DNA template is transcribed bidirectionally by human RNA polymerase alone in the absence of any other transcription factors.

Mesoscopic model for free-energy-landscape analysis of DNA sequences

“…State A identifies the TSS, showing a bubble in this region with the particle placed just there. States B and C are linked to excitations of other important sites such as the TATA box (state B), see [9]. In the same way, we have found a basin related to the TSS in the case of the P5 chain (state C) and the lac operon (state C), together with other regulatory sites.…”

The Transfer Integral Operator Method in the Study of DNA Unzipping and Bubble Formation

“…temporary localized openings along the double strand. These have been shown in a number of studies to reveal information regarding DNA function [1].…”

“…This model was introduced to investigate the mechanism of DNA denaturation, but has since been used to study the dynamics of DNA [1]. The model introduced by Prohofsky et al [36] to study dynamical aspects is essentially the same as the original Peyrard-Bishop-Dauxois model with the important difference that the nearest neighbor coupling is harmonic.…”

“…This idea was further developed by Salerno [31,32] who introduced nonhomogeneities in the model and studied the dynamics of DNA promoters in the context. His results have attracted attention [5,12] and other nonlinear excitations [1,34,35], such as discrete breathers, are emerging as important for DNA dynamics and function. These works take advantage of the large amount of research [3,4,13,14,21,23,24] that has been concerned with understanding discrete breathers in nonlinear systems in recent years.…”

“…Recently, has also proven useful in the study of DNA dynamics [1] and mechanical unzipping [40]. In the framework of the PBD, DNA is modeled as a system of coupled oscillators with an on-site Morse potential modeling the hydrogen bonds between each pair of complementary bases, and anharmonic coupled springs modeling the stacking of adjacent bases.…”