+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Role of DNA binding sites and slow unbinding kinetics in titration-based oscillators



Role of DNA binding sites and slow unbinding kinetics in titration-based oscillators



Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics 92(6): 062712



Genetic oscillators, such as circadian clocks, are constantly perturbed by molecular noise arising from the small number of molecules involved in gene regulation. One of the strongest sources of stochasticity is the binary noise that arises from the binding of a regulatory protein to a promoter in the chromosomal DNA. In this study, we focus on two minimal oscillators based on activator titration and repressor titration to understand the key parameters that are important for oscillations and for overcoming binary noise. We show that the rate of unbinding from the DNA, despite traditionally being considered a fast parameter, needs to be slow to broaden the space of oscillatory solutions. The addition of multiple, independent DNA binding sites further expands the oscillatory parameter space for the repressor-titration oscillator and lengthens the period of both oscillators. This effect is a combination of increased effective delay of the unbinding kinetics due to multiple binding sites and increased promoter ultrasensitivity that is specific for repression. We then use stochastic simulation to show that multiple binding sites increase the coherence of oscillations by mitigating the binary noise. Slow values of DNA unbinding rate are also effective in alleviating molecular noise due to the increased distance from the bifurcation point. Our work demonstrates how the number of DNA binding sites and slow unbinding kinetics, which are often omitted in biophysical models of gene circuits, can have a significant impact on the temporal and stochastic dynamics of genetic oscillators.

(PDF emailed within 0-6 h: $19.90)

Accession: 058785597

Download citation: RISBibTeXText

PMID: 26764732

DOI: 10.1103/PhysRevE.92.062712


Related references

The Two-Dimensional Kinetics of Binding and Unbinding are Both Regulated by Myosin's Actin-Binding Loop. Biophysical Journal 102(3): 16a-17a, 2012

Toward High-Throughput Predictive Modeling of Protein Binding/Unbinding Kinetics. Journal of Chemical Information and Modeling 56(6): 1164-1174, 2017

Slow activation of the cardiac muscarinic K+ channel Kir31-Kir34 is due to polyamines unbinding from charged sites within the channel pore. Journal of Physiology (Cambridge) 527P: 117P, 2000

The kinetics of slow-binding and slow, tight-binding inhibition: the effects of substrate depletion. Biochemical Journal 294: 195-200, 1993

New perspectives on the computational characterization of the kinetics of binding-unbinding in drug design: implications for novel therapies. Boletin Medico del Hospital Infantil de Mexico 73(6): 424-431, 2016

Resolving two-dimensional kinetics of the integrin αIIbβ3-fibrinogen interactions using binding-unbinding correlation spectroscopy. Journal of Biological Chemistry 287(42): 35275-35285, 2013

Role of water and steric constraints in the kinetics of cavity-ligand unbinding. Proceedings of the National Academy of Sciences of the United States of America 112(39): 12015-9, 2016

A putative binding pocket residue in the GABAA receptor selectively mediates unbinding kinetics but not channel gating. Biophysical Journal 82(1 Part 2): 257a, 2002

Binding of actinomycin D to 5dGpdC3 sites with flanking homo-base mismatches, observation of anomalously slow association and dissociation kinetics with T/T mismatches. Journal of Biomolecular Structure & Dynamics 12(6): A147, 1995

Titration of total binding sites for growth hormone in rabbit liver. Quantitative modifications of these sites during pregnancy. Molecular and Cellular Endocrinology 13(1): 11-23, 1979

Distinct sites regulating grayanotoxin binding and unbinding to D4S6 of Na(v)1.4 sodium channel as revealed by improved estimation of toxin sensitivity. Journal of Biological Chemistry 278(11): 9464-9471, 2003

Anomalously slow transport in single-file diffusion with slow binding kinetics. Physical Review. E 98(2-1): 022114, 2018

Titration of low K(d) binding sites: binding of arginine analogs to nitric oxide synthases. Nitric Oxide 5(5): 442-452, 2001

Slow dissociation of the new slow-onset and long-acting calcium antagonist benidipine hydrochloride from 3H-nitrendipine binding sites. Arzneimittel-Forschung 38(11a): 1681-1683, 1988

Isothermal titration calorimetry and surface plasmon resonance allow quantifying substrate binding to different binding sites of Bacillus subtilis xylanase. Analytical Biochemistry 420(1): 90-92, 2012