Disparity in anomalous diffusion of proteins searching for their target DNA sites in a crowded medium is controlled by the size, shape and mobility of macromolecular crowders

Soft Matter ◽  
2019 ◽  
Vol 15 (9) ◽  
pp. 1960-1969 ◽  
Author(s):  
Pinki Dey ◽  
Arnab Bhattacherjee
Keyword(s):  
Dna Binding ◽  
Physical Properties ◽  
Computer Simulations ◽  
Anomalous Diffusion ◽  
Binding Proteins ◽  
Dna Binding Proteins ◽  
Molecular Crowding ◽  
Target Search ◽  
Target Dna

Using extensive computer simulations, we analyzed the role of physical properties of molecular crowding agents such as size, shape and mobility in the target search dynamics of DNA binding proteins.

scholarly journals Structural Basis of Enhanced Facilitated Diffusion of DNA Binding Proteins in Crowded Cellular Milieu

2019 ◽  
Author(s):  
P. Dey ◽  
A. Bhattacherjee
Keyword(s):  
Dna Binding ◽  
Binding Proteins ◽  
Dna Binding Proteins ◽  
Structural Basis ◽  
Facilitated Diffusion ◽  
Molecular Crowding ◽  
Cellular Environment ◽  
Target Dna ◽  
Nonspecific Interactions ◽  
Search Modes

ABSTRACTDNA binding proteins (DBPs) rapidly recognize and specifically associate with their target DNA sites inside cell nucleus that contains up to 400 g/L macromolecules, most of which are proteins. While the fast association between DBPs and DNA is explained by a facilitated diffusion mechanism, where DBPs adopt a weighted combination of 3D diffusion and 1D sliding and hopping modes of transportation, the role of cellular environment that contains many nonspecifically interacting proteins and other biomolecules is mostly overlooked. By performing large scale computational simulations with an appropriately tuned model of protein and DNA in the presence of nonspecifically interacting bulk and DNA bound crowders (genomic crowders), we demonstrate the structural basis of the enhanced facilitated diffusion of DBPs inside a crowded cellular milieu through novel 1D scanning mechanisms. In the presence of bulk crowders, we identify the protein to float along the DNA under the influence of protein-crowder nonspecific interactions. The search mode is distinctly different compared to usual 1D sliding and hopping dynamics where protein diffusion is regulated by the DNA electrostatics. In contrast, the presence of genomic crowders expedite the target search process by transporting the protein over DNA segments through the formation of a transient protein-crowder bridged complex. By analyzing the ruggedness of the associated potential energy landscape, we underpin the molecular origin of the kinetic advantages of these search modes and show that they successfully explain the experimentally observed acceleration of facilitated diffusion of DBPs by molecular crowding agents and crowder concentration dependent enzymatic activity of transcription factors. Our findings provide crucial insights into gene regulation kinetics inside the crowded cellular milieu.SIGNIFICANCE10-40% of the intracellular volume is occupied by proteins, and other biomolecules, collectively known as macromolecular crowders. Their presence has been found to promote faster translocation of DNA binding proteins (DBPs) during the search of their target DNA sites for crucial cellular processes. Using molecular simulations, we probe the underlying structural basis and underscore the existence of novel DNA scanning mechanisms actuated by protein-crowder nonspecific interactions. We show that the observed search modes are kinetically beneficial and can successfully explain the acceleration of facilitated diffusion of DBPs by molecular crowding agents and crowderconcentration dependent enzymatic activity of transcription factors.Our study sheds new light on the long-standing facilitated diffusion problem of DBPs in the crowded cellular environment for regulating gene expression.

scholarly journals Transient non-specific DNA binding dominates the target search of bacterial DNA-binding proteins

2020 ◽  
Author(s):  
Mathew Stracy ◽  
Jakob Schweizer ◽  
David J Sherratt ◽  
Achillefs N Kapanidis ◽  
Stephan Uphoff ◽  
...  
Keyword(s):  
Dna Binding ◽  
Single Molecule ◽  
Binding Proteins ◽  
Search Time ◽  
Dna Binding Proteins ◽  
Protein Diffusion ◽  
Chromosomal Dna ◽  
Dna Interactions ◽  
Target Search ◽  
Molecular Weights

ABSTRACTDespite their diverse biochemical characteristics and functions, all DNA-binding proteins share the ability to accurately locate their target sites among the vast excess of non-target DNA. Towards identifying universal mechanisms of the target search, we used single-molecule tracking of 11 diverse DNA-binding proteins in living Escherichia coli. The mobility of these proteins during the target search was dictated by DNA interactions, rather than by their molecular weights. By generating cells devoid of all chromosomal DNA, we discovered that the nucleoid does not pose a physical barrier for protein diffusion, but significantly slows the motion of DNA-binding proteins through frequent short-lived DNA interactions. The representative DNA-binding proteins (irrespective of their size, concentration, or function) spend the majority (58-99%) of their search time bound to DNA and occupy as much as ∼30% of the chromosomal DNA at any time. Chromosome-crowding likely has important implications for the function of all DNA-binding proteins.

Role of DNA methylation and methyl-DNA binding proteins in the repression of 5-lipoxygenase promoter activity

2010 ◽  
Vol 1801 (1) ◽  
pp. 49-57 ◽  
Author(s):  
Careen Katryniok ◽  
Nicole Schnur ◽  
Ad Gillis ◽  
Andreas von Knethen ◽  
Bernd L. Sorg ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Binding ◽  
Promoter Activity ◽  
Binding Proteins ◽  
Dna Binding Proteins

scholarly journals Predicting Target DNA Sequences of DNA-Binding Proteins Based on Unbound Structures

PLoS ONE ◽  
2012 ◽  
Vol 7 (2) ◽  
pp. e30446 ◽  
Author(s):  
Chien-Yu Chen ◽  
Ting-Ying Chien ◽  
Chih-Kang Lin ◽  
Chih-Wei Lin ◽  
Yi-Zhong Weng ◽  
...  
Keyword(s):  
Dna Binding ◽  
Dna Sequences ◽  
Binding Proteins ◽  
Dna Binding Proteins ◽  
Target Dna

scholarly journals Probing the target search of DNA-binding proteins in mammalian cells using TetR as model searcher

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Davide Normanno ◽  
Lydia Boudarène ◽  
Claire Dugast-Darzacq ◽  
Jiji Chen ◽  
Christian Richter ◽  
...  
Keyword(s):  
Dna Binding ◽  
Mammalian Cells ◽  
Binding Proteins ◽  
Dna Binding Proteins ◽  
Target Search
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