Protein–DNA Electrostatics

Abstract

Gene expression and regulation rely on an apparently finely tuned set of reactions between some proteins and DNA. Such DNA-binding proteins have to find specific sequences on very long DNA molecules and they mostly do so in absence of any active process. It has been rapidly recognized that to achieve this task these proteins should be efficient at both searching (i.e. sampling fast relevant parts of DNA) and finding (i.e. recognizing the specific site).A two-mode search and variants of it have been suggested since the 70s to explain either a fast search or an efficient recognition. Combining these two properties at a phenomenological level is however more difficult as they appear to have antagonist roles. To overcome this difficulty, one may simply need to drop the dichotomic view inherent to the two-mode search and look more thoroughly at the set of interactions between DNA-binding proteins and a given 1 arXiv:1311.7496v1 [physics.bio-ph] 29 Nov 2013 DNA segment either specific or non-specific. This chapter demonstrates that, in doing so in a very generic way, one may indeed find a potential reconciliation between a fast search and an efficient recognition. Although a lot remains to be done, this could be the time for a change of paradigm.

What matters for lac repressor search in vivo—sliding, hopping, intersegment transfer, crowding on DNA or recognition?

“…The model was successful in explaining the high association rate as well as its dependence on the salt concentration, non-specific binding constant and DNA-chain length ( 5 – 8 ). Since its original formulation, the sliding model has been revisited and extended ( 9 – 35 ) and also complemented with informative simulations at levels of detail ranging from atomistic ( 36 , 37 ) to coarse grained ( 13 , 17 , 21 , 38 – 39 ). This has not only generated new insight into e.g.…”

Hedgehog on the Move: Glypican-Regulated Transport and Gradient Formation in Drosophila

“…In addition to the possibility of both Hh binding sites interacting with the same extracellular HS chain, each binding site may also interact directly with different neighbouring chains to switch directly between them and move in the gradient field, a process termed “intersegmental transfer (IST)” ( Figure 5 ). This extracellular transport mode is strikingly similar to the mode used by DNA polymerases, transcription factors, nucleases, and other DNA-binding proteins in the nucleus [ 120 ]. Similar to HS-binding proteins that interact with the sugar–sulphate HS chain, DNA-binding proteins associate with the negatively charged sugar–phosphate DNA backbone through non-specific, long-lived electrostatic interactions [ 121 , 122 ].…”

The role of glycosaminoglycan modification in Hedgehog regulated tissue morphogenesis

“…This, in turn, would allow for uninterrupted, surface-restricted Hh transport. This hypothesis was inspired by the established transport mode of intracellular DNA polymerases, transcription factors, and nucleases that find their target sites by non-specific electrostatic interactions between positively charged amino acids on the DNA-binding protein and the negatively charged DNA backbone [ 64 , 65 ]. The electrostatic attraction allows the protein to move along the axis of the double helix while preventing protein diffusion away from the DNA (a process called ‘sliding’).…”

“…The electrostatic attraction allows the protein to move along the axis of the double helix while preventing protein diffusion away from the DNA (a process called ‘sliding’). In addition, these proteins directly transfer from one DNA backbone to the next in a process called ‘intersegmental protein transfer' [ 64 ]. Intersegmental protein transfer requires two independent DNA-binding sites to eliminate the need to unbind the first DNA before the second DNA can be bound, thus allowing for continuous protein movement along and between adjacent DNAs.…”