Sliding on DNA: From Peptides to Small Molecules.
Many DNA binding proteins utilize one-dimensional (1D) diffusion along DNA to accelerate their DNA target recognition. Although 1D diffusion of proteins along DNA has been studied for decades, a quantitative understanding is only beginning to emerge and few chemical tools are available to apply 1D diffusion as a design principle. Recently, we discovered that peptides can bind and slide along DNA-even transporting cargo along DNA. Such molecules are known as molecular sleds. Here, to advance our understanding of structure-function relationships governing sequence nonspecific DNA interaction of natural molecular sleds and to explore the potential for controlling sliding activity, we test the DNA binding and sliding activities of chemically modified peptides and analogs, and show that synthetic small molecules can slide on DNA. We found new ways to control molecular sled activity, novel small-molecule synthetic sleds, and molecular sled activity in N-methylpyrrole/N-methylimidazole polyamides that helps explain how these molecules locate rare target sites.
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.|Department of Biological Engineering, MIT, Cambridge, MA, 02142, USA.
Kan
0000-0002-0639-5803
K
Xiong
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA.
Graham S
0000-0002-9286-7626
GS
Erwin
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA.
Aseem Z
0000-0003-1432-4498
AZ
Ansari
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.|Department of Biological Engineering, MIT, Cambridge, MA, 02142, USA.
Paul C
0000-0002-4889-8783
PC
Blainey
D004247:DNA / Q000737:chemistry*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D008968:Molecular Conformation; D009757:Nylons / Q000138:chemical synthesis* / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry
D007093:Imidazoles; D009757:Nylons; D010455:Peptides; D011758:Pyrroles; D004247:DNA; C096654:N-methylpyrrole; C018100:1-methylimidazole
drug delivery; molecular sleds; polyamide; single molecule imaging; small molecule