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Small structures: single molecule study of protein ligand interaction: arranging small molecules on DNA origami with sub nanometer precision

chemistry is not only the art of regulating studying molecular structure but also a powerful tool for exploring life developing drugs. One by one the synthesis of nanomolecules has changed from a few tens of nanomolecules to a few tens of nanoproteins. In contrast we are relatively lack of means on the scale of sub nanometer to one nanometer. This is the scale of protein-protein interaction protein-protein interaction as a target is the trend of drug development in the future. We are committed to developing new synthetic analytical technologies on this narrow but very important scale.

DNA origami refers to the technology of folding immobilizing a long DNA single str into a specific nanostructure by using multiple short DNA single strs through base complementary pairing. DNA origami structure has a high degree of positioning function designability which allows multiple biomolecules to be fixed on the surface of DNA origami with nano or sub nano resolution. In the past decade DNA origami nanostructures have developed into a multifunctional platform for the study of many biomolecular interactions such as DNA hybridization protein-DNA binding DNA conformation conversion antibody antigen binding etc. The binding of proteins to small molecule ligs is also a very important class of biomolecular interactions which is the core of drug screening fragment based drug discovery (FBDD).

Professor Adrian Keller Zhang Yixin of nanobiomaterials research group School of chemistry University of padbourne Germany have successfully used DNA origami structure as the substrate to realize the assembly of small molecular fragment nanoarrays Atomic force microscopy (AFM) was used to observe the interaction between proteins nanoarrays to study the binding of single dentate bidentate ligs. Studies have shown that the spacer length of ligs linked to DNA origami will affect the spatial combination of the two ligs greatly affect the binding yield. In this context they further explored the effect of small molecule fragment spacing on protein lig binding in this study to adjust the distance of small molecules on DNA origami with sub nano precision. In order to explore the feasibility of this method we established an experimental system for asymmetric bidentate binding of trypsin with small molecular ligs 4-aminobenzamidine (b) 3-iodo-isothiocyanate (I). In the experiment two ligs were bound to the 5 ‘ 3’ ends of two specific DNA segments respectively. The ligs were fixed on DNA origami by DNA self-assembly the binding yield of protein lig was quantified at the single molecule level by atomic force microscopy. The space between the two ligs on the origami can be adjusted by adjusting the geometry of the ligs. The researchers used oxdna2 coarse particle model for molecular dynamics simulation combined with single molecule AFM detection of the binding yield found the best lig arrangement in the bidentate coordination system pointed out that the bidentate binding yield of trypsin was strongly affected by the lig spacing on the DNA origami at the two-dimensional interface. The local microenvironment of DNA origami surface may also affect the binding of trypsin to ligs. Considering the experimental results of protein lig interaction in solution phase (micro thermophoresis MST) the researchers found that although trypsin has non-specific interaction with DNA origami the interference of non-specific binding in three-dimensional space can be greatly suppressed in two-dimensional interface.

to sum up this paper reported the effect of small molecule lig distance on protein lig interaction explored the feasibility of adjusting lig spacing in sub meter precision.

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