title: Structural Flexibility and Conformation Features of Cyclic Dinucleotides in Aqueous Solutions.
abstract: Cyclic dinucleotides are able to trigger the innate immune system by activating STING. It was found that the binding affinity of asymmetric 2'3'-cGAMP to symmetric dimer of STING is 3 orders of magnitude higher than that of the symmetric 3'3'-cyclic dinucleotides. Such a phenomenon has not been understood yet. Here we show that the subtle changes in phosphodiester linkage of CDNs lead to their distinct structural properties which correspond to the varied binding affinities. 2'-5' and/or 3'-5' linked CDNs adopt specific while different types of ribose puckers and backbone conformations. That ribose conformations and base types have different propensities for anti or syn glycosidic conformations further affects the overall flexibility of CDNs. The counterbalance between backbone ring tension and electrostatic repulsion, both affected by the ring size, also contributes to the different flexibility of CDNs. Our calculations reveal that the free energy cost for 2'3'-cGAMP to adopt the STING-bound structure is smaller than that for 3'3'-cGAMP and cyclic-di-GMP. These findings may serve as a reference for design of CDN-analogues as vaccine adjuvants. Moreover, the cyclization pattern of CDNs closely related to their physiological roles suggests the importance of understanding structural properties in the study of protein-ligand interactions.
authors.affiliation: Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, and Biodynamic Optical Imaging Center, Peking University , Beijing 100871, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Che
authors.affiliation: Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, and Biodynamic Optical Imaging Center, Peking University , Beijing 100871, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, and Biodynamic Optical Imaging Center, Peking University , Beijing 100871, China.
authors.forename: Yanyu
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, and Biodynamic Optical Imaging Center, Peking University , Beijing 100871, China.
authors.forename: Lijiang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, and Biodynamic Optical Imaging Center, Peking University , Beijing 100871, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Quan
authors.affiliation: Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, and Biodynamic Optical Imaging Center, Peking University , Beijing 100871, China.
authors.forename: Yi Qin
authors.initials: YQ
authors.lastname: Gao
mesh_terms: D008024:Ligands; D015394:Molecular Structure; D009712:Nucleotides, Cyclic / Q000737:chemistry*; D012996:Solutions; D014867:Water / Q000737:chemistry*
chemical_list: D008024:Ligands; D009712:Nucleotides, Cyclic; D012996:Solutions; D014867:Water