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Structural Flexibility and Conformation Features of Cyclic Dinucleotides in Aqueous Solutions
Xing Che1, Jun Zhang1, Yanyu Zhu1
1Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, and Biodynamic Optical Imaging Center, Peking University , Beijing 100871, China.
The Journal of Physical Chemistry. B
|February 16, 2016
Summary
Asymmetric cyclic dinucleotides (CDNs) bind STING with higher affinity than symmetric ones due to distinct structural properties. Understanding these structural differences is key for designing effective CDN-based therapeutics.
Area of Science:
- Immunology
- Structural Biology
- Biochemistry
Background:
- Cyclic dinucleotides (CDNs) activate the innate immune system via STING.
- Asymmetric 2'3'-cGAMP exhibits significantly higher binding affinity to STING dimers compared to symmetric CDNs.
- The structural basis for this affinity difference remains poorly understood.
Purpose of the Study:
- To elucidate the structural properties of CDNs that dictate their differential binding affinities to STING.
- To investigate how phosphodiester linkage variations influence CDN structure and STING interaction.
- To provide insights for the rational design of CDN analogs for therapeutic applications.
Main Methods:
- Computational analysis of CDN structural properties, including ribose puckering and backbone conformations.
- Assessment of glycosidic bond conformations and their impact on CDN flexibility.
- Free energy calculations to compare the conformational costs of STING-bound structures.
Main Results:
- Subtle changes in phosphodiester linkages result in distinct CDN structural features.
- Variations in ribose puckering, backbone conformation, and glycosidic linkage influence CDN flexibility.
- The free energy cost for 2'3'-cGAMP to adopt the STING-bound conformation is lower than for symmetric CDNs.
Conclusions:
- CDN structural properties, governed by phosphodiester linkage, directly correlate with STING binding affinity.
- Understanding these structure-affinity relationships is crucial for developing CDN-based vaccine adjuvants.
- The cyclization pattern of CDNs is intrinsically linked to their biological functions and protein interactions.
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