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Structural and Binding Effects of Chemical Modifications on Thrombin Binding Aptamer (TBA)
Vibhav Valsangkar1,2, Sweta Vangaveti2, Goh Woon Lee1,2
1Department of Chemistry, University at Albany, State University of New York, 1400 Washington Avenue, Albany, NY 12222, USA.
Molecules (Basel, Switzerland)
|August 7, 2021
Summary
Chemical modifications to thrombin binding aptamer (TBA) did not significantly alter its G-quadruplex structure or thrombin binding affinity. These findings suggest specific modification sites on TBA that preserve its anticoagulant properties.
Area of Science:
- Biochemistry
- Molecular Biology
- Biotechnology
Background:
- Thrombin binding aptamer (TBA) is a nucleic acid-based anticoagulant with therapeutic potential.
- Chemical modifications can enhance aptamer properties, but their impact on TBA structure and function requires investigation.
Purpose of the Study:
- To investigate the structural and functional effects of dendrimer Trebler and NHS carboxy group modifications on TBA.
- To identify optimal modification sites on TBA that maintain its thrombin binding affinity and G-quadruplex stability.
Main Methods:
- Solid-phase oligonucleotide synthesis to incorporate chemical modifications into TBA.
- Circular dichroism (CD) spectroscopy to assess G-quadruplex structural integrity.
- Surface plasmon resonance (SPR) to measure binding affinity with thrombin.
- Molecular dynamics (MD) simulations to analyze structural interactions.
Main Results:
- All modified TBA variants maintained stable G-quadruplex structures, confirmed by CD spectroscopy.
- SPR analysis showed minimal changes in binding affinity (KD) between modified TBAs and thrombin compared to native TBA.
- MD simulations suggested that modifications were counteracted by disruptions in TBA-thrombin interactions or internal destabilization.
Conclusions:
- Specific chemical modifications at the 5' end or within the thrombin binding site (T4, T13) do not significantly impair TBA's G-quadruplex structure or thrombin binding.
- The study provides insights into rational design strategies for developing enhanced TBA analogues with improved functionality.
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