Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 144, Issue 10, Pages 4507-4514Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.1c12593
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Funding
- NSFC [22134005, 21974111]
- NSF [2025187, 2107393]
- Chongqing Research Program of Basic Research and Frontier Technology [cstc2020jcyjmsxmX0947, cstc2021jcyjmsxmX1033, msxmX0931]
- Chongqing Talents Program for Outstanding Scientists [cstc2021ycjh-bgzxm 0178]
- Venture & Innovation Support Program for Chongqing Overseas Returnees [cx2018088]
- Division of Computing and Communication Foundations
- Direct For Computer & Info Scie & Enginr [2107393] Funding Source: National Science Foundation
- Div Of Civil, Mechanical, & Manufact Inn
- Directorate For Engineering [2025187] Funding Source: National Science Foundation
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Multivalent interaction is commonly used in molecular design to enhance binding avidities. However, there are currently no general design rules for constructing a simple and rigid DNA scaffold to join multiple ligands. This study presents a crystal structure-guided strategy for the rational design of a rigid bivalent aptamer, allowing precise control over spatial separation and orientation. The enhanced binding observed in this study suggests that this strategy may have broad applicability in designing multivalent aptamers.
Multivalent interaction is often used in molecular design and leads to engineered multivalent ligands with increased binding avidities toward target molecules. The resulting binding avidity relies critically on the rigid scaffold that joins multiple ligands as the scaffold controls the relative spatial positions and orientations toward target molecules. Currently, no general design rules exist to construct a simple and rigid DNA scaffold for properly joining multiple ligands. Herein, we report a crystal structure-guided strategy for the rational design of a rigid bivalent aptamer with precise control over spatial separation and orientation. Such a pre-organization allows the two aptamer moieties simultaneously to bind to the target protein at their native conformations. The bivalent aptamer binding has been extensively characterized, and an enhanced binding has been clearly observed. This strategy, we believe, could potentially be generally applicable to design multivalent aptamers.
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