Enhanced Dispersion and Polarization Interactions Achieved through Dithiophosphate Group Incorporation Yield a Dramatic Binding Affinity Increase for an RNA Aptamer-Thrombin Complex

Journal of the American Chemical Society
Martin Egli, Terry P Lybrand

Abstract

Regiospecific replacement of a single phosphate (PO2) by a dithiophosphate (PS2) group in an RNA can dramatically increase its binding affinity for a target protein. Thus, complexes between antithrombin and anti-VEGF RNA aptamers with single dithiophosphate moieties and thrombin and VEGF, respectively, display equilibrium dissociation constants KD of ca. 1 pM, 1000-fold tighter than the native RNA complexes (ca. 1 nM). Inspection of crystal structures of the native and PS2-RNA aptamer:thrombin complexes reveals an RNA-induced fit in the latter. This leads to a close approach between PS2 and the phenyl ring edge of Phe-232 that is surrounded by pairs of lysines and arginines. To better understand the origins of the tighter binding and individual contributions to the interaction energy, we carried out QM calculations with phosphate- and dithiophosphate-benzene and dimethyl phosphate- and dimethyl dithiophosphate-benzene model systems. These calculations demonstrate that the dithiophosphate-benzene interaction is much stronger than the corresponding interaction with phosphate. QM/MM calculations with the full complexes confirmed this finding and support the hypothesis that the electric field generated by basic residues surrounding...Continue Reading

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Citations

May 14, 2021·Beilstein Journal of Organic Chemistry·Christopher LicznerChristopher J Wilds
May 20, 2021·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Mingmei ShenXianwen Kan
Mar 27, 2019·Accounts of Chemical Research·Martin Egli, Muthiah Manoharan
Oct 28, 2019·Analytical Chemistry·Erin Marie McConnellYingfu Li

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