Computational and Experimental Analyses Converge to Reveal a Coherent Yet Malleable Aptamer Structure That Controls Chemical Reactivity

TitleComputational and Experimental Analyses Converge to Reveal a Coherent Yet Malleable Aptamer Structure That Controls Chemical Reactivity
Publication TypeJournal Article
Year of Publication2009
AuthorsWang TJ, Hoy JA, Lamm MH, Nilsen-Hamilton M
Journal TitleJournal of the American Chemical Society
Volume131
Pages14747-14755
Date Published10/21
ISBN Number0002-7863
Accession NumberISI:000271271800046
Keywordsb6c3f(1) mice, binding mechanism, induced-fit, leucomalachite green, ligand-binding, malachite green, molecular-dynamics, recognition, resolution, rna dynamics
Abstract

As short nucleic acids, aptamers in solution are believed to be structurally flexible Consistent with this view, most aptamers examined for this property have been shown to bind their target molecules by mechanisms that can be described as "induced fit". But, it is not known to what extent this. structural flexibility affects the integrity of the target-aptamer interaction Using the malachite green aptarner (MGA) as a model system, we show that the MGA can protect its bound target, malachite green (MG), from oxidation over several days Protection is reversed by an oligonucleotide complementary to the MGA binding pocket. Computational cavity analysis of the MGA-MG structure predicted that IVIG oxidation is protected because a molecule as small as an OH- is sterically excluded from the C1 position of the bound IVIG These results suggest that, while the MGA-MG interface is sufficiently coherent to prevent OH- penetration, the bases involved in the interaction are sufficiently mobile that they can exchange out of the IVIG binding interface to hybridize with a complementary oligonucleotide The computational predictions were confirmed experimentally using variants of the MGA with single base changes in the binding pocket. This work demonstrates the successful application of molecular dynamics simulations and cavity analysis in determining the effects of sequence variations on the structure of a small single-stranded nucleic acid It also shows that a nucleic acid aptamer can control access to specific chemical groups on its target, which suggests that aptamers might be applied for selectively protecting small molecules from modification

URL<Go to ISI>://000271271800046
DOI10.1021/Ja902719q