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Abstract Single‐stranded DNA (ssDNA) plays a pivotal role in both nanotechnology and various biological processes. Many processes and applications can be better understood with enhanced structural characterization of ssDNA; however, the dynamic nature of the molecule makes accurate characterization with atomistic resolution extremely difficult. This study uses a method that integrates experimental small‐angle X‐ray scatter (SAXS) data and molecular modeling data using a genetic algorithm (GA) to predict an all‐atom conformational ensemble of ssDNA. The results of this study also validate the performance of various AMBER force fields and implicit solvent models for ssDNA. Overall, the results are able to determine the most accurate atomistic representation of poly‐Thymine (polyT) in solution to date that closely matches the experimental SAXS observations enabling a better understanding of the behavior of ssDNA in solution. 

RNA-based therapeutics hold a great promise in treating a variety of diseases. However, double-stranded RNAs (dsRNAs) are inherently unstable, highly charged, and stiff macromolecules that require a delivery vehicle. Cationic ligand functionalized gold nanoparticles (AuNPs) are able to compact nucleic acids and assist in RNA delivery. Here, we use large-scale all-atom molecular dynamics simulations to show that correlations between ligand length, metal core size, and ligand excess free volume control the ability of nanoparticles to bend dsRNA far below its persistence length. The analysis of ammonium binding sites showed that longer ligands that bind deep within the major groove did not cause bending. By limiting ligand length and, thus, excess free volume, we have designed nanoparticles with controlled internal binding to RNA's major groove. NPs that are able to induce RNA bending cause a periodic variation in RNA's major groove width. Density functional theory studies on smaller models support large-scale simulations. Our results are expected to have significant implications in packaging of nucleic acids for their applications in nanotechnology and gene delivery.