Multiscale Molecular Simulations Applied to Nucleic Acid-Dendrimer Interactions Studies

Dendrimers are monodisperse, regular, three-dimensional and small-scale macromolecules that can be used to release substances such as drugs, markers, and genetic material into the cells. Among these substances, nucleic acids such as plasmid DNA, antisense oligonucleotides (asODN), and small-interfering RNA (siRNA) are widely used as therapeutic macromolecules for the treatment and prevention of diverse diseases. Several studies were focused on the modification of dendrimers aiming to improve their affinity for nucleic acids and their ability to release nucleic acids inside the cells. However, high-generation dendrimers have been shown to provoke leaking of cell membranes due to high surface-charge density. Thereby, despite the high potential of dendrimers, cytotoxicity still represents a problem to be solved prior to future in-vitro and in-vivo applications. Many approaches have proposed the introduction of diverse functional groups in low generation dendrimers, to reduce potential surface-charge density, without a loss in the ability to interact with nucleic acids. Another issue that should be addressed is how to modulate the affinity of dendrimers for nucleic acids at different pH values to guarantee an adequate release of the cargo in endosomal vesicles. These questions may be addressed through the aid of computational chemistry and bioinformatics tools. Therefore, the present review aims to provide a detailed review focused on the several techniques that have been developed for the study and design of dendrimers as carriers for DNA or RNA.As shown in the present review, molecular dynamics simulations can contribute by studying at theoretical level dendrimer-nucleic acid complexes at different conditions, such as pH or ionic strength. Therefore, different cell conditions such as the stay at the cytoplasm and the transit towards endosomes can be addressed. The influence of different terminal groups of dendrimers to DNA/RNA binding can also be evaluated using molecular simulations and especially, by using free energy methods, which aim to determine affinity of dendrimers for nucleic acids. The development of a library of terminal groups for dendrimers may represent a significant contribution to the design of new dendrimers. In this regard, protein-DNA interactions of structure databases have been analyzed as a way to identify suitable residues that can be incorporated as terminal groups of dendrimers. In summary, computational chemistry and biology tools will aim the design of new dendrimers for different kinds of cargo molecules.