ABSTRACT
Generation 2 cationic carbosilane dendrimers hold great promise as internalizing agents for gene therapy as they present low toxicity and retain and internalize the genetic material as an oligonucleotide or siRNA. In this work we carried out complete in silico structural and energetical characterization of the interactions of a set of G2 carbosilane dendrimers, showing different affinity towards two single strand oligonucleotide (ODN) sequences in vitro. Our simulations predict that these four dendrimers and the relevant ODN complexes are characterized by similar size and shape, and that the molecule-specific ODN binding ability can be rationalized only by considering a critical molecular design parameter: the normalized effective binding energy ΔG(bind,eff)/N(eff), i.e. the performance of each active individual dendrimer branch directly involved in a binding interaction.
Subject(s)
Dendrimers/chemistry , Oligonucleotides/chemistry , Silanes/chemistry , Cations/chemistry , Molecular Conformation , Molecular Dynamics Simulation , Oligonucleotides/metabolism , RNA, Small Interfering/chemistry , RNA, Small Interfering/metabolism , ThermodynamicsABSTRACT
Due to the relative easy synthesis and commercial availability, nanovectors based on dendrimers and dendrons are among the most utilized non-viral vectors for gene transfer. Contextually, recent advances in molecular simulations and computer architectures not only allow for accurate predictions of many structural, energetical, and eventual self-assembly features of these nanocarriers per se, but are able to yield vital (and perhaps otherwise unattainable) molecular information about the interactions of these nanovectors with their nucleic acid cargoes. In the present work, we aim at reviewing our own efforts in the field of multiscale molecular modeling of these interesting materials. In particular, our originally developed computational recipes will be presented, and the link between simulations and experiments will be described and discussed in detail. This review is written by computational scientists for experimental scientists, with the specific purpose of illustrating the potentiality of these methodologies and the usefulness of multiscale molecular modeling as an innovative and complementary tool in their current research.
