In this work, we present a molecular dynamics study to gain an insight into the binding of nucleic acids with spermine functionalized dendrons. We compare UV-degradable dendrons with nondegradable dendrons studied in our previous works. These two dendritic architectures have the same functional surface; however, the branching scaffold exhibits different flexibilities. Here, we explore how the different branching scaffolds influence the ability to interact with DNA and siRNA. The free energies of binding, calculated with the well-known molecular mechanics Poisson-Boltzmann surface area method, are in good accordance with the experimentally observed binding behavior, demonstrating that the theoretical models are reliable and deliver an accurate description of the systems. In general, the interaction of dendrons with the more flexible siRNA is higher than with rigid double-stranded DNA. Importantly, while binding enthalpy best describes the attraction in general--being in direct relationship with the number of opposite charges interacting in the system--binding entropy is correlated with the distribution of these interactions along the binding interface. Higher uniformity in the binding allows it to maintain a strong enthalpic attraction toward the nucleic acid at lower entropic cost. This entropic cost is due to a loss of degrees of freedom in binding, which is related to the nonuniformity in the energetic contribution of the individual ligands. These findings suggest that the estimation of the pure attraction is not enough to fully understand the binding, but also, information about how this attraction is distributed is needed. This proposes new criteria in the design of DNA and siRNA binding agents.