Ability to adapt: different generations of PAMAM dendrimers show different behaviors in binding siRNA

This paper reports a molecular dynamic study to explore the diverse behavior of different generations of poly(amidoamine) (PAMAM) dendrimers in binding siRNA. Our models show good accordance with experimental measurements. Simulations demonstrate that the molecular flexibility of PAMAMs plays a crucial role in the binding event, which is controlled by the modulation between enthalpy and entropy of binding. Importantly, the ability of dendrimers to adapt to siRNA is strongly dependent on the generation and on the pH due to backfolding. While G4 demonstrates good adaptability to siRNA, G6 behaves like a rigid sphere with a consistent loss in the binding affinity. G5 shows a hybrid behavior, maintaining rigid and flexible aspects, with a strong dependence of its properties on the pH. To define the "best binder", the mere energetic definition of binding affinity appears to be no longer effective and a novel concept of "efficiency" should be considered, being the balance between enthalpy and entropy of binding indivisible from the structural flexibility. With this aim, we propose an original criterion to define and rank the ability of these molecules to adapt their structure to bind a charged target.