The simulation of large molecular systems remains a daunting challenge, which justifies the exploration of novel methodologies to keep computers as an ideal companion tool for everyday laboratory work. Whole micelles, bigger than 20 nm in size, formed by the self-assembly of hundreds of copolymers containing more than 50 repeating units, have until now rarely been simulated, due to a lack of computational power. Therefore, a flexible amphiphilic triblock copolymer (mPEG45-α-PLL10-PLA25) containing a total of 80 repeating units, has been emulated and synthesized to embody compactified nanoconstructs of over 900 assembled copolymers, sized between 80 and 100 nm, for siRNA complexing purposes. In this study, the tailored triblock copolymers containing a controlled number of amino groups, were used as a support model to address the binding behavior of STAT3-siRNA, in the formation of micelleplexes. Since increasingly complex drug delivery systems require an ever more optimized physicochemical characterization, a converging description has been implemented by a combination of experimentation and computational simulations. The computational data were advantageous in allowing for the assumption of an optimal N/P ratio favoring both conformational rigidifications of STAT3-siRNA with low competitive phenomena at the binding sites of the micellar carriers. These calculations were consistent with the experimental data showing that an N/P ratio of 1.5 resulted in a sufficient amount of complexed STAT3-siRNA with an electrical potential at the slipping plane of the nanopharmaceuticals, close to the charge neutralization.
Keywords: binding affinity; capillary zone electrophoresis; complexation efficiency; isothermal titration calorimetry; molecular dynamics; polymeric micelles.