Probing the Binding Interactions between Chemically Modified siRNAs and Human Argonaute 2 Using Microsecond Molecular Dynamics Simulations

The use of chemical modifications in small interfering RNAs (siRNAs) is warranted to impart drug-like properties. However, certain chemical modifications especially those on the sugar have deleterious effects on the RNA interference (RNAi) when they are placed at key positions in the seed region of an siRNA guide strand. In order to probe the effect of chemically modified siRNAs [(2′-O-methyl, 4′-C-aminomethyl-2′-O-methyl, 2′-O-(2-methoxyethyl), and 2′-O-benzyl] on human Argonaute 2 (hAGO2), the catalytic engine of RNAi, we have developed a model of its open conformation. Results from microsecond MD simulations of 15 different siRNA−hAGO2 complexes provide insights about how the key noncovalent interactions and conformational changes at the seed region are modulated, depending upon the nature and position of chemical modifications. Such modification induced structural changes can affect siRNA loading into hAGO2, which may influence RNAi activity. Our studies show that microsecond MD simulations can provide useful information for the design of therapeutically relevant siRNAs.