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.