To observe which protein residues and RNA nucleotides have the highest effect on the first PC, we listed the top 10 residues based on their absolute PC weight (Figure , right panel and Supplementary Information Table ). The first PC is heavily affected by the flexible loop around residue 830 in the Amber and AMOEBA force fields. Except for ff19SB+OL3, high weights are observed on residues around 300 which contains the second most flexible region in the AGO2 system, the PAZ domain that binds the 3' end of the RNA. ff19SB+OL3 and O3P simulations are the only simulations where one or two RNA atoms make it into the top weighing residues for PC1. In O3P simulations, the highest contributions are from either of the terminals of the protein which are also fluctuating more than in the other conditions. The N-terminal residues are also important for the AMOEBA PC1.