**Acknowledgements**

**Figure 10.** Representative conformation of the complex between PAZ domain of the human argonaute 2 (hAgo2) and the chemically modified siRNAs at 3′ overhang, obtained from the last nanoseconds of the MD production runs. Panel A illustrates the relative positioning of domains and interdomain linker of the hAgo2 (using the crystal coordinates of PDB ID: 4F3T) and the positioning of the siRNA antisense strand. Panels **B** and **C** show the most representative structures of the complexes formed between PAZ domain and siRNAs, modified with phosphorothioate thymidine (PS) and L-threoninol-thymine (THR), respectively. PS and THR correspond to the second-last residues of the modified siRNAs while PS3' and THR3' correspond to the last one. Hydrogen-bonding interactions between the siRNA nucleotides and the PAZ amino acid residues are represented in black dash lines. The phosphorus, oxygen, nitrogen, hydrogen and sulfur atoms are colored in yellow, red, blue, white, and green respectively. Panels **D** and **E** correspond to the occupancies of the most prominent hydrogen bonds formed between the PAZ binding pocket and 2-nt modified nucleotides with PS and THR, respectively. The analysis of the instantaneous hydrogen bond formation was obtained using an in-house

**Figure 9.** (A) Structural arrangement of a polyrotaxane formed formed by a poly(ethylene glycol chain included in multiple α-cyclodextrins, (B) definition of the reaction coordinate, ξ, in wich both the geometrically restrained (cyan) and free (red) cyclodextrins are presented. (C) Three possible conformations (HH, HT and TT) showing different spatial arrangements of two consecutive α-cyclodextrin molecules. (D-F) Free-energy profiles corresponding to the dimerization of α-cyclodextrins on the poly(ethylene glycol chain, for the HH, HT and TT conformations. (G-I) Individual cyclodextrin-cyclodextrin, cyclodextrin-water, and cyclodextrin-thread energy contributions for the total free-energy, in the three conformations. Reproduced from Ref. [100] with permission from the American Chemical

algorithm. Adapted from Ref. [108].

Society.

24 Molecular Dynamics

The authors acknowledge the Fundação para a Ciência a Tecnologia (FCT), Portuguese Agency for Scientific Research, through the Projects n. 016648 POCI-01-0145-FEDER-016648 and COMPETE POCI-01-0145-FEDER-007440. The Coimbra Chemistry Centre is also supported by FCT through the Projects PEst-OE/QUI/UI0313/2014 and POCI-01-0145-FEDER-007630. Tânia F.G.G. Cova, Sandra C. C. Nunes and Andreia. F. Jorge acknowledge, respectively, the PhD and post-doctoral research Grants SFRH/BD/95459/2013, SFRH/BPD/71683/2010 and SFRH/BPD/104544/2014, assigned by FCT.
