Effect of Arginine-Rich Peptide Length on the Structure and Binding Strength of siRNA–Peptide Complexes
2013
Kim, Minwoo | Kim, Hyun Ryoung | Chae, Su Young | Larson, Ronald G. | Lee, Hwankyu | Park, Jae Chan
Heparin decomplexation experiments, as well as all-atom (AA) and coarse-grained (CG) molecular dynamics (MD) simulations, were performed to determine the effect of the size of arginine(Arg)-rich peptides on the structure and binding strength of the siRNA–peptide complex. At a fixed peptide/siRNA mole ratio of 5:1 or 10:1, the siRNA complexes with peptides longer than nine Arg residues are more easily decomplexed by heparin than are those with nine Arg residues. At these mole ratios, peptides longer than nine Arg residues have cationic/anionic charge ratios in excess of unity, and produce more weakly bound complexes than nine Arg residue ones do. AA simulations of mixtures of peptides with a single siRNA show formation of an electrostatically induced complex, and the longer peptides produce a larger complex, but with no significant increase in the number of Arg residues bound to the siRNA. Larger-scale CG-MD simulations show that multiple siRNAs can be linked together by peptides into a large complex, as observed in the experiments. The peptides longer than nine residues, which at mole ratio 5:1 yield a peptide/siRNA charge ratio in excess of unity, include many noninteracting Arg residues, which repel each other electrostatically. This leads to a less dense complex than for 9-residue peptides, which can explain why these longer complexes are more easily decomplexed by heparin molecules, as observed in the experiments. The key role of the charge ratio is supported by simulations that show that, at a mole ratio of 2.5 peptides per siRNA, the longer 18-residue peptide has a charge ratio of roughly unity and also shows a tight complex, just as the 9-residue peptide does at a 5:1 mole ratio, where its charge ratio is also unity.
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