Peptide-ligand binding modeling of siRNA with cell-penetrating peptides.

Alfonso T García-Sosa,Indrek Tulp,Ülo Langel,Kent Langel

doi:10.1155/2014/257040

Abstract

The binding affinity of a series of cell-penetrating peptides (CPP) was modeled through docking and making use of the number of intermolecular hydrogen bonds, lipophilic contacts, and the number of sp3 molecular orbital hybridization carbons. The new ranking of the peptides is consistent with the experimentally determined efficiency in the downregulation of luciferase activity, which includes the peptides' ability to bind and deliver the siRNA into the cell. The predicted structures of the complexes of peptides to siRNA were stable throughout 10 ns long, explicit water molecular dynamics simulations. The stability and binding affinity of peptide-siRNA complexes was related to the sidechains and modifications of the CPPs, with the stearyl and quinoline groups improving affinity and stability. The reranking of the peptides docked to siRNA, together with explicit water molecular dynamics simulations, appears to be well suited to describe and predict the interaction of CPPs with siRNA.

Highlights

Cell-penetrating peptides (CPPs) are short peptide sequences that are able to deliver biologically active cargos into the cell cytoplasm and nucleus by means of their ability to cross cell membranes [1, 2]
The stability and binding affinity of peptide-small interfering ribonucleic acids (siRNA) complexes was related to the sidechains and modifications of the CPPs, with the stearyl and quinoline groups improving affinity and stability
The newly proposed reranking developed in the present study, SusiScore, together with flexible ligand docking and explicit water molecular dynamics simulations appear to be able to describe the interactions of cell-penetrating peptides with siRNA

Summary

Introduction

Cell-penetrating peptides (CPPs) are short (generally five to 40 amino acid) peptide sequences that are able to deliver biologically active cargos into the cell cytoplasm and nucleus by means of their ability to cross cell membranes [1, 2]. To better develop silencing gene technology and its associated benefits, a better understanding of the mechanism in which CPPs bind to genetic material and help introduce it into cells is needed. This would provide suggestions on how to design peptides with better efficiency. Charged (basic) groups on amino acids like lysine and arginine provide features that are helpful for binding to siRNA. The guanidino group on an arginine residue is especially valuable in binding nucleic acids, given that it can perform electrostatic, hydrogen bond, cation-π, and π-π interactions.

Methods

Results

Conclusion