Free energy landscape of siRNA-polycation complexation: Elucidating the effect of molecular geometry, polymer flexibility, and charge neutralization

• DOI: 10.1371/journal.pone.0186816
• Publication Date: 2017-10-31T18:05:14Z
• Authors: Gianvito Grasso; Marco Agostino Deriu; Viorica Patrulea; Gerrit Borchard; Michael Möller; Andrea Danani
• Keywords: Polylysine; Metadynamics; Static electricity; Energy landscape; Dispersity; Cationic polymerization

The success of medical threatments with DNA and silencing interference RNA is strongly related to the design efficient delivery technologies. Cationic polymers represent an attractive strategy serve as nucleic-acid carriers envisioned advantages complexation, low cost, ease production, well-defined size, polydispersity index. However, balance between efficacy toxicity (safety) these a challenge in need improvement. With aim designing more effective polycationic-based gene carriers, many parameters such carrier morphology, molecular weight, surface chemistry, flexibility/rigidity ratio be taken into consideration. In present work, binding mechanism three cationic (polyarginine, polylysine polyethyleneimine) model siRNA target computationally investigated at atomistic level. order better understand polycationic carrier-siRNA interactions, replica exchange dynamic simulations were carried out provide exhaustive exploration all possible sites, taking fully account flexibility together presence explicit solvent ions. Moreover, well-tempered metadynamics employed elucidate how geometry, polycation flexibility, charge neutralization affect siRNA-polycations free energy landscape term low-energy modes unbinding barriers. Significant differences among polymer have been detected, revealing advantageous properties polyarginine compared polyethyleneimine.