title: Understanding the effect of polylysine architecture on DNA binding using molecular dynamics simulations.
abstract: Polycations with varying chemistries and architectures have been synthesized and used in DNA transfection. In this paper we connect poly-L-lysine (PLL) architecture to DNA-binding strength, and in turn transfection efficiency, since experiments have shown that graft-type oligolysine architectures [e.g., poly(cyclooctene-g-oligolysine)] exhibit higher transfection efficiency than linear PLL. We use atomistic molecular dynamics simulations to study structural and thermodynamic effects of polycation-DNA binding for linear PLL and grafted oligolysines of varying graft lengths. Structurally, linear PLL binds in a concerted manner, while each oligolysine graft binds independently of its neighbors in the grafted architecture. Additionally, the presence of a hydrophobic backbone in the grafted architecture weakens binding to DNA compared to linear PLL. The binding free energy varies nonmonotonically with the graft length primarily due to entropic contributions. The binding free energy normalized to the number of bound amines is similar between the grafted and linear architectures at the largest (Poly5) and smallest (Poly2) graft length and stronger than the intermediate graft lengths (Poly3 and Poly4). These trends agree with experimental results that show higher transfection efficiency for Poly3 and Poly4 grafted oligolysines than for Poly5, Poly2, and linear PLL.
authors.affiliation: Department of Chemical and Biological Engineering, University of Colorado at Boulder, Colorado 80309, United States.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Elder
authors.forename: Todd
authors.initials: T
authors.lastname: Emrick
authors.forename: Arthi
authors.initials: A
authors.lastname: Jayaraman
mesh_terms: D000465:Algorithms; D004247:DNA / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D011107:Polylysine / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D011107:Polylysine; D004247:DNA