Atomic-Scale Molecular Dynamics Simulations of DNA–Polycation Complexes: Two Distinct Binding Patterns

Abstract

Synthetic cationic polymers represent a promising class of delivery vectors for gene therapy. Here, we employ atomistic molecular dynamics simulations to gain insight into the structure and properties of complexes of DNA with four linear polycations: polyethylenimine (PEI), poly-l-lysine (PLL), polyvinylamine (PVA), and polyallylamine (PAA). These polycations differ in their polymer geometries, protonation states, and hydrophobicities of their backbone chains. Overall, our results demonstrate for the first time the existence of two distinct patterns of binding of DNA with polycations. For PEI, PLL, and PAA, the complex is stabilized by the electrostatic attraction between protonated amine groups of the polycation and phosphate groups of DNA. In contrast, PVA demonstrates an alternative binding pattern as it gets embedded into the DNA major groove. It is likely that both the polymer topology and affinity of the backbone chain of PVA to the DNA groove are responsible for such behavior. The differences in binding patterns can have important biomedical implications: embedding PVA into a DNA groove makes it less sensitive to changes in the aqueous environment (pH level, ionic strength, etc.) and could therefore hinder the intracellular release of genetic material from a delivery vector, leading to lower transfection activity.

Structure and dynamics of water in molecular models of hydrated polyvinylamine membranes

“…For this, we employed B3LYP density functional theory 50 with the 6-31G* basis set, followed by the restrained electrostatic potential (RESP) 51 charge fitting using AmberTools. 52 Further investigations revealed that the values obtained are in a good agreement with the partial charges calculated by Kondinskaia et al 53 using a similar methodology. Therefore, for the protonated systems (P20 and P50), rather than performing DFT studies ourselves, we adopted the partial charges provided by Kondinskaia et al 53 Additional details about the model for partial charges and force field parameters can be found in the ESI.…”

CHARMM force field for protonated polyethyleneimine

“…The molecular dynamics (MD) studies of Choudhury et al on the solvation dynamics of linear PEI essentially employed the same Amber FF, without notable improvements. Equally starting from the Amber FF, the partial charges of PEI were derived in the studies of Kondinskaia et al from ab initio calculations on four model trimers by the RESP method.…”

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

“…REMD trajectory at 300K of each molecular system was analyzed to compute the RDF of the polycationic amine nitrogen atoms around O1P and O2P siRNA atoms ( Fig 4A ), in order to investigate the nature of the interactions between protonated amine groups and siRNA phosphate group oxygen atoms, as previously described [ 19 , 20 , 49 ]. The plots reported in Fig 4A are characterized by two different peaks at 2.7 Å and 4.3 Å, in agreement with previous computational observations [ 20 ].…”

“…Several approaches have been applied with success to address this issue, such as Metropolis Monte Carlo [ 42 – 44 ], enveloping distribution sampling [ 45 ], or λ-dynamics [ 46 – 48 ]. However, this work follows the common practice in molecular dynamics [ 19 – 21 , 49 , 50 ] by defining the protonation state at the beginning of the simulation. Further developments of this work may consider to explicitly focus on the dynamic protonation/deprotonation at constant pH in polymer/siRNA complexes.…”

“…In detail, 128 replicas from 300 K to 530 K in NVT ensemble, were simulated for 50 ns, obtaining a cumulative simulation time of 6.5 μs for each system. Shorter simulation time has demonstrated to be effective in correctly describing the interaction between the polycationic chains and nucleic acids [ 19 , 49 ]. Simulated temperatures were distributed following the exponential spacing law as suggested in the literature [ 66 , 67 ], in order to obtain a constant overlap of the potential energy distributions among temperatures ( S1.1 File ).…”