Binding Dynamics of siRNA with Selected Lipopeptides: A Computer-Aided Study of the Effect of Lipopeptides’ Functional Groups and Stereoisomerism

Abstract

The engineering issues pertaining to nanoparticle systems toward targeted gene therapies have not been fully probed. Recent experiments have identified specific structural characteristics of a novel class of lipopeptides (LP) that may lead to potent nanocarriers intended as RNAi therapeutics, albeit the molecular mechanism that underlies their performance remains unexplored. We conducted molecular dynamics simulations in atomistic detail coupled with free energy computations to study the dynamics and thermodynamics of an acrylate- and an epoxide-derived LP, members of the aforesaid class, upon their binding to siRNA in aqueous solution aiming at examining structure-potency relations. We found that the entropic part of the free energy of binding predominates; moreover, the first LP class tends to disrupt the Watson–Crick base pairing of siRNA, whereas the latter leaves the double helix intact. Moreover, the identified tug-of-war effect between LP–water and LP–siRNA hydrogen bonding in the supramolecular complex can underpin synthesis routes toward tuning the association dynamics. Our simulations on two diastereomers of the epoxide-derived LP showed significant structural and energetics differences upon binding, as a result of steric effects imposed by the different absolute configurations at their chiral centers. These findings may serve as crucial design parameters toward modulating the interplay between complex stability and ease of releasing the nucleic acid drug into the cell.

A Localized Enantioselective Catalytic Site on Short DNA Sequences and their Amphiphiles

“…Molecular dynamics (MD) simulations for the binding of dmbipy-Cu on two representative sequences: "21" and "21-10, 11" in ionic aqueous solution were conducted (details in SI). 38 The MD simulations show that the dmbipy-Cu complex (Figure S17) in both sequences binds to the minor groove of DNA without intercalating its double helix. As shown from the time evolution of the distance between the dmbipy-Cu and the DNA in Figure S18, the molecules remain bound along the entire equilibrated MD trajectory.…”

Effects of the structure of lipid-based agents in their complexation with a single stranded mRNA fragment: a computational study

“…This starting configuration was preferred against the condensed monolayer or double-layer arrangement of the lipids, on one hand because both of the examined phospholipids were found to form micelle-like aggregates in water and in the absence of RNA under the examined conditions, and on the other hand to facilitate the comparison with the behavior of the diketopiperazine-core molecules which do not form layered phases. 47,77 Although amphiphiles with two hydrocarbon chains per head group are expected to form extended bilayers 78 or vesicles 79 rather than spherical or ellipsoidal micelles in an aquatic environment, micellization is the first stage involved in the relevant self-assembly kinetics. 80,81 In order for the association process to develop towards the formation of these morphologies, a much larger number of lipids than the one used here, would be required.…”

“…Apart from the energetics of the association between mRNA and the complexation agents, another parameter that is known to affect the residence time of a ligand (being ionizable or not) near a nucleic acid fragment, is hydrogen bonding. [104][105][106] It is also associated with the tendency of the ligands (here the complexation agents) to form clusters. 47 To obtain information regarding the formation of hydrogen bonds either between the complexation agents, or between the latter and mRNA, we have performed a hydrogen bonding analysis following characteristic geometric criteria: (1) the distance r between a hydrogen donor and an acceptor, r(DÁ Á ÁA) r 3.5 Å, and (2) the angle HDA r 301, where A and D represent an acceptor and a donor respectively, bonded to a hydrogen (H) atom.…”

A Simulation Study of the Effect of Naturally Occurring Point Mutations on the SRY-DNA Complex

“…The TIP3P water model was employed; randomly selected water molecules were replaced by the appropriate number of Na cations to neutralize the system. For the equilibration of the system, prior to the MD production runs, we followed the equilibration protocol described in our previous work …”