Abstract
Polymeric nanoparticles, which by virtue of their size (1–1000 nm) are able to penetrate even into cells, are attracting increasing interest in the emerging field of nanomedicine, as devices for, e.g., drugs or vaccines delivery. Because of the involved dimensional scale in the nanoparticle/cell membrane interactions, modeling approaches at molecular level are the natural choice in order to understand the impact of nanoparticle formulation on cellular uptake mechanisms. In this work, the passive permeation across cell membrane of oligomers made of two employed polymers in the biomedical field [poly-D,L-lactic acid (PDLA) and poly(3-hydroxydecanoate) (P3HD)] is investigated at fundamental atomic scale through molecular dynamics simulations. The free energy profile related to membrane crossing is computed adopting umbrella sampling. Passive permeation is also investigated using a coarse-grained model with MARTINI force field, adopting well-tempered metadynamics. Simulation results showed that P3HD permeation is favored with respect to PDLA by virtue of its higher hydrophobicity. The free energy profiles obtained at full atomistic and coarse-grained scale are in good agreement each for P3HD, while only a qualitative agreement was obtained for PDLA. Results suggest that a reparameterization of non-bonded interactions of the adopted MARTINI beads for the oligomer is needed in order to obtain a better agreement with more accurate simulations at atomic scale.
Highlights
The detailed knowledge of drug/membrane interactions plays a key role for the determination of the ADME profile of active compounds
The continuous development and improvement of accurate force fields tailored for lipid bilayers; the reliability of molecular dynamics (MD) simulations outcomes is strongly dependent on the robustness of the chosen force field, whose importance cannot be underestimated
well-tempered metadynamics (WTMD) attracted some interest for the study of the permeation of small molecules, because of its increased computational efficiency with respect to umbrella sampling (US) and to the possibility to add a bias potential to other collective variables (CV) that can play a role in membrane permeation, such as permanent orientation or intramolecular hydrogen bonds (Minozzi et al, 2011; Jambeck and Lyubartsev, 2013; Loverde, 2014; Saeedi et al, 2017)
Summary
The detailed knowledge of drug/membrane interactions plays a key role for the determination of the ADME (adsorption, distribution, metabolism and excretion) profile of active compounds. A lipid bilayer is a heterogeneous environment because of the presence of polar head groups and hydrophobic chains (Nagle and Tristram-Nagle, 2000) These aspects can be accounted for, in detail, by means of simulations at molecular level, which allow developing mechanistic interpretations and models for lipophilic compounds permeation, as widely discussed by Dickson and coworkers (Dickson et al, 2017). The excessive accumulation of degradation products inside cells may lead to adverse effects (Ramot et al, 2016); on the other side, a deeper understanding of the endocytic pathway for nanoparticle uptake can support the experimental design of new and more effective formulations This constitutes the starting point of this work, which is structured as follows. The assessment of the suitability of a coarsegrained model, parameterized on more accurate simulations at atomic scale, is fundamental to investigate the permeation of entire nanoparticles in model membranes, which would not be feasible with full atomistic simulations due to the involved time and length scales
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