Abstract
The design and synthesis of enhanced membrane-intercalating biomaterials for drug delivery or vascular membrane targeting is currently challenged by the lack of screening and prediction tools. The present work demonstrates the generation of a Quantitative Structural Activity Relationship model (QSAR) to make a priori predictions. Amphiphilic macromolecules (AMs) “stealth lipids” built on aldaric and uronic acids frameworks attached to poly(ethylene glycol) (PEG) polymer tails were developed to form self-assembling micelles. In the present study, a defined set of novel AM structures were investigated in terms of their binding to lipid membrane bilayers using Quartz Crystal Microbalance with Dissipation (QCM-D) experiments coupled with computational coarse-grained molecular dynamics (CG MD) and all-atom MD (AA MD) simulations. The CG MD simulations capture the insertion dynamics of the AM lipophilic backbones into the lipid bilayer with the PEGylated tail directed into bulk water. QCM-D measurements with Voigt viscoelastic model analysis enabled the quantitation of the mass gain and rate of interaction between the AM and the lipid bilayer surface. Thus, this study yielded insights about variations in the functional activity of AM materials with minute compositional or stereochemical differences based on membrane binding, which has translational potential for transplanting these materials in vivo. More broadly, it demonstrates an integrated computational-experimental approach, which can offer a promising strategy for the in silico design and screening of therapeutic candidate materials.
Highlights
Membrane lipid bilayers provide a natural environment for the immobilization and entrapment of bioactive small molecules and macromolecules
Quartz Crystal Microbalance with Dissipation (QCM-D) experiments and coarse-grained molecular dynamics (CG molecular dynamics (MD)) simulations were performed on each amphiphilic macromolecules (AMs), providing the input data to build a preliminary Quantitative Structural Activity Relationship model (QSAR) model
Values of the mass deposition were predicted for two additional AMs with varying hydrophobic moieties novel to the QSAR model
Summary
Membrane lipid bilayers provide a natural environment for the immobilization and entrapment of bioactive small molecules and macromolecules. The present study describes the evaluation of a focused set of AMs (Figure 1) in terms of their interaction with and binding to a model lipid membrane bilayer [5,6,7] These AMs were originally developed as delivery systems, with the designed feature of spontaneous micelle formation in aqueous solution [6]. Computational molecular simulations of multicomponent ensembles entail methods in which AMs are judiciously placed above model lipid bilayer membranes (Figure 2) This provides a powerful tool for probing the fundamental intermolecular interactions between the AMs and lipid bilayers. QCM-D experiments and CG MD simulations were performed on each AM, providing the input data to build a preliminary QSAR model This method identified key physicochemical features (known as molecular descriptors) of the AMs in relation to percent mass deposition on model lipid membranes. It provides the molecular-level resolution of AA MD simulations required for descriptor generation and detailed analysis of AM-membrane interactions [17,18,19,20]
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