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Carbohydrate-derived amphiphilic macromolecules: a biophysical structural characterization and analysis of binding behaviors to model membranes.

Martin AA, Tomasini M, Kholodovych V, Gu L, Sommerfeld SD, Uhrich KE, Murthy NS, Welsh WJ, Moghe PV - J Funct Biomater (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Rutgers University, Piscataway, 675 Hoes Lane, Piscataway, NJ 08854, USA. adrianamartin7@gmail.com.

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.

No MeSH data available.


Comparison of mass deposition on a supported lipid membrane for AMs at concentration of 1 × 10−6 M.
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jfb-06-00171-f003: Comparison of mass deposition on a supported lipid membrane for AMs at concentration of 1 × 10−6 M.

Mentions: A particularly attractive feature of AMs (Figure 1) as drug delivery and surface modifying agents is their ability to interact with lipid membranes. In the present context, 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. Complications of this task include the necessity of high resolution and anisotropy of the lipid membrane composition. Toward that end, the present study employed an integrated computational-experimental approach to investigate a set of AMs with respect to their interaction with, and binding to, a model lipid bilayer system (Figure 3, Figure 4 and Figure 5). The primary aim was to elucidate key physicochemical features of these AMs that affect their association with biological lipid membranes [8]. The development of a Quantitative SAR (QSAR) model (Figure 6 and Figure 7) has demonstrated satisfactory findings. The present investigation will ultimately guide the rational design of AMs with optimal membrane binding capabilities for therapeutic applications [10,11].


Carbohydrate-derived amphiphilic macromolecules: a biophysical structural characterization and analysis of binding behaviors to model membranes.

Martin AA, Tomasini M, Kholodovych V, Gu L, Sommerfeld SD, Uhrich KE, Murthy NS, Welsh WJ, Moghe PV - J Funct Biomater (2015)

Comparison of mass deposition on a supported lipid membrane for AMs at concentration of 1 × 10−6 M.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493506&req=5

jfb-06-00171-f003: Comparison of mass deposition on a supported lipid membrane for AMs at concentration of 1 × 10−6 M.
Mentions: A particularly attractive feature of AMs (Figure 1) as drug delivery and surface modifying agents is their ability to interact with lipid membranes. In the present context, 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. Complications of this task include the necessity of high resolution and anisotropy of the lipid membrane composition. Toward that end, the present study employed an integrated computational-experimental approach to investigate a set of AMs with respect to their interaction with, and binding to, a model lipid bilayer system (Figure 3, Figure 4 and Figure 5). The primary aim was to elucidate key physicochemical features of these AMs that affect their association with biological lipid membranes [8]. The development of a Quantitative SAR (QSAR) model (Figure 6 and Figure 7) has demonstrated satisfactory findings. The present investigation will ultimately guide the rational design of AMs with optimal membrane binding capabilities for therapeutic applications [10,11].

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Rutgers University, Piscataway, 675 Hoes Lane, Piscataway, NJ 08854, USA. adrianamartin7@gmail.com.

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.

No MeSH data available.