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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.


(I) Chemical structure of carbohydrate-based backbone versions of amphiphilic macromolecules (AMs), variations include the polarity of the head group (–COOH, NH2), number of aliphatic side chains, and aromaticity; (II) Simulation beads composed of heavy atoms represented using CG MARTINI force field developed by Marrink et al. [9]. The bead types are as follows: Q—charged; P—polar; N—non-polar; C—apolar; n or x refers to 113 units of poly(ethylene glycol) and truncated PEG length of 45 used to reduce computational cost for the molecular dynamics studies.
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jfb-06-00171-f001: (I) Chemical structure of carbohydrate-based backbone versions of amphiphilic macromolecules (AMs), variations include the polarity of the head group (–COOH, NH2), number of aliphatic side chains, and aromaticity; (II) Simulation beads composed of heavy atoms represented using CG MARTINI force field developed by Marrink et al. [9]. The bead types are as follows: Q—charged; P—polar; N—non-polar; C—apolar; n or x refers to 113 units of poly(ethylene glycol) and truncated PEG length of 45 used to reduce computational cost for the molecular dynamics studies.

Mentions: The recent development of experimental methods to measure relevant features of permeation and partition into lipid bilayers has advanced the ability of scientists to design and fine tune biological 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]. More recently, studies from our laboratories have established AMs can bind to scavenger receptors and thus block oxidized low-density lipoprotein interaction, thereby mitigating downstream consequences of initial cellular insult [5,8].


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)

(I) Chemical structure of carbohydrate-based backbone versions of amphiphilic macromolecules (AMs), variations include the polarity of the head group (–COOH, NH2), number of aliphatic side chains, and aromaticity; (II) Simulation beads composed of heavy atoms represented using CG MARTINI force field developed by Marrink et al. [9]. The bead types are as follows: Q—charged; P—polar; N—non-polar; C—apolar; n or x refers to 113 units of poly(ethylene glycol) and truncated PEG length of 45 used to reduce computational cost for the molecular dynamics studies.
© Copyright Policy
Related In: Results  -  Collection

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

jfb-06-00171-f001: (I) Chemical structure of carbohydrate-based backbone versions of amphiphilic macromolecules (AMs), variations include the polarity of the head group (–COOH, NH2), number of aliphatic side chains, and aromaticity; (II) Simulation beads composed of heavy atoms represented using CG MARTINI force field developed by Marrink et al. [9]. The bead types are as follows: Q—charged; P—polar; N—non-polar; C—apolar; n or x refers to 113 units of poly(ethylene glycol) and truncated PEG length of 45 used to reduce computational cost for the molecular dynamics studies.
Mentions: The recent development of experimental methods to measure relevant features of permeation and partition into lipid bilayers has advanced the ability of scientists to design and fine tune biological 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]. More recently, studies from our laboratories have established AMs can bind to scavenger receptors and thus block oxidized low-density lipoprotein interaction, thereby mitigating downstream consequences of initial cellular insult [5,8].

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.