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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) Electrostatic surface map for AMs. Generated using MOE (Molecular Operating Environment, 2013.08, Montreal, Canada). Panels: (i) 0cG, (ii) 0cM, (iii) 1cAR, (iv) 1cT, (v) 1nM, (vi) 1cM, (vii) 2cBM, (viii) PEG. Key: Red, Hydrogen bond Acceptor; Blue, Hydrogen bond Donor. (II) Charge presentation. Final structural arrangement effect on charge presentation: (A) 1cM has the charge center exposed to solution versus (G) 1cS stereoisomer of 1cM has a protected charge group sequestered in a cage like conformation. (A) 1cM, (B) 0cM, (C) 1nM, (D) 0cG, (E) PEG control, (F) 1cAR, (G) 1cS, (H) L-1cT, (I) M-1cT, (J) 2cBM, (K) 0cG-L. Conformations correlate to the structural arrangement of the lowest energy achieved for the run. The green: negative charge; blue: positive charge; pink: neutral carbon capped chain; and yellow: cyclic group.
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jfb-06-00171-f008: (I) Electrostatic surface map for AMs. Generated using MOE (Molecular Operating Environment, 2013.08, Montreal, Canada). Panels: (i) 0cG, (ii) 0cM, (iii) 1cAR, (iv) 1cT, (v) 1nM, (vi) 1cM, (vii) 2cBM, (viii) PEG. Key: Red, Hydrogen bond Acceptor; Blue, Hydrogen bond Donor. (II) Charge presentation. Final structural arrangement effect on charge presentation: (A) 1cM has the charge center exposed to solution versus (G) 1cS stereoisomer of 1cM has a protected charge group sequestered in a cage like conformation. (A) 1cM, (B) 0cM, (C) 1nM, (D) 0cG, (E) PEG control, (F) 1cAR, (G) 1cS, (H) L-1cT, (I) M-1cT, (J) 2cBM, (K) 0cG-L. Conformations correlate to the structural arrangement of the lowest energy achieved for the run. The green: negative charge; blue: positive charge; pink: neutral carbon capped chain; and yellow: cyclic group.

Mentions: Molecular descriptors were generated to encode various physicochemical properties of the AM including spatial organization, chemical composition and stereochemistry. Following filtering and prioritization of descriptors based on their information content, QSAR models were constructed using Partial Least Squares (PLS) regression to predict the AM bioactivity (i.e., rate and extent of mass deposition). A statistically strong correlation (r2 = 0.9,= 0.7) between predicted and observed values of mass deposition was achieved with four PLS terms (latent variables). Values of the mass deposition were predicted for two additional AMs with varying hydrophobic moieties novel to the QSAR model. The predictions were consistent with experimental QCM-D membrane binding in terms of binding rank order. The low-energy conformations reflected the effects of structural changes on conformation and solvent exposure of charge density (Figure 1 and Figure 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) Electrostatic surface map for AMs. Generated using MOE (Molecular Operating Environment, 2013.08, Montreal, Canada). Panels: (i) 0cG, (ii) 0cM, (iii) 1cAR, (iv) 1cT, (v) 1nM, (vi) 1cM, (vii) 2cBM, (viii) PEG. Key: Red, Hydrogen bond Acceptor; Blue, Hydrogen bond Donor. (II) Charge presentation. Final structural arrangement effect on charge presentation: (A) 1cM has the charge center exposed to solution versus (G) 1cS stereoisomer of 1cM has a protected charge group sequestered in a cage like conformation. (A) 1cM, (B) 0cM, (C) 1nM, (D) 0cG, (E) PEG control, (F) 1cAR, (G) 1cS, (H) L-1cT, (I) M-1cT, (J) 2cBM, (K) 0cG-L. Conformations correlate to the structural arrangement of the lowest energy achieved for the run. The green: negative charge; blue: positive charge; pink: neutral carbon capped chain; and yellow: cyclic group.
© Copyright Policy
Related In: Results  -  Collection

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

jfb-06-00171-f008: (I) Electrostatic surface map for AMs. Generated using MOE (Molecular Operating Environment, 2013.08, Montreal, Canada). Panels: (i) 0cG, (ii) 0cM, (iii) 1cAR, (iv) 1cT, (v) 1nM, (vi) 1cM, (vii) 2cBM, (viii) PEG. Key: Red, Hydrogen bond Acceptor; Blue, Hydrogen bond Donor. (II) Charge presentation. Final structural arrangement effect on charge presentation: (A) 1cM has the charge center exposed to solution versus (G) 1cS stereoisomer of 1cM has a protected charge group sequestered in a cage like conformation. (A) 1cM, (B) 0cM, (C) 1nM, (D) 0cG, (E) PEG control, (F) 1cAR, (G) 1cS, (H) L-1cT, (I) M-1cT, (J) 2cBM, (K) 0cG-L. Conformations correlate to the structural arrangement of the lowest energy achieved for the run. The green: negative charge; blue: positive charge; pink: neutral carbon capped chain; and yellow: cyclic group.
Mentions: Molecular descriptors were generated to encode various physicochemical properties of the AM including spatial organization, chemical composition and stereochemistry. Following filtering and prioritization of descriptors based on their information content, QSAR models were constructed using Partial Least Squares (PLS) regression to predict the AM bioactivity (i.e., rate and extent of mass deposition). A statistically strong correlation (r2 = 0.9,= 0.7) between predicted and observed values of mass deposition was achieved with four PLS terms (latent variables). Values of the mass deposition were predicted for two additional AMs with varying hydrophobic moieties novel to the QSAR model. The predictions were consistent with experimental QCM-D membrane binding in terms of binding rank order. The low-energy conformations reflected the effects of structural changes on conformation and solvent exposure of charge density (Figure 1 and Figure 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.