Influence of Surface Ligand Molecular Structure on Phospholipid Membrane Disruption by Cationic Nanoparticles.

Cationic nanoparticles are known to interact with biological membranes and often cause serious membrane damage. Therefore, it is important to understand the molecular mechanism for such interactions and the factors that impact the degree of membrane damage. Previously, we have demonstrated that spatial distribution of molecular charge at cationic nanoparticle surfaces plays an important role in determining the cellular uptake and membrane damage of these nanoparticles. In this work, using diamond nanoparticles (DNPs) functionalized with five different amine-based surface ligands and small phospholipid unilamellar vesicles (SUVs), we further investigate how chemical features and conformational flexibility of surface ligands impact nanoparticle/membrane interactions. 31P-NMR T2 relaxation measurements quantify the mobility changes in lipid dynamics upon exposing the SUVs to functional DNPs, and coarse-grained molecular dynamics simulations further elucidate molecular details for the different modes of DNP-SUV interactions depending on the surface ligands. Collectively, our results show that the length of the hydrophobic segment and conformational flexibility of surface ligands are two key factors that dictate the degree of membrane damage by the DNP, while the amount of surface charge alone is not predictive of the strength of interaction.

Interfacial water and ion distribution determine ζ potential and binding affinity of nanoparticles to biomolecules.

The molecular features that dictate interactions between functionalized nanoparticles and biomolecules are not well understood. This is in part because for highly charged nanoparticles in solution, establishing a clear connection between the molecular features of surface ligands and common experimental observables such as ζ potential requires going beyond the classical models based on continuum and mean field models. Motivated by these considerations, molecular dynamics simulations are used to probe the electrostatic properties of functionalized gold nanoparticles and their interaction with a charged peptide in salt solutions. Counterions are observed to screen the bare ligand charge to a significant degree even at the moderate salt concentration of 50 mM. As a result, the apparent charge density and ζ potential are largely insensitive to the bare ligand charge densities, which fall in the range of ligand densities typically measured experimentally for gold nanoparticles. While this screening effect was predicted by classical models such as the Manning condensation theory, the magnitudes of the apparent surface charge from microscopic simulations and mean-field models are significantly different. Moreover, our simulations found that the chemical features of the surface ligand (e.g., primary vs. quaternary amines, heterogeneous ligand lengths) modulate the interfacial ion and water distributions and therefore the interfacial potential. The importance of interfacial water is further highlighted by the observation that introducing a fraction of hydrophobic ligands enhances the strength of electrostatic binding of the charged peptide. Finally, the simulations highlight that the electric double layer is perturbed upon binding interactions. As a result, it is the bare charge density rather than the apparent charge density or ζ potential that better correlates with binding affinity of the nanoparticle to a charged peptide. Overall, our study highlights the importance of molecular features of the nanoparticle/water interface and underscores a set of design rules for the modulation of electrostatic driven interactions at nano/bio interfaces.

Molecular Dynamics Simulation of Interaction between Functionalized Nanoparticles with Lipid Membranes: Analysis of Coarse-Grained Models.

We compare atomistic and two popular coarse-grained (POL- and BMW-MARTINI) models by studying the interaction between a cationic gold nanoparticle functionalized with primary alkane amines and a lipid bilayer that consists of either zwitterionic lipids or a mixture of zwitterionic and anionic lipids. In the atomistic simulations, the nanoparticle does not exhibit any notable affinity to the zwitterionic bilayer but readily binds to the 9:1 zwitterionic:anionic bilayer, and nanoparticle adsorption leads to local segregation of anionic lipids and slowing down of their diffusion. At the coarse-grained level, the POL-MARTINI model does not lead to nanoparticle-membrane binding for either bilayer system, while the BMW-MARTINI model leads to nanoparticle binding to both bilayers; with the BMW-MARTINI model, nanoparticle binding leads to much less demixing of zwitterionic and anionic lipids and moderately higher rates of lipid diffusion. Analysis of nanoparticle properties in solution reveals notable discrepancies in the interfacial charge and water distributions at the coarse-grained level that are likely relevant to their limitations in describing binding interactions with other (bio)molecules.

Hydration of diblock copolymer micelles: Effects of hydrophobicity and co-solvent.

Diblock polymer micelles dispersed in an aqueous environment are being actively investigated for various applications, but there is only a qualitative understanding of the effect of the chemical structure on the micelle hydration and water dynamics as these properties are difficult to assess experimentally. Using all-atom molecular dynamics simulations, we investigate aqueous solutions of three comparable in size diblock copolymer micelles with core-forming blocks of different hydrophobicity: polybutadiene (PB), polycaprolactone (PCL), and polytetrahydrofuran (pTHF) with the same hydrophilic block, polyethylene oxide (PEO). We found that core-block hydrophobicity and ability to form hydrogen bonds with water strongly affect the water dynamics near the core: water molecules spend considerably less time in contact with the PB block than with PCL and pTHF blocks. We obtained polymer and solvent volume fraction profiles and determined that the interfacial width systematically increases with a decrease of core block hydrophobicity with water penetration into the core being negligible for PB-PEO and PCL-PEO micelles, while for pTHF-PEO micelles the interface is more diffuse and there is a noticeable penetration of water (17% by volume). For PCL-PEO micelles, which are commonly used in biomedical applications, we also investigated tetrahydrofuran (THF) penetration into the micelles from mixed THF:water solution at early stages of micelle dissolution. We found an inhomogeneous solvent distribution with a maximum of THF volume fraction in the interfacial core-corona region and partial exclusion from the PEO corona, which slows down micelle dissolution. These results can have important implications for micelle stability and use in biomedical applications.

The dynamics of solvation dictates the conformation of polyethylene oxide in aqueous, isobutyric acid and binary solutions.

Polymers hydrogen-bonding with solvent represent an important broad class of polymers, properties of which depend on solvation. Using atomistic molecular dynamics simulations with the OPLS/AA force field we investigate the effect of hydrogen bonding on PEO conformation and chain mobility by comparing its behavior in isobutyric acid and aqueous solutions. In agreement with experimental data, we found that in isobutyric acid PEO forms a rather rigid extended helical structure, while in water it assumes a highly flexible coil conformation. We show that the difference in PEO conformation and flexibility is the result of the hydrogen bond stability and overall solvent dynamics near PEO. Isobutyric acid forms up to one hydrogen bond per repeat unit of PEO and interacts with PEO for a prolonged period of time, thereby stabilizing the helical structure of the polymer and reducing its segmental mobility. In contrast, water forms on average 1.2 hydrogen bonds per repeat unit of PEO (with 60% of water forming a single hydrogen bond and 40% of water forming two hydrogen bonds) and resides near PEO for a noticeably shorter time than isobutyric acid, leading to the well-documented high segmental mobility of PEO in water. We also analyze PEO conformation, hydrogen bonding and segmental mobility in binary water/isobutyric acid solutions and find that in the phase separated region PEO resides in the isobutyric-rich phase forming about 25% of its hydrogen bonds with isobutyric acid and 75% with water. We show that the dynamics of solvation affects the equilibrium properties of macromolecules, such as conformation, and by mixing of hydrogen bond-donating solvents one can significantly alter both polymer conformation and its local dynamics.

Spontaneous Insertion, Helix Formation, and Hydration of Polyethylene Oxide in Carbon Nanotubes.

Hydration strongly affects macromolecular conformation in solution and under nanoconfinement as encountered in nature and nanomaterials. Using atomistic molecular dynamics simulations we demonstrate that polyethylene oxide spontaneously enters single wall carbon nanotubes (CNTs) from aqueous solutions and forms rodlike, helix, and wrapped chain conformations depending on the CNT diameter. We show that water organization and the stability of the polyethylene oxide hydration shell under confinement is responsible for the helix formation, which can have significant implications for nanomaterial design.