Sharon M. Loverde

Nanoparticle Shape Improves Delivery: Rational Coarse Grain Molecular Dynamics (rCG‐MD) of Taxol in Worm‐Like PEG‐PCL Micelles

Nanoparticle shape can improve drug delivery, based in part on recent fi ndings that fl exible, worm-like nanocarriers (Worms) increase the amount of drug delivered to tumors and shrink the tumors more effectively than spherical micelles (Spheres). Here, all-atom molecular dynamics (MD) simulations are used to build a rational coarse grain (rCG) model that helps clarify shape-dependent effects in delivery of the widely used anticancer drug Taxol by block copolymer micelles. Potentials for rCG-MD were developed to examine the partitioning of this hydrophobic-aromatic drug into Worms and Spheres that selfassemble in water from poly(ethyleneglycol)-poly(caprolactone) (PEG-PCL), a weakly segregating amphiphile. PCL is a biodegradable, hydrophobic polymer widely used in biomaterials and accurately modeled here. Thermodynamic integration of the force to pull a single Taxol molecule from the micelles into solvent shows that twice as much drug loads into Worms than Spheres, fully consistent with experiments. Diffusivity of drug in the hydrated PEG corona is surprisingly slow compared to that in the core, indicative of strong but transient drug-polymer interactions. The distinctly distended corona of the Worms enhances such interactions and refl ects the same balance of molecular forces that underlie an experimentally-validated phase diagram for simulated Spheres, Worms, and Bilayers. Moreover, with realistic drug loadings in micro-second simulations, Taxol is seen to draw PEG chains into the PCL core, dispersing the drug while localizing it near the interface—thus providing a molecular explanation for a measurable burst release of drug as well as the enhanced delivery seen with Worms. Cancer is diagnosed today in about 50% of the population over the average lifetime of a person, with nearly all therapies pushed from bench to bedside based solely on trial-and-error experimentation, particularly when it comes to formulation. Current treatments generally include chemotherapy, and many of the top anticancer drugs in the clinic have a hydrophobic and/or aromatic character that allows them to permeate cell

Molecular Simulation of the Transport of Drugs across Model Membranes

This Perspective describes recent progress in the area of the molecular simulation of the interactions of hydrophobic and hydrophilic solutes with membranes. The ability to predict drug solubility prior to synthesis is an extremely desirable goal for pharmaceutical research. A major advantage of molecular dynamics is the ability to computationally probe both the drug solubility as well as the pathway for the transport of drugs across membranes. Computational methods to predict the interaction free energy of solutes with membranes have advanced significantly in recent years and can characterize the intra- and intermolecular state of the drug as well as perturbations of the drug to the membrane environment itself. In addition to a brief review on computational methods to characterize the transport of drugs across membranes, we will highlight recent discoveries and discuss the challenges and opportunities in the field.

π–π Stacking Mediated Chirality in Functional Supramolecular Filaments

While a great diversity of peptide-based supra-molecular filaments have been reported, the impact of an auxiliary segment on the chiral assembly of peptides remains poorly understood. Herein we report on the formation of chiral filaments by the self-assembly of a peptide-drug conjugate containing an aromatic drug camptothecin (CPT) in a computational study. We find that the chirality of the filament is mediated by the π‒π stacking between CPTs, not only by the well-expected intermolecular hydrogen bonding between peptide segments. Our simulations show that π‒π stacking of CPTs governs the early stages of the self-assembly process, while a hydrogen bonding network starts at a relatively later stage to contribute to the eventual morphology of the filament. Our results also show the possible presence of water within the core of the CPT filament. These results provide very useful guiding principles for the rational design of supramolecular assemblies of peptide conjugates with aromatic segments.

Molecular simulation of the concentration-dependent interaction of hydrophobic drugs with model cellular membranes.

We report here the interactions between a hydrophobic drug and a model cellular membrane at the molecular level using all-atom molecular dynamics simulations of paclitaxel, a hydrophobic cancer drug. The calculated free energy of a single drug across the bilayer interface displays a minimum in the outer hydrophobic zone of the membrane. The transfer free energy shows excellent agreement with reported experimental data. In two sets of long-time simulations of high concentrations of drug in the membrane (12 and 11 mol %), the drugs display substantial clustering and rotation with significant directional preference in their diffusion. The main taxane ring partitions in the outer hydrophobic zone, while the three phenyl rings prefer to be closer to the hydrophobic core of the membrane. The clustering of the drug molecules, order parameters of the lipid tails, and water penetration suggest that the fluidity and permeability of the membrane are affected by the concentration of drugs that it contains. Furthermore, at the high-concentration limit, the free energy minimum shifts closer to the hydrophobic core and the central barrier to cross the membrane decreases. Moreover, the transfer free energy change substantially increases, suggesting that increasing concentration facilitates drug partitioning into the membrane.

Computer simulation of polymer and biopolymer self-assembly for drug delivery

Molecular simulation is an emerging tool to bridge relevant time- and length-scales in self-assembly and interfacial processes in soft matter and biological systems. In this review, we highlight mesoscale and coarse-grained molecular dynamics simulation techniques as applied to poly(ethylene oxide)-based diblock copolymer self-assembly. Moreover, we review recent progress pertaining to diblock copolymer and biopolymer self-assembly, stability, and finally, interactions of hydrophobic drugs with polymer membranes. We expect that these computational investigations should provide a useful complement to experimental studies that address open questions in the field of polymeric drug delivery.

Characterisation of the hydrophobic collapse of polystyrene in water using free energy techniques

Abstract We characterise the hydrophobic collapse of single polystyrene chains in water using molecular dynamics simulations. Specifically, we calculate the potential of mean force for the collapse of a single polystyrene chain in water using metadynamics, comparing the results between all atomistic with coarse-grained (CG) molecular simulation. We next explore the scaling behaviour of the collapsed globular shape at the minimum energy configuration, characterised by the radius of gyration, as a function of chain length. The exponent is close to one third, consistent with that predicted for a polymer chain in bad solvent. We also explore the scaling behaviour of the solvent accessible surface area (SASA) as a function of chain length, finding a similar exponent for both all atomistic and CG simulations. Furthermore, calculation of the local water density as a function of chain length near the minimum energy configuration suggests that intermediate chain lengths are more likely to form dewetted states, as compared to shorter or longer chain lengths.

Asymmetric breathing motions of nucleosomal DNA and the role of histone tails

The most important packing unit of DNA in the eukaryotic cell is the nucleosome. It undergoes large-scale structural re-arrangements during different cell cycles. For example, the disassembly of the nucleosome is one of the key steps for DNA replication, whereas reassembly occurs after replication. Thus, conformational dynamics of the nucleosome is crucial for different DNA metabolic processes. We perform three different sets of atomistic molecular dynamics simulations of the nucleosome core particle at varying degrees of salt conditions for a total of 0.7 μs simulation time. We find that the conformational dynamics of the nucleosomal DNA tails are oppositely correlated from each other during the initial breathing motions. Furthermore, the strength of the interaction of the nucleosomal DNA tail with the neighboring H2A histone tail modulates the conformational state of the nucleosomal DNA tail. With increasing salt concentration, the degree of asymmetry in the conformation of the nucleosomal DNA tails decreases as both tails tend to unwrap. This direct correlation between the asymmetric breathing motions of the DNA tails and the H2A histone tails, and its decrease at higher salt concentrations, may play a significant role in the molecular pathway of unwrapping.

Polymersomes and Filomicelles

Amphiphilic block copolymers represent a major field of research in the design and creation of innovative materials for biomedical applications. Self-directed assemblies of such copolymers have been of great value in the development of novel drug delivery systems. Polymeric vesicles (polymersomes) and worm-like micelles (or filomicelles) are particularly appealing due to their structure and composition that provides them with specific and tunable properties. The work reviewed at an introductory level in this chapter highlights some of the features of such aggregates and reviews the synthesis of their components, their assembly, and characterization. Degradation and drug release kinetics are described as well as their application in therapeutics.

Effect of Nucleotide State on the Protofilament Conformation of Tubulin Octamers

At the molecular level, the dynamic instability (random growth and shrinkage) of the microtubule (MT) is driven by the nucleotide state (GTP vs GDP) in the β subunit of the tubulin dimers at the MT cap. Here, we use large-scale molecular dynamics (MD) simulations and normal-mode analysis (NMA) to characterize the effect of a single GTP cap layer on tubulin octamers composed of two neighboring protofilaments (PFs). We utilize recently reported high-resolution structures of dynamic MTs to simulate a GDP octamer both with and without a single GTP cap layer. We perform multiple replicas of long-time atomistic MD simulations (3 replicas, 0.3 μs for each replica, 0.9 μs for each octamer system, and 1.8 μs total) of both octamers. We observe that a single GTP cap layer induces structural differences in neighboring PFs, finding that one PF possesses a gradual curvature, compared to the second PF which possesses a kinked conformation. This results in either curling or splaying between these PFs. We suggest that this is due to asymmetric strengths of longitudinal contacts between the two PFs. Furthermore, using NMA, we calculate mechanical properties of these octamer systems and find that octamer system with a single GTP cap layer possesses a lower flexural rigidity.

Molecular Dynamics Simulations of Supramolecular Anticancer Nanotubes

We report here on long-time all-atomistic molecular dynamics simulations of functional supramolecular nanotubes composed by the self-assembly of peptide-drug amphiphiles (DAs). These DAs have been shown to possess an inherently high drug loading of the hydrophobic anticancer drug camptothecin. We probe the self-assembly mechanism from random with ∼0.4 μs molecular dynamics simulations. Furthermore, we also computationally characterize the interfacial structure, directionality of π-π stacking, and water dynamics within several peptide-drug nanotubes with diameters consistent with the reported experimental nanotube diameter. Insight gained should inform the future design of these novel anticancer drug delivery systems.