Molecular Dynamics Simulations of Self-Assemblies in Nature and Nanotechnology

Nature usually divides complex systems into smaller building blocks specializing in a few tasks since one entity cannot achieve everything. Therefore, self-assembly is a robust tool exploited by Nature to build hierarchical systems that accomplish unique functions. The cell membrane distinguishes itself as an example of Nature’s self-assembly, defining and protecting the cell. By mimicking Nature’s designs using synthetically designed self-assemblies, researchers with advanced nanotechnological comprehension can manipulate these synthetic self-assemblies to improve many aspects of modern medicine and materials science. Understanding the competing underlying molecular interactions in self-assembly is always of interest to the academic scientific community and industry. This dissertation uses molecular dynamics (MD) simulations with free energy techniques, such as the Adaptive Biasing Force (ABF) methodology as well as Metadynamics (METAD), to elucidate the molecular interactions that drive self-assembly in Nature and nanotechnology. In the pharmaceutical industry, drug permeation and diffusion through the cell membrane is recognized as one of the most challenging barriers. Thus, an effective way of predicting such drug partitioning can provide insight how to engineer novel delivery agents. Using the ABF method to enhance sampling of the transportation of an anticancer drug Camptothecin across multiple interfaces (octanol bilayer, a thick octanol/water interface, and a model 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (POPC)/water interface), we investigate the enthalpic and entropic contributions to the transfer free energy profile. We also observe that membrane-drug and drug-drug interactions affect the rotational drug entropy. We calculate a partition coefficient that agrees with experimental data. Furthermore, long-time MD simulations of high concentrations of Camptothecin show crystalline drugs formed above model POPC bilayers. Moreover, only singular drugs penetrate the head group region. There is a strong competition between the drug-membrane and drug-drug interaction, preventing large clusters of drugs from breaching the cell membrane simultaneously. Switching gears to biomedical applications of nanotechnology, we characterize the long-time dynamics and interactions of peptide-based Drug Amphiphiles (DAs) with model cellular membranes. DAs yield a better pharmacokinetic profile than free Camptothecin because DAs can self-assemble into nanofilaments or nanotubes (diameter ~ 6-10 nm), which strongly impacts the circulation time and the efficacy of the drug. Moreover, the self-assembled morphology is known to be dictated by the number of conjugated drugs. We performed MD simulations (up to 25 µs) to investigate and characterize the molecular interactions between the DAs and POPC membrane bilayers. Our results conclude that the intrinsic filamentous design of DAs causes repulsion in membrane-DAs interactions. However, the results also suggest hydrogen bonding density as the modulator that promotes the DA\u27s penetration. Altogether, these results suggest methods to improve the rational design of peptide-based drug delivery vehicles. Another class of peptide-based delivery agent is known as “Tubustecan.” This generation of DA system also self-assembles into nanotubes. In mass production, these DAs\u27 nucleation/self-assembly process is crucial in controlling their production and purity. Electrostatics and van de Waal interactions are the main protagonists in the assembly process, yet they are difficult to characterize experimentally. Here we utilize enhanced sampling methods in molecular dynamics using a reaction coordinate based on drug positions to promote the structural reorganization of these DAs into a Tubustecan droplet. Our results indicate that the polyethylene glycol tail disrupts the intrinsic π-π stacking of Camptothecin. Moreover, we demonstrated that our choice of reaction coordinates in conjunction with Metadynamics encourages drug rearrangement. Ultimately, we observed high-density droplets, followed by ordered droplet formation, suggesting that PAs\u27 nucleation has multiple steps and follows the “two-step mechanism” for crystalline growth