Oral Defense of Doctoral Dissertation Modeling and Simulation of Polymeric Macromolecules
Jan 15, 2021, 11:00 AM - 12:30 PM
Oral Defense of Doctoral Dissertation Doctor of Philosophy in Computational Sciences and Informatics
Department of Computational and Data Sciences
College of Science
George Mason University
Modeling and Simulation of Polymeric Macromolecules
Bachelor of Arts, Hood College, 2013
All are invited to attend.
Meeting ID: 971 2031 5336
Poly-lactic-co-glycolic acid (PLGA) is a biodegradable co-polymer with common use in nanoparticle drug encapsulation and delivery. Although its extensive empirical use, the mechanical behavior of PLGA is not well understood at the atomic level. My dissertation research centers around the study of PLGA using molecular modeling techniques with the final goal of describing the mechanism by which macromolecular entities adhere to the nanoparticle surface interfacing with various solvents.
To achieve my goal I have studied first the solvent effects that promote preferred solvated structures of PLGA with 50:50 ratio of lactic acid to glycolic acid components with various molecular weights in ethyl acetate, water, and a mixture of both solvents. We develop new parametrization for the all-atom Generalized Amber Force Field (GAFF) and conduct explicit solvent molecular dynamics simulations for inspection of the solvated polymer structures at ambient conditions. Our novel parametrization simulates with excellence the liquid phase-separation between ethyl acetate and water, a phenomenon extremely challenging to simulate. The energetics, polymer radius of gyration, end-to-end distance, orientational order parameter, flexibility coefficient, and backbone dihedral angles are reported along with a size scaling property yielding a power law for PLGA polymer chains in each of the three solvents considered. It is found that the PLGA polymer chains have two characteristic states identified by a set of extended chain structures and a set of collapsed ball-like structures, the former being energetically preferred in ethyl acetate and its mixture with water. In contrast, chains collapse into a cluster-like compact structure when solvated in water. Our analysis and findings are the first of their nature appearing in the scientific literature.
Our second pursued advance was the investigation of PLGA in its condensed glassy phases. Here, we conduct all-atom molecular dynamics simulations of PLGA 50:50 ratio for five samples of the polymer condensed phases that span 1579 u to 20183 u in molecular weight. We predict several PLGA thermodynamic properties that will improve the knowledge of its atomistic organization in the glassy solid, rubber, and liquid states. We report the impact of molecular weight on cohesive energy, solubility, thermodynamic response properties, structural properties related to chain entanglement, and glass transition temperatures. Properties are compared against known experimental values when available. We find that the restrained electrostatic potential atomic charges used in GAFF are superior for simulating the polymer caloric curve across the 200-500 K temperature range yielding a glass transition temperature in excellent agreement with experiments. Modeling and simulation approaches for recognizing the complex structural motifs of materials such as copolymers are necessary to assist on controlling factors that improve the material function in specific settings. It is our expectation that predictions put forward in this dissertation and published accompanying work will entice further experimentation in search of full answers concerning PLGA amorphous structure and internal chain entanglement.
As a third and final stage of our work, we explore the formation of macromolecular patches on the surface of the PLGA nanoparticles interfacing with various solvents. Thus, we perform all-atom, explicit solvent, molecular dynamics simulations on a block of PLGA in its glassy solid state interfacing with water, ethyl acetate, and their solvent mixture. In addition we model and simulate the formation of PEGylated DSPE (DSPE-PEG) patches onto the PLGA surface. We characterize in detail the interface PLGA-solvent and follow in time the deposition of the DSPE-PEG macromolecules onto the PLGA surface forming “droplets” that remain adsorbed to the surface despite the presence of the solvent. These droplets have a preferential hemispherical shape when formed at the interface with PLGA-water and flatten when ethyl acetate is present. A thorough analysis of the interaction energies droplet-PLGA and droplet-solvent indicates that dispersive forces are dominant in the droplet adhesion to the surface while electrostatic forces are dominant for keeping the solvent around the new macromolecular formations. Various 3D contour analyses aid in the prediction of the DSPE-PEG droplet wetting angles with the PLGA surface. We additionally predict that the wetting angle is larger at the water interface and decreases significantly at the ethyl acetate interface. Our predicted mechanism of droplet formation contributes to the development of approaches that tailor the synthesis of nanotherapeutics for specific drug delivery conditions.