Polymer Structure In Solution For Drug Delivery From Simulation and Experiment

Abstract

To achieve accurate determination of macromolecular structures, combination of experimental and computational efforts often requires. Wide-angle neutron scattering (WANS) opens up avenues to accurately measure the positions of atoms within a material, enabling the precise mapping of atomic structures. In this thesis, molecular dynamic simulations beside small-angle neutron scattering (SANS) and Near and InterMediate Range Order Diffractometer (NIMROD) at ISIS facility were used to investigate polyethylene glycol (PEG) and Polyvinylpyrrolidone (PVP) in dilute solutions. This involves validation of force fields (OPLS-AA, CHARMM, AMBER) for both (molecules and water) and timescale. A good agreement in the radius of gyration value was achieved between the experimental SANS, ≈26 ± 2.5 Å, and MD, ≈22 ± 3.2 Å, data for PEG (13,000 g/mol) using OPLS- AA/TIP3P models. A further improvement in the radius of gyration, ≈ 25 ± 6 Å, was obtained using a simulation box with similar experimental concentration. However, the discrepancy of the radius of gyration value for PVP (10,000 g/mol) between the SANS, ≈ 19 ± 2.5 Å, and MD, ≈ 14 ± 0.5 Å data was observed even with the simulation box applied the experimental concentration. This resulted in the last chapter of this thesis using the SANS-driven MD methods, which can overcome the inaccuracies of the force fields and account for the hydration layer that affects the radius of gyration value. A better SANS fit was obtained for PVP than for PEG. This is due to the chain flexibility movement for PEG, which demanded a long simulation period to investigate several conformations while simultaneously calculating and fitting the scattering curve into the experimental data. The higher number of water molecules in the solvation shell of PEG indicates that it is more soluble in water than PVP. The application of the SANS-driven MD method confirms that the hydration layer can indeed have an impact on the radius of gyrations, particularly for PVP. Using MD simulation in the Dissolve program, the total neutron scattering (NIMROD) for the both mentioned polymers was examined. This study represents the initial endeavor to utilize the Dissolve to determine highly localised structure of polymers in solution from the total neutron scattering data. After using the Empirical Potential Structural Refinement method (EPSR) and adjusting the water geometry, a good agreement was obtained between the calculated and experimental total weighted neutron structure F(q) and weighted neutron radial distribution function G(r), especially for the deuterated solvent samples. The position of atoms within a material, including bond lengths and angles between atoms, can be determined using Dissolve. However, Dissolve is currently under development and requires improvements in various areas, particularly the timestep.