Peptide-polymer conjugates are versatile molecular building blocks that can self-assemble into well-defined nanostructures with customizable biofunctionality and tunable physical properties for a wide range of biomedical applications. In this dissertation, two structural analogues of peptide-polymer conjugates are discussed: peptide amphiphiles and block copolymers with the difference between their respective domains tailored for specific applications. Self-assembly process of these peptide-polymer conjugates into different nanostructure morphologies is examined via molecular dynamics simulations using our recently developed integrated simulation package, called BioModi (Biomolecular Multiscale Models at UC Irvine). This simulation package consists of coarse-grained models that mimic realistic molecules and molecular interactions of amino acids, nucleic acids, and polymers, yet are simplified enough to allow molecular simulation of large systems over long time scales.

For peptide amphiphiles, emphasis is placed on achieving a fine balance between the two distinct hydrophobic and hydrophilic domains to attain a supramolecular architecture that can serve as a biomimetic hydrogel scaffold for tissue engineering. The role of different environmental factors (e.g. temperature, pH, solvent) on the self-assembly behavior of peptide amphiphiles is elucidated in detail. Our simulations show that under optimal conditions, spontaneously self-assembly results in the formation of cylindrical nanofibers that can switch into spherical micelles in response to a small pH range as similarly observed by in vitro experiments. Moreover, phase diagrams are constructed to identify morphological transitions, and unique self-assembly kinetic mechanisms are characterized. Chemical modification of the peptide amphiphile sequence is investigated and contrasting structural characteristics are observed to correlate with differences in mechanical behavior of the resulting gel.

For block copolymers, the inherent design utilizes a cationic polypeptide conjugated to a synthetic polymer that promotes favorable electrostatic interactions with nucleic acid fragments upon the formation of a polyionic complex as an effective gene carrier. Efficient complexation of block polymers with siRNA is determined via molecular dynamics simulations to be a function of the length of the polymer and the charge density of the system.

Implementation of our newly developed coarse-grained models, BioModi, and insight gained from our simulations will provide key parameters to advance computer-aided design and development of innovative smart biomaterials.

DNA nanotechnology has been a rapidly growing field with many applications in drug delivery, energy, and molecular computing. First, a novel coarse-grained model of DNA is developed for elucidating the effects of sequence and environmental factors on DNA hybridization. This coarse-grained model has been integrated into our recently developed simulation package called BioModi (Biomolecular Multiscale Models at UC Irvine), enabling the study of the molecular interactions of large systems consisting of amino acids, nucleic acids, and polymers over long time scales. Second, for a design of organic nanowires, a DNA base surrogate, perylene-3,4,9,10-tetracarboxylic diimide, is parameterized and simulated via all-atom simulations to understand kinetic mechanisms of stacking and structural arrangement at equilibrium for optimized transfer of electrical charge.

DNA hybridization processes in a crowded environment are investigated using Biomodi. This model has been shown to capture the mechanical and thermal melting properties of DNA as compared to experimental data. Moreover, the effect of sequence, temperature and DNA concentration is elucidated in detail on the self-assembly process of DNA, giving insight to choosing the right environmental conditions for the formation of double helices. Furthermore, DNA hybridization processes demonstrate many kinetic pathways that are dependent on the sequence.

The overlapping π system of stacked natural DNA bases can mediate the transfer of electrical charge over long distances. To enhance such electron transport property, novel nanowires can be designed by replacing the sugar group and natural DNA bases with perylene-3,4,9,10-tetracarboxylic diimides. Therefore, it is necessary to understand the stacking kinetics of such perylenediimide DNA base surrogates and their equilibrium structures. Simulations demonstrate the different kinetic pathways for stacking depending on the length of the nanowire even when the base is PEGylated. Equilibrium structures obtained are shown to be similar to expected structures found in experiments.

Implementation of our newly developed coarse-grained models, BioModi, and insight gained from our simulations will provide key parameters and understanding to advance computer-aided design and development of innovative smart biomaterials. Moreover, our parameterization, simulation and analysis methods developed for DNA base surrogates will enable the creation and design of organic nanowires with enhanced electron transport properties.