Biomolecular simulation protocols enabling effective peptide therapeutic design: model validation and optimization

dissertationMolecular simulation protocols have been utilized for decades in order to study physical phenomena and bolster knowledge of biomolecular systems; however a divide between theoretical simulation and physical experiment frequently persists - often boiling down to a lack of knowledge (or lack of confidence) by experimental scientists of theoretical modeling techniques, a lack in broad applicability of theoretical techniques, or a combination of both. Much of the research described in this dissertation is focused on the development and evaluation of modeling protocols that expand the applicability of molecular modeling techniques in order to foster a relationship between the theoretical and experimental sciences so that biomolecular simulation techniques may better serve experimental scientists in advancing the treatment of disease. Necessary in the development of all experimental methods is the ability to validate against known experimental parameters. While protein force fields are often perceived as well-established and accurate in describing the molecular motions and nuances of biomolecular systems, research performed highlights the shortcomings of studying highly complex and intricate physical systems in silico - aiding theoretical and experimental scientists alike in understanding of the limitation of the method. The development of a biomolecular simulation framework designed to optimize peptide therapeutics has the potential to facilitate the treatment of disease in a broad and comprehensive manner. The refinement of peptide therapies which can be considered for clinical trials is notoriously time-consuming and costly. However utilizing high-throughput biomolecular simulation techniques it is possible to optimize peptide sequences in silico. The deployment of an in silico framework with the capability to swiftly build, relax, and evaluate candidate peptides in a high-throughput manner can overcome bottlenecks in the experimental approach and guide development in a directed and focused manner in order to curb the costly and time-intensive processes associated with the development of high-quality peptide therapeutics