Computational studies reveal mutation effects in proteins: From disease-causing variants to strategies in targeted therapeutic

Protein function is intrinsically linked to its three-dimensional structure, which is determined by amino acid sequence. Mutations altering this sequence can elicit a broad spectrum of effects, ranging from subtle structural perturbations to profound functional impairments. Even though mutations are frequently implicated in pathological conditions, they also serve as essential mechanisms enabling organisms to adapt and survive under harsh conditions. Leveraging this principle, researchers can introduce mutations in native proteins to enhance their utility in industrial applications or scientific investigations. Numerous experimental approaches have been developed to characterize mutation effects; however, they are often labor-intensive, resource-demanding, and constrained in their ability to explain experimental outcomes at the molecular level.

This dissertation presents three distinct computational studies using molecular dynamics simulation to address research questions that are commonly encountered by biochemists. Those questions include the impacts of single point and multiple mutations on protein structure and function, with applications spanning vaccine development, elucidation of disease-associated molecular mechanisms, and the analysis of cross-species viral transmission. Using atomistic molecular dynamics simulations, we elucidated the molecular mechanism of a single amino acid substitution to facilitate the adaptation of avian influenza viruses to human hosts and potentially enhances transmission among human population. We also characterize how an amino acid substitution can perturb leptin hormone structure and the relationship between this perturbation and congenital leptin deficiency/dysfunction disease. Furthermore, with coarse-grained molecular dynamics simulation, we identified promising mutations that enhance the overall structural stability of hemagglutin, a major antigen used in influenza vaccine development. These stabilizing mutations potentially ensure vaccine efficacy and reduces cost associated with vaccine storage, transportation, and distribution. Collectively, through the conducted studies, we devised versatile simulation and analysis frameworks that can be adopted by the broader research community to advance protein engineering and biomedical discovery.