(3cy) Biomolecular Simulation Approaches for Proteins and Nucleic Acids with Novel Therapeutic and Biomedical Applications

Engineering biomolecules for novel therapeutic applications requires
developing a detailed mechanistic and functional understanding of
potential drug targets. Cellular membranes often present a major
physical barrier for the delivery of synthetic compounds that mimic
their physiological counterparts such as small peptide hormones,
growth factors, vitamins, and neurotransmitters. Binding of these
molecular ligands to the integral membrane proteins largely mediates
downstream cellular signaling events. My doctoral and postdoctoral
work has spanned various classes of membrane proteins such as hormone
receptors involved in diabetes and cancer, nutrient/toxin
transporters, and G-protein coupled receptors that are targets of at
least a third of marketed drugs. With the integration of biophysical
theory, modeling, and atomistic simulation approaches on multiple
length- and time-scales, I have explored the vast conformational
repertoire of these biomolecules, which can be exploited for various
pharmaceutical applications. Specifically, I am going to present part
of my doctoral work in this poster where I studied the hormones and
receptors of the insulin family, both of which are key players in the
type-1 and type-2 diabetes at various levels, and also a homologous
family of insulin-like growth factors that have been implicated in
various cancers. Mechanistic principles that have emerged from this
work have key implications for the design of novel insulin mimetic
peptide agonists with tuned specificities for their cognate
receptors. From my postdoctoral work, I will address key questions
related to the coupling of conformational transitions in the
nucleotide-binding motifs and the transmembrane domains of ATP-binding
cassette (ABC) transporters that allow unidirectional transport of
nutrients into, and toxins out of, cytoplasm. Lastly, I will also
address the question of biogenesis of large ribonucleoprotein
complexes known as the ribosomes (the protein-factory in all cells),
which are targets of existing and novel antibacterial drugs.