Graduate Seminar Series
Every week at 11:30 AM • ENGR 406
See below for exact dates
Dr. Eric Schmidt — 9/20/2017
Bioinspired Design Principles for Synthetic Biology of Organic Compounds
Wednesday 11:30 AM • ENGR 406
One of the goals of synthetic biology broadly defined is to use genetic engineering methods to rationally produce desired chemicals or compound libraries. Hindering this goal is an imperfect understanding of the intrinsic promiscuity of biosynthetic pathways. We have sought naturally plastic biosynthetic pathways to natural products, aiming to understand the fundamental principles that enable promiscuity. By applying these principles, we have designed new materials aimed at drug discovery.
Dr. Monica Serban — 9/06/2017 — "Engineering of Natural and Synthetic Biomaterials for Medical Applications"
Biomaterials, synthetic or natural, are the preferred building blocks for therapeutics and medical devices, because of their excellent biocompatibility. Two such building blocks – hyaluronan (HA), a glycosaminoglycan abundant in mammalian extracellular matrices, and silk fibroin (SF), an insect derived polymeric protein – have been extensively functionalized to present various biological clues; however, few of such approaches sought to synergistically build on the endogenous cellular interactions of these macromolecules. Specifically, native HA has been reported to have antagonistic effects in inflammatory processes depending on the macromolecule’s molecular weight. One of our projects is aimed at building on this fact and further engineer large molecular weight HA to have dual antioxidant and anti-inflammatory effects. These functionalized molecules will be explored as therapeutics for cytomegalovirus induced hearing loss (pathology with a reactive oxygen species-induced inflammation etiology). Similarly, we are exploring the effect of SF secondary structure on its interactions of SF with biological substrates prior to further functionalizing the molecule for in vitro diagnostics and other medical applications. In parallel, our laboratory is exploring other materials - such as starch-derived glucaric acid polymers or tetraethyl orthosilicate thixogels - as novel drug delivery systems.
Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) adaptive immune systems, that protect bacteria and archaea from invasive viruses and plasmids, have recently been repurposed for a myriad of genetic engineering tools. In search of additional CRISPR-based genome editing tools, and to better understand crRNA-guided DNA interference in E. coli, we determined the 3.24 Å crystal structure of the 405 kDa multi-subunit Cascade (CRISPR associated complex for antiviral defense) complex. The Cascade structure reveals that a 61-nucleotide CRISPR derived RNA (crRNA) assembles with eleven proteins into a seahorse-shaped complex. Proteins at opposite ends of the complex bind conserved sequences at the 3’ and 5’ ends of the crRNA, while the guide sequence is displayed in five-nucleotide segments across a helical assembly of six interwoven subunits. Using additional structures of Cascade bound to nucleic acid targets, we performed molecular dynamics simulations that predicted functional roles in dsDNA binding for residues in the tail, backbone, and belly of Cascade, which we confirmed biochemically in vivo and in vitro. Additionally, we used architectural information to design longer Cascade complexes that bind DNA with higher specificity. Collectively, our results explain the mechanisms that drive target-induced conformational changes in Cascade upon DNA binding, reveal specific residues important for non-self target recognition, and directed the design of elongated complexes that may be used for gene regulation.
Assistant Professor, Utah State University
Department of Mathematics