Speaker: Dr. Andrew McShan, Georgia Institute of Technology
Title: "Generative Diffusion-Based De Novo Protein Design of New Therapeutics to Fight Disease"
Abstract: De novo protein design has experienced a renaissance in recent years due to advances in generative diffusion-based approaches to develop high affinity, target-specific binders. However, the ability of these tools to generate “new-to-nature” proteins with unique backbones and amino acid sequences that target challenging therapeutic targets, such as lipids and oligomeric assemblies, has not yet been explored. Here, we apply an end-to-end design pipeline using RFdiffusionAA, LigandMPNN, Chai-1, and Rosetta to develop (1) lipid antigen/CD1-restricted T cell receptor (TCR) mimics, and (2) proteins that disassemble bacterial pathogen type III secretion systems. Designed proteins were recombinantly expressed in E. coli with secondary structure folds and thermal stabilities validated in vitro. Biophysical assays confirmed that the designs bound to their molecular targets with high affinity and specificity. Finally, X-ray crystallography and solution NMR provided mechanistic insights into the design/target binding modes, which were consistent with the computational design models. Together, our results demonstrate that generative diffusion-based de novo protein design approaches can robustly produce new binders against unconventional targets. This work will enable new therapeutic avenues for diagnostics, antimicrobial agents, immunotherapy, and vaccine development centered on protein design.

Bio: Dr. McShan's expertise spans biophysics, structural biology, computational biology, and immunology. They joined the faculty at Georgia Tech as an Assistant Professor in the School of Chemistry and Biochemistry in Summer 2022. Previously, they were a postdoctoral fellow in the lab of Dr. Nikolaos Sgourakis at the Children's Hospital of Philadelphia & The University of Pennsylvania (2020-2022) studying antigen presentation of classical peptide/MHC-I molecules. Before that, they were also with Dr. Sgourakis at the University of California, Santa Cruz (2016-2020). They also worked as a biotechnology intern in the lab of Y. John Wang at Genentech (2015). They obtained their Ph.D. in Molecular, Cellular & Developmental Biology at the University of Kansas in the lab of Dr. Roberto De Guzman (2011-2016) studying bacterial type III section systems. They carried out undergraduate research in epigenetics (also at KU) in the lab of Dr. Justin Blumenstiel. Dr. McShan has received many prestigious awards and honors including the NSF CAREER Award (2025), the Shurl and Kay Curci Foundation Research Grant (2024), Thank A Teacher Certificates; Georgia Tech Center for Teaching and Learning and the Inclusive STEM Teaching Fellow, Georgia Tech (2023).

The Chemistry and Biochemistry Departmental Seminar Series covers a broad range of fields in the Chemical and Biochemical Sciences. In past seminars, scientists from Academia, Government, and Industry have presented their most recent discoveries and contributions in their respective areas. This Seminar Series offers students and faculty the opportunity to interact directly with other leaders in their specializations and to gain a good overview of the entire range of fields in Chemistry and Biochemistry.