Professor Ganapathy Ayappa's Talk

Nov 03, 2021 - 14:30
Nov 03, 2021 - 15:30
Online Webinar
Event Type
Professor Ganapathy Ayappa Department of Chemical Engineering, Indian Institute of Science, Bangalore, India 560012
Unravelling Membrane-Protein Intermediates and Lipid Modulation by Pore Forming Proteins

Protein-membrane interactions play an important role in our understanding of diverse phenomena ranging from membrane-assisted protein aggregation, oligomerization and folding. Pore-forming toxins (PFTs) a subclass of proteins expressed by bacteria are the primary vehicle for infection and are responsible for over 40 % of  bacterial infections. With the rise in antimicrobial resistance a molecular understanding of the infection pathways could open up novel treatment strategies. PFTs expressed in a water-soluble form (monomers) bind to the target membrane and self-assemble to form multimeric transmembrane pore complexes.   In this talk, I will summarize our ongoing work on determining oligomerization pathways and intermediates, as well as monitoring lipid modulation and disruption during  pore formation. Using a combination of molecular dynamics simulations at atomistic and coarse grained levels of description and experiments on supported bilayer and vesicle platforms we unravel the process of pore formation of both bacterial α and b-PFTs. We show that transmembrane oligomeric intermediates or “arcs” form stable proteolipid complexes consisting of protein arcs with toroidal lipids lining the free edges. Spontaneous lipid evacuation occurs on the time scale of tens of nanoseconds, suggesting that transmembrane arcs rapidly stabilize to form functional water channels capable of leakage and lysis. Kinetic models of calcein leakage experiments on small unilamellar vesicles reveal that arcs do indeed play an important role. We connect membrane insertion and ensuing conformational changes with recent single molecule and vesicle leakage data and discuss the vital role played by cholesterol during  the pore forming pathway.

Professor Ayappa obtained his Bachelors degree in Chemical Engineering from Mangalore University, India in 1984, and an MS and PhD in Chemical Engineering with a Minor in Mathematics from the Department of Chemical Engineering and Materials Science at the  University of Minnesota, in 1992. He was a post-doctoral fellow at the Minnesota Supercomputer Institute and subsequently joined the Department of Chemical Engineering at the Indian Institute of Science in 1993. Professor Ayappa has held visiting positions at the University of North Carolina, the James Franck Institute at the University of Chicago and Department of Materials at ETH Zurich. He is a fellow of the Indian National Academy of Engineers and the National Science Academy. His research interests lie in developing a molecular understanding of structure and dynamics of 
molecules at the nanoscale using molecular simulations and statistical mechanics. Current research interests are in the area of biomembranes, membrane-protein interactions and dynamics of fluids at the nanoscale.