DE NOVO DESIGN OF ALPHA HELICAL AND BETA BARREL PROTEIN CHANNELS AND PORES FOR MOLECULAR SENSING
Abstract
Transmembrane pores are one of the major families of membrane proteins that carry out biological sensing in nature. Although they are ideal in physiological settings, these membrane proteins are generally quite unstable in vitro and not robust to substantial reengineering toward generating new sensors. We propose to create novel and robust nanopore sensors from scratch both to illuminate basic principles of molecular sensing, and to provide new and useful sensing modalities. This work will build on our recent breakthroughs in protein design which have enabled the design of membrane pores that can conduct ions through the pore with different sizes and topologies. We propose to combine these breakthroughs to broaden the use of our robust de novo integral membrane protein nanopores in two major directions: 1) To rapidly generate electrical or optical signals in response to ligands, pH or light, and 2) to specifically control the transport of macromolecules through the pore. The research will iterate between computational design and experimental testing, with at each stage feedback from experiments used to guide improvement of the computational model and design approach. This “bottom up” design approach should generate new and useful robust nanopore based sensors, and shed new light on the principles underlying membrane nanopore structure and function which is difficult to discern from the study of highly evolved native proteins.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 20, 2023
- Source ID
- FA95502210506
Entities
People
- David Baker
Organizations
- Air Force Office of Scientific Research
- United States Air Force
- University of Washington