A transistor model for the cystic fibrosis transmembrane conductance regulator

William D Hunt; Nael A McCarty; Eduardo Martinez Marin; Ryan S Westafer; Phillip R Yamin; Guiying Cui; Andrew W Eckford; Douglas R Denison

doi:10.1016/j.bpr.2023.100108

A transistor model for the cystic fibrosis transmembrane conductance regulator

Biophys Rep (N Y). 2023 Apr 14;3(2):100108. doi: 10.1016/j.bpr.2023.100108. eCollection 2023 Jun 14.

Authors

William D Hunt¹, Nael A McCarty², Eduardo Martinez Marin¹, Ryan S Westafer³, Phillip R Yamin¹, Guiying Cui², Andrew W Eckford⁴, Douglas R Denison³

Affiliations

¹ Georgia Institute of Technology, Atlanta, Georgia.
² Emory University School of Medicine, Atlanta, Georgia.
³ GTRI, Atlanta, Georgia.
⁴ York University, Toronto, Ontario, Canada.

Abstract

In this paper we present a transistor circuit model for cystic fibrosis transmembrane conductance regulator (CFTR) that seeks to map the functional form of CFTR both in wild type and mutants. The circuit architecture is configured so that the function, and as much as possible the form, faithfully represents what is known about CFTR from cryo-electron microscopy and molecular dynamics. The model is a mixed analog-digital topology with an AND gate receiving the input from two separate ATP-nucleotide-binding domain binding events. The analog portion of the circuit takes the output from the AND gate as its input. The input to the circuit model and its noise characteristics are extracted from single-channel patch-clamp experiments. The chloride current predicted by the model is then compared with single-channel patch-clamp recordings for wild-type CFTR. We also consider the patch-clamp recordings from CFTR with a G551D point mutation, a clinically relevant mutant that is responsive to therapeutic management. Our circuit model approach enables bioengineering approaches to CFTR and allows biophysicists to use efficient circuit simulation tools to analyze its behavior.