Computer Modelling the Root Cause of Cystic Fibrosis

Abstract

Sophisticated quantitative and physical thinking is revolutionising biology. Here we will present a small example of this paradigm shift, by demonstrating how a physical mindset can contribute to the study of a disease-Cystic Fibrosis. Cystic Fibrosis is the most common fatal genetic condition in Caucasians. It is caused by deleterious mutations to a protein known as the Cystic Fibrosis Transmembrane conductance Regulator (CFTR). This protein functions as an anion channel-in order to balance the levels of salts across epithelial membranes, it must conduct chloride and bicarbonate. A breakthrough in CF care has been the discovery of drugs called CFTR modulators. These act directly on mutant CFTR to restore its function. Unfortunately, since CF is a rare disease, there is insufficient clinical data to determine whether patients carrying rare mutations will respond to modulator therapy. This often leads them excluded from access to these life saving medications. In this work, we used extensive molecular dynamics (MD) and free energy calculations to study how CFTR works and characterise the numerous ways it can misfunction from rare mutations. This was done in close collaboration with cell biologists at Sydney Children's hospital, in order to understand what types of molecular defects may be treated by existing modulators. Our findings indicate that each CFTR mutation is largely unique, with each one causing misfunction in a different way. What is then remarkable, is that these different mutations all appear to respond to CFTR modulators. This strongly indicates the possibility that a larger population of those afflicted with CF will benefit from the right choice of medication. This physical understanding of the underlying cause of CF leads us to suggest that patients carrying missense mutations should be systematically theratyped, and the choice of modulators can be informed by the molecular understanding of CFTR misfunction we present in this thesis.