Insertion Properties of Cftr Explored with High Throughput, Coarse Grain Molecular Dynamics

Abstract

Transmembrane helix insertion into the membrane occurs through a complex process, involving dedicated cellular machinery. Recent experimental work has been able to show that the insertion of peptides by the translocon shows high correlation with hydrophobic scales based on water/octanol partitioning, but that the absolute energies of insertion of different amino acids are consistently different by an order of magnitude. Similarly, energies of transmembrane insertion from explicit energy calculations on detailed molecular model also appear to differ, by up to 2 orders of magnitude. Coarse grain (CG) techniques are an increasingly popular approach for the molecular modelling of biomolecules, which increase the effective timescale or system size which can be modelled compared to more common atomistic techniques. We adopt a high throughput, CG approach to understanding helix insertion into the membrane. Using self assembly of systems of peptides derived from the cystic fibrosis protein, we are able to predict transmembrane insertion energies with a correlation coefficient of up to 0.86, and energies within a factor of 2 of the experimentally determined energies. Additionally, we show that the insertion behaviour observed is sensitive to membrane thickness, and in agreement with explicit energy calculations and experimental evidence, find that thinner membrane bilayers favour a transmembrane conformation. Alongside results from PMF calculations, the results here appear to suggest that the energy differences measured in the translocon experiments represent the differences in energy between the interfacial and the transmembrane conformations for a helix.