Evaluating inositol phospholipid interactions with inward rectifier potassium channels and characterising their role in disease.

ABSTRACT: Membrane proteins are frequently modulated by specific protein-lipid interactions. The activation of human inward rectifying potassium (hKir) channels by phosphoinositides (PI) has been well characterised. Here, we apply a coarse-grained molecular dynamics free-energy perturbation (CG-FEP) protocol to capture the energetics of binding of PI lipids to hKir channels. By using either a single- or multi-step approach, we establish a consistent value for the binding of PIP₂ to hKir channels, relative to the binding of the bulk phosphatidylcholine phospholipid. Furthermore, by perturbing amino acid side chains on hKir6.2, we show that the neonatal diabetes mutation E179K increases PIP₂ affinity, while the congenital hyperinsulinism mutation K67N results in a reduced affinit

SUBMITTER: Pipatpolkai T 

PROVIDER: S-EPMC9814360 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature