All-Atom Structural Models of the Transmembrane Domains of Insulin Receptor and Type-1 Insulin-Like Growth Factor Receptor

Abstract

The binding of insulin and insulin-like peptides to their cell surface receptors is the first key step in triggering signaling pathways for controlling processes related to normal cellular growth and metabolism. However, the mechanistic details of this first step remain poorly understood at a molecular scale in part due to the lack of knowledge of intact structures of full-length receptors. Constructing such structural models would require information on the structures of extracellular domains, intracellular domains, and more importantly the transmembrane domains (TMDs) that serve a critical role in signal transduction. In this work, we present all-atom structural models of TMDs of the insulin receptor (IR) and the type-1 insulin-like growth factor receptor (IGF1R) constructed using atomistic molecular dynamics (MD) simulations. In particular, the folding/unfolding behavior of membrane-embedded peptide sequences from IR and IGF1R was studied using enhanced sampling methods such as metadynamics. Simulations reveal that a proline residue in IR-TMD results in increased flexibility in comparison to IGF1R-TMD, while the metastable structures of both peptides have kinks near the N-terminus. The predicted structure of IR-TMD is consistent with a recent experimental structure determined in micelles using NMR, and the IGF1R-TMD structure is consistent with predictions from long unbiased MD simulations. These results have key implications for future work aimed at constructing all-atom structural models of full-length receptors.