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

Abstract

The receptor tyrosine kinase superfamily comprises many cell-surface receptors including the insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF1R) that are constitutively homodimeric transmembrane glycoproteins. Therefore, these receptors require ligand-triggered domain rearrangements rather than receptor dimerization for activation. Specifically, binding of peptide ligands to receptor ectodomains transduces signals across the transmembrane domains for trans-autophosphorylation in cytoplasmic kinase domains. The molecular details of these processes are poorly understood in part due to the absence of structures of full-length receptors. Using MD simulations and enhanced conformational sampling algorithms, we present all-atom structural models of peptides containing 51 residues from the transmembrane and juxtamembrane regions of IR and IGF1R. In our models, the transmembrane regions of both receptors adopt helical conformations with kinks at Pro961 (IR) and Pro941 (IGF1R), but the C-terminal residues corresponding to the juxtamembrane region of each receptor adopt unfolded and flexible conformations in IR as opposed to a helix in IGF1R. We also observe that the N-terminal residues in IR form a kinked-helix sitting at the membrane–solvent interface, while homologous residues in IGF1R are unfolded and flexible. These conformational differences result in a larger tilt-angle of the membrane-embedded helix in IGF1R in comparison to IR to compensate for interactions with water molecules at the membrane–solvent interfaces. Our metastable/stable states for the transmembrane domain of IR, observed in a lipid bilayer, are consistent with a known NMR structure of this domain determined in detergent micelles, and similar states in IGF1R are consistent with a previously reported model of the dimerized transmembrane domains of IGF1R. Our all-atom structural models suggest potentially unique structural organization of kinase domains in each receptor.

Insulin mimetic peptide S371 folds into a helical structure

“…We carried out four metadynamics runs for each peptide (the native insulin B‐chain and S371), the details of which are summarized in Table . We briefly note that metadynamics algorithm has been successfully applied to study a number of conformational sampling problems including peptide‐folding studies in the insulin family …”

“…We briefly note that metadynamics algorithm has been successfully applied to study a number of conformational sampling problems [57][58][59][60][61][62][63][64][65] including peptide-folding studies in the insulin family. [49,66] our set of CVs (RMSD, R g ) to study the folding of this 18residue peptide (see Methods and Fig. 1c for details on sequences and alignment).…”

“…To understand the flexibility mechanisms of receptors of the insulin family and elucidate the details of hormone/receptor interactions, we have previously shown that all‐atom molecular dynamics (MD) simulations are a highly promising tool . In addition, we have recently combined MD simulations with metadynamics, an enhanced conformational sampling algorithm, to predict all‐atom structural models of the transmembrane domains of receptors of the insulin family . In this current work, we study the folding properties and structure of a potent Site 1 insulin‐mimetic peptide S371 in all‐atom detail with explicit‐solvent using metadynamics.…”

“…[42][43][44][45][46][47] In addition, we have recently combined MD simulations with metadynamics, an enhanced conformational sampling algorithm, [48] to predict all-atom structural models of the transmembrane domains of receptors of the insulin family. [49] In this current work, we study the folding properties and structure of a potent Site 1 insulin-mimetic peptide S371 in allatom detail with explicit-solvent using metadynamics. To benchmark our folding studies of S371 and validate the predictive capability of collective variables (CVs) used, we first carry out folding studies of the insulin B-chain, which is known to form a canonical a-helix.…”

Interplay of cysteine exposure and global protein dynamics in small‐molecule recognition by a regulator of G‐protein signaling protein

“…The metadynamics method has been successfully applied to study many biophysical problems including computational drug design. [60][61][62][63][64][65][66] In this work, we used an eigenvector as a CV 67…”