Structural models of viral insulin‐like peptides and their analogs

Abstract

The insulin receptor (IR), the insulin-like growth factor-1 receptor (IGF1R), and the insulin/IGF1 hybrid receptors (hybR) are homologous transmembrane receptors. The peptide ligands, insulin and IGF1, exhibit significant structural homology and can bind to each receptor via site-1 and site-2 residues with distinct affinities. The variants of the Iridoviridae virus family show capability in expressing single-chain insulin/IGF1 like proteins, termed viral insulin-like peptides (VILPs), which can stimulate receptors from the insulin family. The sequences of VILPs lacking the central C-domain (dcVILPs) are known, but their structures in unbound and receptor-bound states have not been resolved to date. We report all-atom structural models of three dcVILPs (dcGIV, dcSGIV, and dcLCDV1) and their complexes with the receptors (μIR, μIGF1R, and μhybR), and probed the peptide/receptor interactions in each system using allatom molecular dynamics (MD) simulations. Based on the nonbonded interaction energies computed between each residue of peptides (insulin and dcVILPs) and the receptors, we provide details on residues establishing significant interactions. The observed site-1 insulin/μIR interactions are consistent with previous experimental studies, and a residue-level comparison of interactions of peptides (insulin and dcVILPs) with the receptors revealed that, due to sequence differences, dcVILPs also establish some interactions distinct from those between insulin and IR. We also designed insulin analogs and report enhanced interactions between some analogs and the receptors.

Towards a Truly General Intermolecular Binding Affinity Calculator for Drug Discovery & Design

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Spontaneous Dimerization and Distinct Packing Modes of Transmembrane Domains in Receptor Tyrosine Kinases

“…35 Molecular dynamics (MD) simulations have been proposed and used as a tool to validate or supplement structural data as well as to provide atomistic insights into the conformational dynamics of IR and IGF1R. 10,26,[48][49][50][51][52][53][54][55][56][57] MD simulations have also been used to characterize membrane proteins and their interactions with lipid molecules in the membrane. [58][59][60][61] These studies have highlighted that the lipid composition modulates spatial configurations of transmembrane proteins and affects their dimerization process.…”