Molecular Interactions of Viral Insulin/IGF-like Peptides with Zebrafish Receptors

Signaling through the insulin receptor (IR) and the type 1 insulin-like growth factor receptor (IGF1R) is modulated by secreted hormones and growth factor ligands (e.g. insulin and insulin-like growth factor 1, IGF1). Impaired signaling in these receptors often leads to diabetes and oncogenic diseases. The discovery of entirely novel viral insulin/IGF-like peptides (VILPs) that can stimulate receptors from the insulin family has raised questions about their structures and binding modes to receptors. These peptides exist in a single-chain (sc) or a double-chain (dc) configuration with folds likely similar to IGF1 and insulin, respectively. The interactions of VILPs with the human receptors are beginning to be mapped but little is known about their interactions with the receptors in fish-the host organism for viruses known to carry these peptide sequences. We have previously reported [Chuard et al., Cell Rep. 2025 44(8):116149] structural models of several VILPs from the Iridoviridae virus family bound to their cognate receptors in Zebrafish (Zeb). In this work, we conducted all-atom molecular dynamics (MD) simulations of these peptides and their receptor-bound complexes along with free energy calculations to assess the energetic contributions of VILP residues for their binding to Zebrafish receptors. Most of the observed Zeb insulin/Zeb µIR and Zeb IGF1/Zeb µIGF1R site 1 interactions are consistent with previously known interactions of human peptides with their receptors, highlighting similarities in their binding modes. However, we also report some non-conserved residues in VILPs that establish significant and unique interactions with residues in Zeb receptors. Furthermore, we identified residues in each VILP which can be potentially mutated into conserved insulin/IGF1 residues to possibly enhance the binding affinity of these peptides.