Insulin (Ins) and insulin-like growth factor-1 (IGF1) bind to the insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF1R), respectively, to stimulate several biological processes. IR and IGF1R can also heterodimerize during co-expression to form insulin/IGF1 hybrid receptors (hybR). The macroscopic organisms (like cone snails) and microscopic pathogens (like virusus) have developed venomous or viral insulin like-peptides for defense, prey, or survival. Specifically, cone snails release specialized insulin-like protein toxins in water to immobilize fish and catch their prey. Viruses have evolved critical molecular mimicry mechanisms to express host-like proteins that can affect the host immune system. These venomous or viral insulin-like peptides exhibit moderate human insulin-like biological activity. We have modeled different variants of insulin-like peptides from cone snails (Con-Ins) and viruses (VILPs), and characterized their binding to the members of the IR family. We performed atomistic molecular dynamics (MD) simulations of each modeled venomous insulin-like peptides complexed with the members of the IR family. We found that Con-Ins closely resemble Ins as they bind to IR with the highest affinity, while VILPs closely resemble IGF1 as it binds to the IGF1R with the highest affinity. The binding energy contribution of each residue of peptide ligands and Ins with the receptors were compared to judiciously identify favorable substitutions in Ins that may likely enhance the binding affinity of insulin analogs toward the receptors. The findings from our work are potentially useful in designing monomeric insulin analogs with enhanced bioactivity.

Insulin Analogs Derived from Venomous and Viral Insulin-like Peptides

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