AbstractThe venomous insulin‐like peptides released by certain cone snails stimulate hypoglycemic shock to immobilize fish and catch the prey. Compared to human insulin (hIns), the cone snail insulins (Con‐Ins) are typically monomeric and shorter in sequence, yet they exhibit moderate hIns‐like biological activity. We have modeled six variants of Con‐Ins (G3, K1, K2, T1A, T1B, and T2) and carried out explicit‐solvent molecular dynamics (MD) simulations of eight types of insulins, two with known structures (hIns and Con‐Ins‐G1) and six Con‐Ins with modeled structures, to characterize key residues of each insulin that interact with the truncated human insulin receptor (μIR). We show that each insulin/μIR complex is stable during explicit‐solvent MD simulations and hIns interactions indicate the highest affinity for the “site 1” of IR. The residue contact maps reveal that each insulin preferably interacts with the αCT peptide than the L1 domain of IR. Through analysis of the average nonbonded interaction energy contribution of every residue of each insulin for the μIR, we probe the residues establishing favorable interactions with the receptor. We compared the interaction energy of each residue of every Con‐Ins to the μIR and observed that γ‐carboxylated glutamate (Gla), His, Thr, Tyr, Tyr/His, and Asn in Con‐Ins are favorable substitutions for GluA4, AsnA21, ValB12, LeuB15, GlyB20, and ArgB22 in hIns, respectively. The identified insulin analogs, although lacking the last eight residues of the B‐chain of hIns, bind strongly to μIR. Our findings are potentially useful in designing potent fast‐acting therapeutic insulin.