Grapholita molesta is a notorious fruit borer globally, causing severe damage to fruit production. To control the pest, one commonly used mean is pheromone-mediated management. As an important sex pheromone, Z-8-dodecenyl acetate (Z8–12: Ac), is often coformulated with other active ingredients to regulate the behavior of G. molesta. To uncover its interactions with G. molesta pheromone binding protein 2 (GmolPBP2) is used to help develop insect attractants. During 200 ns molecular dynamics simulations, two representative conformations of the GmolPBP2-Z8–12: Ac complex are selected. Conformation II at the time of 14–106 ns is dominantly maintained by the hydrophobic interactions and hydrogen bond. In Conformation I, which lasts from 106 to 200 ns, the hydrophobic interactions are enhanced while the hydrogen bond is quite weakened, due to the formation of a more sophisticated hydrophobic binding pocket and the enlargement of hydrogen bond distance. Taking the two conformations as a whole, the affinity between GmolPBP2 and Z8–12: Ac is crucially determined by three hot-spots including Phe11, Trp36, and Ile51. These results would provide a basis for the discovery, optimization, and design of leading compounds potentially active to attract G. molesta.

BACKGROUND: Cydia pomonella, a worldwide quarantine fruit pest, causes great damage to fruit production every year. Sex pheromone-mediated control of C. pomonella has been widely used. As an indispensable ingredient of commercial sex attractants, 1-dodecanol (Dod) works to synergize the effect of codlemone in attracting male moths of C. pomonella. The interactions between Dod and its transporter protein, C. pomonella pheromone-binding protein 2 (CpomPBP2), provide inspiration for chemical optimizations to improve the synergistic effects of Dod. RESULTS: In this research, molecular simulations and biological verifications were used in combination to uncover key residues in CpomPBP2 essential for sensing Dod. After performing 150 ns molecular dynamics (MD) simulations, the C1-C12 chain of Dod was found to be locked by the van der Waals energy contributed by the hydrophobic residues Phe12, Leu68, and Ile113, whereas the-OH part of Dod was anchored by the H-bond derived from Glu98 and the salt-bridge derived from Arg109. Because of the importance of these two electrostatic interactions, Glu98 and Arg109 were further verified as key residues in determining the binding affinity between Dod and CpomPBP2. In addition, interactions unfavorable to the binding of Dod were described. CONCLUSION: The research detailed the discovery of key residues involved in CpomPBP2-Dod interactions. Our results provide guidance and caution for the prospective discovery, optimization, and design of novel chemicals with a similar or stronger synergistic effect to codlemone in controlling C. pomonella. Supporting information may be found in the online version of this article.

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BACKGROUND Pheromone‐based management is a leading nonpesticidal strategy among integrated pest management options. Improving the potency of pheromone products by adding synergists would be a practical way to popularize pheromone‐based management as well as to reduce pesticide use. RESULTS Using reverse chemical ecology, synergists for Grapholita molesta sex pheromone were screened. Combined molecular docking and in vitro binding assay led to the determination of four potentially active odorants showing high affinity to G. molesta pheromone binding protein 2 (GmolPBP2). Thereafter, the high affinity between Codlemone and GmolPBP2 was further verified by exploration of GmolPBP2–Codlemone interactions. As the only sex pheromone synergist validated by both laboratory behavioral tests and field trapping, Codlemone was used to optimize commercial sex attractants currently used in G. molesta control. The recommended formulation [(Z)‐8‐dodecenyl acetate:(E)‐8‐dodecenyl acetate:Codlemone = 95:4:10] was found to trap about five to six times more G. molesta adults than the commercial sex attractant [(Z)‐8‐dodecenyl acetate:(E)‐8‐dodecenyl acetate: (Z)‐8‐dodecenol = 95:4:1]. CONCLUSION Codlemone is an excellent pheromone synergist that can be potentially sensed by GmolPBP2, which can remarkably improve the potency of G. molesta sex attractants. It is believed that the introduction of reverse chemical ecology would increase the chance of discovering pheromone synergists, promoting the development of more efficacious pheromone products that can be used in controlling G. molesta and beyond. © 2021 Society of Chemical Industry.