(627c) Novel Computational Protocol for Small-Molecule : Protein Receptor Docking; Application to 1,4-Dhna and Tcdd Binding to AhR Mouse Protein

Docking algorithms are widely used to understand the relationship between the structure and function of interactions with small molecule : protein complexes that govern biological functions. Despite the advances made in computational chemistry, and the variety of docking frameworks to study small molecule : receptor binding, there is still significant room for improvement in obtaining highly accurate computational predictions of the structure of small-molecule : receptor complexes [1]. We have developed a CHARMM-based docking protocol that innovatively combines the following key features: (1) the use of multiple short molecular dynamics (MD) docking simulations, with residues within the protein receptor’s binding pocket unconstrained, to nearly exhaustively search the binding modes of the ligand in the binding pocket of the receptor, (2) the use of both harmonic and quartic spherical potentials to constrain the ligand to the binding pocket during the multiple short MD docking simulations, and (3) the selection of the most probable binding modes using interaction energy calculations, as well as the use of explicit water, all-atom MD simulations and physical-chemistry based free energy calculations to computationally elucidate the most favorable binding mode of the ligand in complex with the protein receptor.

In this study, we applied our docking protocol to determine the binding of 1,4-dihydroxy-2-naphthoic acid (1,4-DHNA) and TCDD to the mouse AhR protein [2]. The most energetically favored binding mode of TCDD with the AhR based on our docking protocol is in high accordance with previous experimental and computational studies examining this interaction [2, 3, 4, 5, 6]. The most energetically favored binding mode of 1,4-DHNA shows that both 1,4-DHNA and TCDD predominantly form strong interactions with the same residues of AhR. More polar interactions occur in the AhR : 1,4-DHNA complex in comparison to the AhR : TCDD complex due, in part, to differences in overall charge and substituent interactions with various amino acid side-chains. Association free energy calculations suggest that 1,4-DHNA binds with a lower affinity. This result is consistent with experimental observations showing similar efficacies of 1,4-DHNA and TCDD as AhR agonists but differences in their potencies [2]. The strong agreement of our work in comparison with previous studies investigating TCDD in complex with AhR support the validity of our docking protocol and suggest that the computationally derived binding modes most likely represent the naturally occurring binding modes of TCDD and 1,4-DHNA with residues in the AhR ligand binding pocket.

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[6] Soshilov AA, Denison MS. (2014). Ligand promiscuity of aryl hydrocarbon receptor agonists and antagonists revealed by site-directed mutagenesis. Mol Cell Biol. 34, 1707–1719.