Receptor Assembly Changes the Interpretation of Natural Product Docking at the Optineurin-TANK-Binding Kinase 1 Interface

Background: Docking a compound against an isolated protein pair can place it in a space occupied by another subunit of the deposited assembly. We examined whether this problem changed the interpretation of a natural product docking panel at the optineurin (OPTN)-TANKbinding kinase 1 (TBK1) interface.Methods: Eleven compounds were docked against the wild-type (WT) and E50K crystal fragments in 2 OPTN-TBK1 chain-pair frames (AC and BD), with 10 seeds per condition. A post hoc audit of 440 archived outputs motivated a comparison of pair-only and 4-chain receptors. The comparison preserved prepared target atoms, ligand inputs, grids, and search settings, generating 880 new outputs on 1 graphics processing unit. First-ranked poses were assessed for complementary-chain distances, target-pair contacts, and seed dispersion.Results: In the new comparison, 35/440 pair-only poses approached complementary-chain heavy atoms within 2 Å; 31 satisfied the original dual-chain contact criterion. No 4-chain pose had this flag. For coptisine in E50K_AC, flags fell from 5/10 to 0/10 while mean scores changed from -6.3497 to -6.3409 kcal/mol. Median within-condition root-mean-square deviation fell from 16.017 to 0.206 Å. Across all 44 compound-system strata, the number with median root-mean-square deviation ≤ 2 Å changed from 18 to 17. Coptisine retained a recurrent WT_AC pose.Conclusion: Similar scores can conceal different assembly compatibility and pose locations. These calculations support checking assembly context before interpreting natural product docking contacts, but do not establish ligand binding, OPTN-TBK1 modulation or the predictive accuracy of the revised receptor representation.