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Abstract In the ligand prediction category of CASP15, the challenge was to predict the positions and conformations of small molecules binding to proteins that were provided as amino acid sequences or as models generated by the AlphaFold2 program. For most targets, we used our template‐based ligand docking program ClusPro ligTBM, also implemented as a public server available athttps://ligtbm.cluspro.org/. Since many targets had multiple chains and a number of ligands, several templates, and some manual interventions were required. In a few cases, no templates were found, and we had to use direct docking using the Glide program. Nevertheless, ligTBM was shown to be a very useful tool, and by any ranking criteria, our group was ranked among the top five best‐performing teams. In fact, all the best groups used template‐based docking methods. Thus, it appears that the AlphaFold2‐generated models, despite the high accuracy of the predicted backbone, have local differences from the x‐ray structure that make the use of direct docking methods more challenging. The results of CASP15 confirm that this limitation can be frequently overcome by homology‐based docking.