Ligand fitting withCCP4

Abstract

Crystal structures of protein–ligand complexes are often used to infer biology and inform structure-based drug discovery. Hence, it is important to build accurate, reliable models of ligands that give confidence in the interpretation of the respective protein–ligand complex. This paper discusses key stages in the ligand-fitting process, including ligand binding-site identification, ligand description and conformer generation, ligand fitting, refinement and subsequent validation. TheCCP4 suite contains a number of software tools that facilitate this task:AceDRGfor the creation of ligand descriptions and conformers,LidiaandJLigandfor two-dimensional and three-dimensional ligand editing and visual analysis,Cootfor density interpretation, ligand fitting, analysis and validation, andREFMAC5 for macromolecular refinement. In addition to recent advancements in automatic carbohydrate building inCoot(LO/Carb) and ligand-validation tools (FLEV), the release of theCCP4i2 GUI provides an integrated solution that streamlines the ligand-fitting workflow, seamlessly passing results from one program to the next. The ligand-fitting process is illustrated using instructive practical examples, including problematic cases such as post-translational modifications, highlighting the need for careful analysis and rigorous validation.