Ligands

Why

The goal of a crystallographic study is often to visualize the interaction of a small molecule or ligand with a macromolecule. This is core process in the development of new therapeutics. It is also not uncommon to discover density for an unanticipated small molecule in complex with a protein during the process of solving a structure. In both cases it is necessary to fit the small molecule into density to complete the atomic model. As part of this process it is often necessary to generate appropriate stereochemical restraints for new ligands for use in structure refinement.

How

The principal tool for fitting ligands into density in Phenix is phenix.ligand_fit. This identifies unfilled electron density in a map and attempts to place the user defined ligand in the density by rotation around any torsional degrees of freedom. The process requires an electron density map, coordinates for the macromolecule, and information about the ligand, either as coordinates or a chemical description which can be used to generate coordinates. The output are the coordinates of the fit ligand. After ligand(s) are fit, subsequent refinement steps will require stereochemical restraints. In some cases these may be present in the default restraint libraries, however, in many cases new restraints may need to be generated. In Phenix, the phenix.elbow program can be used to do this, starting from a variety of different formats.

How to use the ligand fitting GUI: Click here

How to use the phenix.elbow GUI: Click here

Common issues

• Frequently asked questions about ligands

Related programs

• phenix.guided_ligand_replacement: This program uses prior knowledge from a previously fit ligand to expedite the fitting of a similar ligand into the same or similar protein. This is very useful when studying a series of compounds for the same or related macromolecular targets.
• phenix.ligand_identification: This program can be used to determine the identity of an unknown ligand by performing ligand fitting with a library of small molecules and then ranking each molecule by density fit and chemical interaction with the macromolecule.
• phenix.ligand_pipeline: This program can be used to generate a near-finished structure of a protein-ligand complex starting from a current protein model, diffraction data, and information about ligands. It combines Xtriage, Phaser, eLBOW, phenix.refine, AutoBuild, and LigandFit, with optional interaction with Coot. It can significantly reduce the manual effort required for more difficult structures.

Phenix reference manual for phenix.ligand_fit Phenix reference manual for phenix.elbow