2. Theory

Current methods of ligand fitting that are based on either topological analysis of electron density[3], global optimization of position and conformation of a ligand in a density blob[4], interatomic distance matrix[5,6] or on varying torsion dihedral angles of shape-matched ligand conformations[7] are unable to prevent creation of high energy, sometimes even chemically unrealistic, ligand models. As a result, there are a number of PDB ligands with unlikely, very high-energy structures[8]. For example, the PDB structure of an inhibitor of RNA polymerase in 1nhu has significant repulsion between the two methylene groups).

Flynn is composed of two main components, location of ligand density and ligand fitting. Location of density generally works well with clean density but there are times when ligand density is unclear or not well resolved. In the latter cases, the user should supply a bounding box or simply just input the ligand density by itself and use the density as is.

By default, flynn samples bioactive conformations[9,10] of the input ligand, however, there are times when it might be desireable to input the ligand and use it as is (see section 3.1.4 for more details).

Once the location of the ligand in the map and the conformations have been selected, flynn then adapts the the initial conformations to the ligand density using a modern force-field, MMFF94 [11,12,13,14,15,16,17].

The potential function being used to adapt the ligand is

$V = V_{ff} + \lambda V_{shape}$

where $V_{ff}$ represents the internal energy of the ligand and $V_{shape}$ is the overlap between the ligand and the electron density. $\lambda$ is a mixing parameter that represents the degree to which the shape of the density to dominate the combined potential[18].

The strain placed on the ligand is bounded while the function is optimized producing high-quality fits with low-strain ligand conformations.

Subsections

				FLYNN

				FLYNN