Boston De Novo Design
Regine Bohacek, PhD
Lzm is the graphical interface used by AlleGrow. It is part of the FLO+ molecular modeling suite.
Once molecules generated by AlleGrow have been optimized by energy minimization, they can be evaluated using the solvent accessible surface and the atom scores.
Looking at a ligand and the solvent accessible surface mesh it becomes immediately obvious to what extent the ligand occupies the binding site and gives a sense of the quality of the protein/ligand interactions.
The atom scores assign a numerical energy to each ligand atom showing the contribution that atom makes to the total predicted binding energy. Color is also used to display the range of energies.
However, the most important feature of inspecting AlleGrow generated molecules with lzm, is the ease with which the AlleGrow molecule can be modified. New atoms can be added, undesired atom removed and with one click the molecule is reminimized in the binding site and new scores displayed at the bottom of the screen. In this way, the user can take the AlleGrow generated molecules as a starting point for ligand design.
Solvent Accessible Surface
The solvent accessible surface of the binding site is shown in a mesh. It is computed at the van der Waals radius of the binding site atoms plus a probe distance of 1.4 Angstroms. The mesh is colored according to the chemical specificity of binding site atoms: yellow shows hydrophobic regions, blue hydrogen bond acceptors and red hydrogen bond donors.
Looking at a ligand and the solvent accessible surface mesh one can immediately see to what extent the ligand occupies the binding site, how well the ligand complements the chemical specificity of the binding site and gives a sense of the quality of the protein/ligand interactions.
Ligand atoms in ideal van der Waals contact with the binging site atoms lie on or near the surface mesh. Ligand atoms that form hydrogen bonds with binding site atoms, penetrate the mesh.
Ideal complementarity is shown when the hydrophobic ligand atoms lie near the yellow surface, when hydrogen bonding hydrogens penetrate the blue surface and hydrogen bond accepting atoms, penetrate the red surface.
Reference: Bohacek and McMartin, J.Med.Chem . ( 1992 ), 35 , 1671-81.
The extent to which a single ligand atom contributes to the total predicted binding energy is represented by a numerical value. In addition, color is used to highlight the relative energy values with white indicating those atoms most important to affinity.