The modify panel

The modify panel offers the following operations:

Image ligand_optimizer_element_changes
Figure 9.32: The element buttons make it possible to change the element type for an atom, or to add an element to the ligand (this is done by selecting a hydrogen atom and choosing the desired element).

1) Change the element for an existing atom (figure 9.32). To do this select a non-hydrogen atom on the ligand, and click the desired element button from the top row. It is also possible to select more exotic elements using the Other... button. Replacing an element will automatically adjust bond lengths and the number of attached hydrogens.

2) Add new elements to the ligand (figure 9.32). This is done by selecting a hydrogen atom, which will serve as the attachment point. After selecting the hydrogen atom, click on an element button to replace the hydrogen atom. As above, bond lengths and hydrogens are automatically adjusted.

Image ligand_optimizer_fragment_panel
Figure 9.33: Fragments are attached by selecting a hydrogen atom on the ligand, and a hydrogen atom on the fragment. Any Molecule Project may be used as a source for fragments.

3) Attach a new fragment to the ligand (figure 9.33). This works similar to adding a new element, but requires selecting an attachment point on the fragment as well: first select a hydrogen on the ligand, then select a hydrogen on the fragment. The fragment will be attached to the ligand by replacing the selected hydrogens with a covalent bond. As above, bond lengths and hydrogen counts are automatically adjusted. It is also possible to just select a heavy atom with at least one hydrogen attached on the ligand. In this case an arbitrary hydrogen on the heavy atom will be used as the attachment point for the fragment.

It is possible to choose between different fragment libraries using the Fragments... button. Two small libraries are provided with the Ligand Optimizer (one for ring systems, and one for common chemical groups, such as carboxylate and phosphate groups), but it is possible to use molecules from any Molecule Project as fragments. To do this, choose the Fragments... | From Molecule Project... menu entry. Any ligands in the selected Molecule Project will appear as attachable fragments in the Ligand Optimizer. This also makes it possible to attach fragments drawn in a 2D sketcher: simply paste the SMILES string from the 2D sketcher into a Molecule Project (as described in Copy-paste of SMILES strings), and use the Molecule Project as a fragment library.

Fragment modifications are previewed in real-time in the 3D view. After a fragment has been added, the newly attached part of the ligand will be subjected to a quick geometry optimization in order to place the fragments in the most energetically favorable way with regard to the protein context.

4) Delete parts of the ligand

Image ligand_optimizer_delete
Figure 9.34: Choose an atom, and press the Delete... button in order to remove a part containing the selected atom.

The Delete... button (figure 9.33) makes it possible to delete any part of the molecule containing the selected atom. However, a part can only be deleted if the remaining part of the molecule is still connected, and no rings are broken (whole rings may be deleted though). The atoms connected to removed parts are automatically repaired by adding hydrogens.

5) Change atom type

Image ligand_optimizer_atom_changes
Figure 9.35: Choose an atom and press the Atom... button to change the number of hydrogens or hybridization.

The Atom... button (figure 9.35) makes it possible to change the atom type (the number of hydrogens and formal charges). If the atom type needs to be changed into a different hybridization, it might be necessary to change the bonds connected to it by using the Bond... tool described below.

6) Change bond order

Image ligand_optimizer_bond_changes
Figure 9.36: Choose two covalently connected atoms and press the Bond... button to change the bond order.

The Bond... button (figure 9.36) makes it possible to change bond orders. Start by choosing two covalently bonded atoms, and press the Bond... button. The different possible bond orders are then shown (e.g. single, double, triple). If the Adjust atoms checkbox is checked, neighboring atoms will automatically have their hybridization and hydrogen count corrected. In cases where the automatic adjustments are unwanted, the Adjust atoms option can be disabled, which makes it possible to change bond order without updating atom hybridizations and geometry even though it might lead to chemistry issues.

7) Change stereochemistry

Image ligand_optimizer_stereo_changes
Figure 9.37: press the Stereo... button to change stereo chemistry.

The Stereo... button (figure 9.37) makes it possible to change the stereo chemistry of a ligand. In order to do this, a stereo center must be selected on the ligand. If the selected atom is not a stereo center (or there is no atom currently selected), any valid stereo centers will be automatically shown using cyan overlays on the 2D depiction.

Two types of stereo chemistry changes are possible: E/Z swaps (for SP2 hybridized atoms), where the groups on one side of a double (or delocalized bond) are rotated 180 degrees, and R/S inversions (for SP3 hybridized atoms) where two different groups are swapped. For R/S inversions, we swap the two smallest attached groups. The stereochemistry options are not enabled on atoms with two identically attached groups.

8) Rotate around bonds

Image RotateAroundBonds
Figure 9.38: Tick off the Rotate around bonds check box, to enable manual rotation around bonds in the ligand.

It is possible to rotate part of a ligand relative to the rest, around a covalent bond.

In order to do this, first check the Rotate around bonds option. Then select a single atom. Circular double-headed arrows will then appear on rotatable bonds next to the selected atom in the 3D view (figure 9.39).

Image BondRotationArrows
Figure 9.39: Click-hold-drag from an arrow in the 3D view, to rotate that part of the molecule with respect to the rest.

Click the arrow belonging to the part of the molecule you wish to move, and hold the mouse button while dragging. The part of the ligand containing the selected atom will stay in place. Release the mouse button when the rotated part of the molecule is in the wanted position.

While dragging, the arrow will turn green and snap to the most natural rotamers. For instance, two covalently bonded SP3 atoms will snap to the staggered positions with a 120 degrees rotational symmetry.

Notice that it is not possible to rotate around bonds in ring structures or bonds that only connect to terminal atoms.

9) Modifying rings

It is possible to modify ring geometry in the Ligand Optimizer. This is somewhat slower than other operations, since the small molecule geometry is subsequently minimized using a MMFF94-like force field. After that, the molecule is minimized with regards to the binding pocket geometry, similar to other Ligand Optimizer modifications.

Ring modifications may be performed by selecting two atoms and pressing the Bond... button. The following operations are possible:

Breaking a ring It is possible to break a ring by selecting two covalently bonded heavy atoms in a ring.

Creating a ring A ring may be formed by selecting two heavy atoms and pressing the Bond... button. (It is also possible to select hydrogens: a selected hydrogen will be treated as a selection on the heavy atom it belongs to.). Atoms inside an existing ring may also be fused. The ligand optimizer will present options for creating either an aromatic or aliphatic ring. Notice that aromatic ring creation is not always possible.

Changing bond order It is possible to modify the bond order by selecting two covalently bond heavy atoms, which are part of the same aliphatic ring structure.

Image break_ring
Figure 9.40: Breaking a ring in the Ligand Optimizer