Journal Articles

Molecular Builders

by S. Murray

The Molecular Operating Environment known as MOE contains a collection of molecular builders that open the way to building and editing molecular systems of varying complexity, from small molecules and carbohydrates to crystals, in 3D space. The common thread that joins MOE builders -- by the same means setting them apart from other tools -- is their easy operation and the relative ease with which they can be customized by users to perform routine tasks.

To use the MOE builders, one need simply push a series of buttons (or enter strings) to obtain dynamic results in the 3D rendering window. Adding residues to a protein sequence or carbohydrate, or building fused ring systems of a small molecule is easy to accomplish. Builders are written in SVL (Scientific Vector Language developed by CCG), and all SVL code is shipped to end users making it possible to customize the builders as well as to develop applications.

This article outlines the features of each MOE builder:

Small Molecule Builder

One of MOE's long-standing features is the Small Molecule Builder, a convenient desktop tool for building molecular systems in MOE's 3D rendering window. The Molecule Builder is a substituent-based builder which provides a fast and effective way of constructing and editing molecular systems. Valence is automatically filled, and bond lengths and bond angles are determined, thereby substantially decreasing the need for minimization. Running the GizMOE Minimizer in parallel ensures that low energy conformations are generated.

Using the Builder, molecules are formed by making substitutions, usually at terminal hydrogen atoms, on smaller kernel molecules. The starting kernel molecule can either be loaded from an existing file or database, or "made from scratch" by performing substitutions on templates provided by the Builder. The series of ready-made templates, or molecular fragments, greatly facilitate substitutions and include ring systems, alkane chains, and functional groups. Substituents can be added or removed by customizing the contents of the Builder. Ring fusion substitutions are also possible. Yet another advantage is the ability to build custom ring systems by bonding atoms at the ends of chains.

The Builder is particularly handy in situations where one wishes to make multiple modifications to a single molecular template. A typical instance would be building a molecular database. In this case, the template is first built and saved to a database. Using the Molecule Builder, the template is progressively modified to produce the various derivatives of the basic molecule and populate the database.

In a few words, the Molecule Builder allows one to:

  • Enter new compound names
  • Edit molecular elements
  • Add standard substituents using built-in pushbuttons
  • Build alkane chains of varying length
  • Build ring systems
  • Add custom substituents using SMILES codes

Protein Builder

The Protein Builder constructs polypeptides from a library of 20 standard amino acids, three variants of histidine, and one hydroxylated proline. Pressing one of the buttons in the Residue bank appends the selected amino acid to the carboxyl terminal of the chain being built. As is the case for the Small Molecule Builder, residues can be added or removed from the library, leading to a customized version of the Protein Builder.

The Geometry button bank contains most common backbone dihedral angles. If Custom is selected, backbone conformation angles are determined by phi and psi values. The left-handed helices option forces left-handed geometry, negating the phi and psi angles of the standard helix conformations (non-helix geometries are not affected). Selecting the cis conformation sets the omega angle to 0 degrees.

The Acetylate N-Term creates an ACE N-terminus, the Amidate C-Term an NME C-terminus. Once an NME has been attached to a protein, no further residues can be appended.

Create Sequence Builder

The Create Sequence panel allows one to make polypeptide or DNA fragments from a string of single-letter identifiers. You can create a sequence of empty residues (i.e., without atoms) or a fully populated peptide chain in either extended or alpha-helix conformation. As for the DNA options, they create fully populated strands in A, B or C conformations.

Carbohydrate Builder

The MOE Carbohydrate Builder creates carbohydrate polymers by linking individual sugar residues at specific positions. In essence, it is very similar to the Protein Builder: one builds carbohydrate polymers by linking carbohydrate residues from a database of carbohydrate monomers. The Carbohydrate Builder contains a library of common residues, which are provided by a database supplied with MOE. This database can easily be customized to include new residues required by the user.

The builder also allows you to invert individual chiral centers or entire residues, mutate residues in existing carbohydrate structures, and specify the glycosidic torsion angles between residues when adding new residues to an existing structure.

Crystal Builder

As its name implies, the Crystal Builder builds and edits crystal structures. It offers 2D and 3D building capabilities, as well as full space group support. The image below, obtained using the Crystal Builder, shows an image of insulin, a cubic crystal with space group I213.

Graphical editing controls permit easy modification of both the unit cell parameters and asymmetric unit. The unit cell can be replicated into a supercell that can, in turn, be used as the asymmetric unit in subsequent crystal building.

The Crystal Builder provides the following functionality:

  • Builds/unbuilds crystals
  • Provides 230 three-dimensional and 87 two-dimensional space groups
  • Dynamic editing of unit cell using graphical controls
  • Re-positioning and re-orienting the asymmetric unit

The Crystal Builder displays information about the current cell. This information is updated dynamically as edits to the unit cell are made. The reported information is:

  • Full Hermann-Mauguin crystallographic space group symbol and International Tables of X-Ray Crystallography space group number
  • Crystallographic point group
  • Bravais lattice system
  • Cell volume (Ang3)
  • Cell density (grams/cc)

In Closing

MOE's family of builders allows users to create and edit small molecules, proteins, sequences, carbohydrates, and crystals. In addition to their distinctive features, all MOE Builders share fundamental characteristics: they are easy to use and provide immediate visual results in 3D. They can be used individually or, if need be, in conjunction with one another. Furthermore, as one becomes more and more familiar with SVL, one can customize their look, their features and their functionality.