If applications are hard to design and toolkits are harder, then frameworks are hardest of all. A framework designer gambles that one architecture will work for all applications in the domain. Any substantive change to the framework's design would reduce its benefits considerably, since the framework's main contribution to an application is the architecture it defines. Therefore it's imperative to design the framework to be as flexible and extensible as possible.

-Erich Gamma, Richard Helm, Ralph Johnson, and John Vlissides- Design Patterns

One of the most important considerations when building an application is the choice of framework. As the quote from the Gang of Four implies, there's much more to frameworks than just a collection of re-usable code. At their best, frameworks provide a foundation for thinking about a problem domain and a language for communicating with other developers about it. In this article, I'll introduce Octet, an object-oriented framework for molecular representation.

The Molecular Representation Problem

Isn't molecular representation a solved problem? After all, don't SMILES, Molfile, InChI, and CML adequately represent any molecule the average software developer is likely to see?

As previously discussed, molecular representation technologies have stagnated while the molecules chemists themselves now routinely make and use have continued to become more and more "exotic." Developers are now faced with the thorny problem that a variety of common structural motifs in chemistry can't be adequately represented with industry-standard cheminformatics tools.

This point is so important, I'll repeat it: cheminformatics has fallen behind chemistry in the kinds of molecules it can work with. Quick fixes only allow the problem to fester; what's needed is a comprehensive solution. This is Octet's problem domain.

Every framework is bounded by a specific problem domain. Although the size of the domain can vary, a framework provides a comprehensive solution within it. For complex and poorly standardized domains (such as molecular representation), a good framework can greatly accelerate application development.

A good frameworks stays within its problem domain. One of the most important reasons is to prevent featuritis, the root of much software evil. Keeping a framework focused on its core mission makes it much more likely that it can remain documented, tested, extensible, and efficient.

By intention, a variety of features fall outside Octet's problem domain and so will never be directly supported. For example, rendering 2-D structure diagrams is a common problem in cheminformatics that has nothing to do with solving the molecular representation problem. Similarly, reading and writing SMILES strings and Molfiles are supported by many toolkits, but not by Octet directly. After all, it's the inherent limitations of these languages that Octet is trying to overcome.

Higher-level functionality such as legacy language support and 2-D rendering, although not part of Octet itself, can be developed with Octet as a foundation. For example, two Octet add-on frameworks specifically address these problems. They are called Rosetta and Structure, respectively.

About This Series

This article is the first in a series discussing Octet. Future articles will describe in detail Octet's design, implementation, and use. Although Octet has come a long way, it's far from finished. My motivation for writing these articles is to hear what you have to say about Octet, so please feel free to contact me.

Although Octet is written in Java, code examples discussed here will be written in Ruby. I've taken the same approach in discussing the Chemistry Development Kit (CDK) and Structure-CDK. Ruby's brevity and comfortable syntax make it ideal for both writing and discussing code.

Ruby Java Bridge (RJB) is the magic technology that makes this possible. Previous articles have discussed the installation and use of RJB on Windows and Linux.

A Simple Test

Assuming you've installed Ruby, RubyGems and Ruby Java Bridge, you can perform a simple demonstration of Octet in Ruby:

require 'rubygems'
require_gem 'rjb'
require 'rjb'

BasicMoleculeBuilder = Rjb::import('net.sf.octet.builder.BasicMoleculeBuilder')
RepresentationKit = Rjb::import('net.sf.octet.util.RepresentationKit')
MoleculeKit = Rjb::import('net.sf.octet.util.MoleculeKit')
System = Rjb::import('java.lang.System')

builder = BasicMoleculeBuilder.new

RepresentationKit.buildHexane(builder)

molecule = builder.releaseMolecule

MoleculeKit.printMolecule(molecule, System.out)

$ export CLASSPATH=./octet-0.8.2.jar
$ ruby test.rb
**Molecule Properties**

Atom Count: 6, Bonding System Count: 5

Atoms:
atom: C[0] (2nu 0e, 0or, 0.0fc, 1bs, 1n, 4.0val, 3ih )
atom: C[1] (2nu 0e, 0or, 0.0fc, 2bs, 2n, 4.0val, 2ih )
atom: C[2] (2nu 0e, 0or, 0.0fc, 2bs, 2n, 4.0val, 2ih )
atom: C[3] (2nu 0e, 0or, 0.0fc, 2bs, 2n, 4.0val, 2ih )
atom: C[4] (2nu 0e, 0or, 0.0fc, 2bs, 2n, 4.0val, 2ih )
atom: C[5] (2nu 0e, 0or, 0.0fc, 1bs, 1n, 4.0val, 3ih )

No non-natural isotopic distributions specified.

No Orbitals specified.

Bonding Systems:
bonding system:  ( 2be, 0abe, 2a, 1ap ) [ (0, 1) ]
bonding system:  ( 2be, 0abe, 2a, 1ap ) [ (1, 2) ]
bonding system:  ( 2be, 0abe, 2a, 1ap ) [ (2, 3) ]
bonding system:  ( 2be, 0abe, 2a, 1ap ) [ (3, 4) ]
bonding system:  ( 2be, 0abe, 2a, 1ap ) [ (4, 5) ]

Atom Pairs:
atom pair: (0, 1) (1.0 bo)
atom pair: (1, 2) (1.0 bo)
atom pair: (2, 3) (1.0 bo)
atom pair: (3, 4) (1.0 bo)
atom pair: (4, 5) (1.0 bo)

No Atomic Configurations specified.
No Conformation specified.

As you can see, Octet shares the same concepts and vocabulary as FlexMol. We'll drill down into the meaning of the output in later articles. The important thing to remember is that we can print out a report like the one above for any Molecule, no matter how complex.

Conclusions

Octet is an object-oriented framework designed to solve the molecular representation problem and serve as a solid foundation for a variety of cheminformatics applications. Of course, there's much more to Octet than the simple example shown here. Future articles will describe in greater detail the design and use of Octet through illustrative examples.

The representation of molecular structure decisively determines the scope of a chemical computer program. Our goal is to provide a versatile computer-oriented molecular structure representation for chemical information storage and retrieval as well as for computer-assisted synthesis design. Structural formulas describe molecular structure on the proper level of abstraction for these applications. ... It is therefore desirable that the computer-oriented representation of molecular structure be as expressive as the structural formulas.

-Andreas Dietz, J. Chem. Inf. Comput. Sci. 1995, 35, 787-802

A recent Depth-First article highlighted the difficulty that existing molecular languages have in communicating the generalized, multi-atom bonding present in metallocenes such a ferrocene. For software and Web services that do not interact with the outside world, the Ferrocene Problem may not be a big deal. But for the growing number that do, the Ferrocene Problem is but the tip of a very large iceberg.

Today's Weird-Looking Molecule is Tomorrow's Molecule of the Month

Consider the problem of axial chirality, such as that present in certain biaryls. None of the molecular languages currently in widespread use (InChI, SMILES, Molfile, or CML) provide a mechanism to faithfully represent and communicate this structural motif. In the 1980s, axial chirality was a novelty. Today it is ubiquitous. Consider this graphical abstract from the current issue of Organic Letters:

If you were asked to create an application capable of distinguishing substituted (R) and (S) binol enantiomers, could you do it? If your system needed to reliably interact with the outside world, could it do so? If you're working with any of the cheminformatics tools currently in widespread use, chances are good that the answers to these questions would be "no".

Do you still think of metallocenes as curiosities studied by a handful of organometallic chemists? Consider this J. Org. Chem. ASAP contents article describing one of the most fundamental transformations in organic chemistry:

The problem only gets worse as concepts like axial and planar chirality are increasingly co-mingled with multi-atom bonding. For example, consider the following graphical abstract, taken from J. Org. Chem. ASAP contents:

These molecules, and many others like them, were used in the context of organic chemistry. Moreover, the papers describing their use were published in widely-respected journals specializing in organic chemistry. Yet dozens of popular cheminformatics tools specifically designed for use with organic chemisty are incapable of faithfully representing the most interesting features of these molecules. In other words, the problem is both real and immediate.

Chemistry relentlessly marches forward, revealing even greater molecular information problems on the horizon. For software to remain relevant, it must be based on tools that are up to the challenge.

A Solution

The system proposed by Dietz offers a solution to nearly all of the bonding and stereochemistry problems of existing molecular languages. As a tradeoff, Dietz's system is significantly more complicated to implement. This places an increased burden on software to make the system as simple and understandable as possible.

Java and XML Implementations

Any specification, if it is to become more than just an academic exercise, requires a software implementation. Fortunately, for Dietz's system both a software implementation and an XML Schema have been developed and are freely-available.

The software implementation can be found in the Java framework Octet. In addition to fully-implementing Dietz's specification, Octet enables ring perception, substructure and query structure matching, breadth-first traversal, and of course, depth-first traversal. Add-on libraries are available for 2-D structure depiction, and Molfile and SMILES input and output. A CDK News article discusses CDKTools, a bridge to the Chemistry Development Kit. Octet remains, to my knowledge, the first and only implementation of the Dietz system.

The first, and to my knowledge only, XML implementation of the Dietz molecular representation system is FlexMol (Flexible Molecular Object Language). A commented W3C schema is distributed with Octet. Browser-ready HTML documentation can be found here, or from the sidebar links under "APIs and Schema Documentation." Octet is able to read and write FlexMol documents, providing an open, end-to-end solution to the problem of representing and transmitting molecules containing "nonstandard" bonding and stereochemistry.

Conclusions

Both FlexMol and Octet are convenient tools for working with the Dietz molecular representation system. Future articles in this series will show how they can be used to solve current, real-world molecular representation problems.