Depth-First: Tag configuration

A Molecular Language for Modern Chemistry: FlexMol, Tetrahedral Chirality, and Monolaterol

Rich Apodaca — Thu, 25 Jan 2007 15:16:00 +0000

Models of structure and bonding play a critical role in guiding chemical research. These models also define the scope and limitations of any cheminformatics system. Within the last several years, the gap between the structure and bonding models used by chemical information systems and by the chemists who use them has been widening. On this front, chemistry is moving much faster than cheminformatics. Sooner or later the difference must be reconciled.

A Looming Problem

Models of structure and bonding in cheminformatics, although adequate for organic chemistry in the 1970s, are outdated today. As recently discussed, some of the most interesting molecules in organic chemistry can't be adequately represented by 99% of the available cheminformatics tools. This may not be a problem if your clients never work with these molecules (but they probably are already). It may not be a problem if your system never interacts with the outside world where these molecules are prevalent (but it will eventually). A quick fix is likely to produce even bigger problems down the road. What's needed is a comprehensive solution.

FlexMol is a molecular language designed to solve this problem. For example, recent articles have demonstrated how FlexMol is capable of representing some of today's most difficult structural motifs: metallocenes; biaryl axial chirality; non-biaryl axial chirality; planar chirality; and non-tetrahedral stereochemical configuration.

Although FlexMol handles these tough cases, it's not merely a specialty language for "weird" molecules. Rather, FlexMol provides a basic set of elements and principles that can be applied to any molecule, regardless of its peculiarities or lack thereof. For example, FlexMol defines a clean system for the representation for alkene geometry. This basic level of functionality is not even provided by the industry-standard Molfile format, which requires 2-D atom coordinates.

In this demonstration, we'll turn our attention to one of the most basic problems in cheminformatics - the representation of tetrahedral chirality. Using an example molecule from the recent literature, we'll see how the principles outlined in previous FlexMol examples also apply to stereogenic carbons.

Conformation or Configuration?

We need to answer a basic question before we can represent tetrahedral chirality: should we use configuration or conformation? Following the simple principle that isomers interconvertible by bond rotation are conformational isomers and all others are configurational isomers, it's clear that we'll be using configuration. More rigorous definitions are offered by Dietz.

An Example

A recent paper describes the isolation of the plant natural product Monolaterol and the assignment of its absolute configuration. Using the structure and atom numbering system shown above, we can construct a complete FlexMol representation of Monolaterol. Rather than reproduce it here, let's just consider the stereochemically-relevant part:

<!-- snip -->
<configuration>
  <configurationWheel>
    <atomPair source="15" target="16"></atomPair>
    <halfPlane>
      <lower atom="14"></lower>
    </halfPlane>
    <halfPlane></halfPlane>
    <halfPlane></halfPlane>
    <halfPlane>
      <lower atom="12"></lower>
    </halfPlane>
  </configurationWheel>
  <configurationWheel>
    <atomPair source="15" target="12"></atomPair>
    <halfPlane>
      <lower atom="16"></lower>
    </halfPlane>
    <halfPlane></halfPlane>
    <halfPlane></halfPlane>
    <halfPlane>
      <lower atom="14"></lower>
    </halfPlane>
  </configurationWheel>
  <configurationWheel>
    <atomPair source="15" target="14"></atomPair>
    <halfPlane>
      <lower atom="12"></lower>
    </halfPlane>
    <halfPlane></halfPlane>
    <halfPlane></halfPlane>
    <halfPlane>
      <lower atom="16"></lower>
    </halfPlane>
  </configurationWheel>
</configuration>
<!-- snip -->

Notice that three configurationWheels are defined. As in the case of representing the configuration of square-planar species, each substituent of the chiral center is in turn placed along a wheel's axis, giving three wheels in total for Monolaterol. The relationships among atoms, planes, and axes is represented in the following cartoon:

Notice also that there are two empty half-planes in each conformationWheel. Half-planes occur in pairs spaced 180 degrees apart. Given that there are two neighboring atoms to place into half-planes, two half-planes will be empty. We nevertheless must include them as placeholders. Notice that virtual hydrogens (those hydrogens not explicitly defined as part of the atoms element) are not placed into half-planes.

It should be clear that the FlexMol representation of Monolaterol's (R)-enantiomer is distinguishable by visual inspection or by software. Each configurationWheel would be enantiomeric. As a result, the ordering of half-planes about their respective axes would be inverted.

So What?

Most cheminformatics tools can represent tetrahedral chirality. In nearly every case, this is accomplished with stereodescriptors, atom parities, or chiral flags. Extending these systems to non-tetrahedral chirality requires more templates - a difficult, if not impossible, task in most cases. Worse still, such systems are often based on poorly-documented conventions, resulting in a great deal of confusion when writing software implementations.

FlexMol takes a completely different approach by actually describing the chiral environment around an atom in terms of a simple system of axes and planes. The rules governing these elements are applied regardless of the kind of chirality being represented. This results in a system that works consistently for known forms of chirality, and which can be extended as new forms of chirality are encountered.

A Software Implementation

Any new molecular language requires a software implementation. For FlexMol, that implementation is provided by the Octet Framework. Octet is open source software written in Java that provides a FlexMol reader, a FlexMol writer, and many tools for working with molecular representations.

Conclusions

Although not often discussed, models of bonding and structure figure prominently in the ability of cheminformatics software to solve relevant problems. This is especially true in the increasingly important area of molecular chirality. In this area, FlexMol offers a system with unprecedented flexibility; it works just as well with stereogenic carbon as with numerous, less common forms of chirality.

A Molecular Language for Modern Chemistry: Cisplatin, Transplatin, and Molecular Configuration

Rich Apodaca — Wed, 17 Jan 2007 15:18:00 +0000

Recent articles have discussed FlexMol as a new language capable of representing many of today's most difficult molecules: metallocenes; axially-chiral biaryls; and other forms of axial chirality. FlexMol can also encode more common molecular features such as E/Z alkene geometrical isomerism. So far, discussions of stereochemistry have been limited to molecular conformation. In this article, I'll demonstrate how FlexMol encodes molecular configuration, using cisplatin and transplatin as examples.

The Difference Between Configuration and Conformation

FlexMol's distinction between configuration and conformation is a simple one: if two isomers can't be interconverted by bond rotations, then configuration is used to describe them. Otherwise, conformation is used. The geometrical isomers of dichlorodiamino platinum fall into the former category. For more rigorous definitions, see Dietz' original specification on which FlexMol is built.

Cisplatin

Cisplatin consists of a central platinum atom surrounded by two chloro ligands and two amino ligands arranged at the corners of a square. Using the numbering system present in the structure above, we can construct a complete FlexMol representation. Rather than reproduce the entire document here, I'll just highlight the stereochemical aspects. In contrast to the other FlexMol examples covered on Depth-First to date, this example contains a configuration element:

<!-- snip -->
<configuration>
  <configurationWheel>
    <atomPair source="Pt0" target="N4"></atomPair>
    <halfPlane>
      <center atom="Cl2"></center>
    </halfPlane>
    <halfPlane>
      <center atom="N3"></center>
    </halfPlane>
  </configurationWheel>
  <configurationWheel>
    <atomPair source="Pt0" target="N3"></atomPair>
    <halfPlane>
      <center atom="N4"></center>
    </halfPlane>
    <halfPlane>
      <center atom="Cl1"></center>
    </halfPlane>
  </configurationWheel>
  <configurationWheel>
    <atomPair source="Pt0" target="Cl1"></atomPair>
    <halfPlane>
      <center atom="N3"></center>
    </halfPlane>
    <halfPlane>
      <center atom="Cl2"></center>
    </halfPlane>
  </configurationWheel>
  <configurationWheel>
    <atomPair source="Pt0" target="Cl2"></atomPair>
    <halfPlane>
      <center atom="Cl1"></center>
    </halfPlane>
    <halfPlane>
      <center atom="N4"></center>
    </halfPlane>
  </configurationWheel>
</configuration>
<!-- snip -->

Notice that the most of the subelements of cisplatin's configuration were also used in the context of conformation. The three main differences are:

The element configurationWheel is used in place of conformationWheel;
Instead of a gammaSequence each chiral axis is described by an atomPair only;
There are as many configurationWheels as neighbors on a configurational atom. In this case, platinum is the configurational atom. It has four neighbors, and so four configurationWheels appear. Each neighbor is in turn placed at the target of the chiral axis.

To better visualize cisplatin's configuration, consider the four diagrams below, each of which represents one configurationalWheel. Given the cisplatin's square-planar geometry, each "wheel" in this case consists of only two opposing halfPlanes.

There are a few things to notice. First, each configurational halfPlane is divided into three sections: lower; upper; and center. A center designation means that an atom sits precisely on the line bisecting a given half-plane. As with conformational half-planes, upper means the part of the half-plane closest to the axis endpoint; lower means the part of the half-plane furthest from this atom. Second, notice that an atom oriented 180 degrees from the direction of the chiral axis is not assigned to a halfPlane because it occupies none. As we shall see, this is not a limitation.

Transplatin

How does this system allow us to distinguish cisplatin from transplatin? Given the atom numbering as shown above, we can construct the complete FlexMol representation. The configuration element is shown below:

<!-- snip -->
<configuration>
  <configurationWheel>
    <atomPair source="Pt0" target="Cl2"></atomPair>
    <halfPlane>
      <center atom="N3"></center>
    </halfPlane>
    <halfPlane>
      <center atom="N4"></center>
    </halfPlane>
  </configurationWheel>
  <configurationWheel>
    <atomPair source="Pt0" target="N3"></atomPair>
    <halfPlane>
      <center atom="Cl1"></center>
    </halfPlane>
    <halfPlane>
      <center atom="Cl2"></center>
    </halfPlane>
  </configurationWheel>
  <configurationWheel>
    <atomPair source="Pt0" target="Cl1"></atomPair>
    <halfPlane>
      <center atom="N3"></center>
    </halfPlane>
    <halfPlane>
      <center atom="N4"></center>
    </halfPlane>
  </configurationWheel>
  <configurationWheel>
    <atomPair source="Pt0" target="N4"></atomPair>
    <halfPlane>
      <center atom="Cl1"></center>
    </halfPlane>
    <halfPlane>
      <center atom="Cl2"></center>
    </halfPlane>
  </configurationWheel>
</configuration>
<!-- snip -->

The arrangement of planes can be represented by the diagram below:

As you can see, the cisplatin and transplatin configurations are clearly distinguishable by inspection. Notice that we have not resorted to chiral flags, atom parities, or any form of stereochemical template. When a new atom geometry is desired, for example trigonal bipyramidal, octahedral, t-shaped, or otherwise, exactly the same rules apply.

A Software Implementation

It's not difficult to write software designed to compare stereochemical configurations in the same way as it is done manually. For example, this has been fully implemented in Octet.

So What?

At least one other language shares FlexMol's ability to encode square planar stereochemistry: SMILES. The difference is that FlexMol uses no templates, resulting in a rule-based, extensible language. SMILES, on the other hand, uses chiral templates. If your molecule doesn't fit one of these pre-defined templates, you can't encode its stereochemistry with SMILES and expect a third party to be able to understand it. This is the unavoidable consequence of a template-based stereochemistry encoding system such as the one used by SMILES.

Conclusions

FlexMol offers a completely new way to think about encoding stereochemistry with computers. The method is both flexible and systematic. It does away with the need for inherently confusing and limited constructs such as atom parities, chiral flags, and stereochemical templates in favor of actually describing the stereochemical environment of atoms in a molecule. One stop remains on this introductory tour of FlexMol and stereochemistry: tetrahedral chirality.

A Molecular Language for Modern Chemistry: FlexMol and Alkene Geometrical Isomerism

Rich Apodaca — Tue, 02 Jan 2007 15:39:00 +0000

The fundamental idea behind our representation of stereochemistry is to really describe the relative spatial arrangements of the atoms of a chemical structure. For a given constitution, we obtain a unique and unambiguous stereochemical representation. No limitation to predefined types or steregenic units exits; any conceivable relative spatial arrangement of atoms may be uniformly represented by one universally applicable formalism. ...

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

A recent article introduced FlexMol, a molecular language designed to encode the multi-atom bonding arrangements present in molecules being increasingly made and used by today's chemists. But FlexMol was designed with much more than bonding in mind. Of all of the difficult areas in molecular representation, perhaps none are more daunting than stereochemistry. This article will introduce the basic ideas behind FlexMol's stereochemistry capabilities using the geometrical isomers of 2-butene as an example.

The Difference Between Configuration and Conformation

FlexMol distinguishes between two complementary stereochemical concepts - conformation and configuration. The difference between the two lies in whether isomers can be interconverted through bond rotations. To paraphrase Dietz:

Conformation. Two molecules with identical atom connectivities and bonding differ with respect to their conformation if if they possess different relative spatial arrangements of atoms that can be interconverted by rotations about bonds.
Configuration. Two molecules with identical atom connectivities and bonding differ with respect to their configuration if they possess different relative spatial arrangements of atoms that can not be interconverted by rotations about bonds.

Notice that these definitions say nothing about whether a bond rotation is likely to occur; they simply refer to the possibility of isomer interconversion through bond rotation. Clearly, double bond geometrical isomerism arises from restricted bond rotation. So we'll be relying on FlexMol's support for conformational stereochemistry.

Encoding Cis/Trans Isomerism: 2-Butene

Consider the two isomers of 2-butene. The cis isomer can be encoded in FlexMol as follows:

<!-- cis-2-butane -->
<?xml version="1.0" standalone="yes"?>

<molecule>
  <constitution>
    <atoms>
      <atom id="C0" symbol="C" hydrogens="3" ionization="4"></atom>
      <atom id="C1" symbol="C" hydrogens="1" ionization="4"></atom>
      <atom id="C2" symbol="C" hydrogens="1" ionization="4"></atom>
      <atom id="C3" symbol="C" hydrogens="3" ionization="4"></atom>
    </atoms>
    <bonding>
      <bond source="C0" target="C1" bondingElectrons="2"></bond>
      <bond source="C1" target="C2" bondingElectrons="4"></bond>
      <bond source="C2" target="C3" bondingElectrons="2"></bond>
      <bond source="C3" target="C4" bondingElectrons="2"></bond>
    </bonding>
  </constitution>
  <conformation>
    <conformationWheel>
      <gammaSequence source="C1" target="C2">
        <connections>
          <atomPair source="C1" target="C2"></atomPair>
        </connections>
      </gammaSequence>
      <halfPlane></halfPlane>
      <halfPlane>
        <lower atom="C0"></lower>
        <upper atom="C3"></upper>
      </halfPlane>
    </conformationWheel>
  </conformation>
</molecule>

In contrast to previous FlexMol examples, this representation contains a conformation element, which in turn contains a conformationWeel subelement. The conformationWheel is composed of a gammaSequence and two halfPlanes. The relationship among these elements can be seen in the diagram below.

Stereochemical representation in FlexMol boils down to placing atoms into a set of half-planes intersecting a given axis (Dietz refers to this arrangement as a "pencil of planes"). In the case of cis-2-butene, this axis, or gamma sequence, is the atom pair between atoms C1 and C2. A gamma sequence can consist of two or more atoms, a very useful feature for representing allene stereochemistry, for example. Half planes are specified in clockwise order about this axis. Because half planes always occur in pairs separated by 180 degrees about their common axis, the number of half planes will always be even. Each conformational half plane is further subdivided into two regions labeled appropriately enough "upper" and "lower".

A conformation wheel will always have an equivalent, but opposite representation. For example, cis-2-butene could also be represented with an axis of opposite orientation (C2->C1), opposite ordering of half planes (in this case the same ordering because there are only two half planes), and inverted upper/lower designations. FlexMol only requires that one of these two equivalent arrangements be specified.

In a similar fashion, we can generate a FlexMol representation for trans-2-butene:

<!-- trans-2-butane -->
<?xml version="1.0" standalone="yes"?>

<molecule>
  <constitution>
    <atoms>
      <atom id="C0" symbol="C" hydrogens="3" ionization="4"></atom>
      <atom id="C1" symbol="C" hydrogens="1" ionization="4"></atom>
      <atom id="C2" symbol="C" hydrogens="1" ionization="4"></atom>
      <atom id="C3" symbol="C" hydrogens="3" ionization="4"></atom>
    </atoms>
    <bonding>
      <bond source="C0" target="C1" bondingElectrons="2"></bond>
      <bond source="C1" target="C2" bondingElectrons="4"></bond>
      <bond source="C2" target="C3" bondingElectrons="2"></bond>
      <bond source="C3" target="C4" bondingElectrons="2"></bond>
    </bonding>
  </constitution>
  <conformation>
    <conformationWheel>
      <gammaSequence source="C1" target="C2">
        <connections>
          <atomPair source="C1" target="C2"></atomPair>
        </connections>
      </gammaSequence>
      <halfPlane>
        <upper atom="C3"></upper>
      </halfPlane>
      <halfPlane>
        <lower atom="C0"></lower>
      </halfPlane>
    </conformationWheel>
  </conformation>
</molecule>

This representation contains a conformationWheel with two filled half planes containing the atoms C3 and C0, respectively. The arrangement among the conformational elements can be better seen in the following diagram:

So What?

There are many ways to represent alkene geometrical isomerism, most of which are far simpler than the one outlined here. So what does this additional complexity buy us? In FlexMol, we can use exactly the same formalisms we used for 2-butene isomers to represent the stereochemistries of molecules that simply can not be represented in other systems. Two specific examples include the axial chirality of allenes and biaryls. If you'd like some hints on how to accomplish this, see the allene and binaphthyl FlexMol examples contained in the flexmol directory of the Octet source distribution.

Notice how FlexMol does away with the need to define conformation in terms of sterochemical descriptors, which are quite limited. Instead, FlexMol provides a small set of modular concepts that, when used together, actually describe the underlying conformational features of a molecule. Of course, (E) and (Z) descriptors (and a host of others as well) can be derived from a FlexMol representation given the right software.

Conclusions

We've covered the essentials for conformational representation in FlexMol, and we've seen how to differentiate double bond geometrical isomers. The same principles described here are also used in encoding stereochemical configuration, which will be the subject of a future tutorial.