Introduction of True Home Page

Release 2.4.0

The main change in this update is the addition of the first draft of a true home page for the site. Essentially, the new page serves to provide an outline of the chief functionality of the site in the format of interactive demonstrations. The key functionality verbs are "Explore" - demonstrating the ability to view and interact with the chemical structure of various organic molecules in the molecule editing tool, "Innovate/Solve" - demonstrating the ability of the pathway generator utility to find a molecular pathway between two organic molecules given optimization preferences, "Review/Deliver" - demonstrating the ability of the site to review, annotate, and approve or disapprove of proposed pathways, and "Discover" - a yet to be designed feature of the site to encourage exploration of hypothetical products of molecules in certain reactions.

In addition to serving as a demonstration of the chief functionality of the site, the page also serves to provide an overall snapshot of the current status and order of the site. As such, I expect the page to evolve as the rest of the functionality and the design of the site does. Ultimately this page may serve as a "lite" demonstration for non-registered users.

Standards - The standards of the home page directly mirror those of the rest of the site as they draw upon the same resources. E.g., the same IUPAC standards for molecule nomenclature are adhered to here as well.

Controls - The demonstrations have been designed to be self-explanatory. The "Try it!" section of each action description contains instructions for interacting with each section.

Future considerations - Certainly this page can benefit from a styling face-lift at some point, but the idea for this update was to get a functional draft of the demonstrations up. Further possible updates might be: the introduction of more sample metabolic pathways to view, support for more sample start/goal molecules in the pathway searcher, more organic molecules shown to explore, a more interactive sample of the process of reviewing a pathway, and the introduction of a discover demonstration.

Introduction of support for side chain alkyl substituents of molecules (Part I), molecules containing Sulfur atoms, molecules containing CoEnzyme A, and Modeling of Glycolysis and Tricarboxylic/Citric Acid cycle

Release 2.3.0
Another exciting update. Both the interface and the pathway search engine now support molecules containing simple side chains. Specifically, methyl radicals, including substituted methyl radicals. The user can view this additional feature by beginning with a pentane skeleton and adding a Carbon atom to either the second, third, or fourth Carbon of the pentane chain, thus creating either 3-methylpentane or 2-methylpenate. It should be noted that adding the Carbon to the first or fifth, the terminal Carbons of the skeleton, will cause a change in the recognized primary skeleton, by lengthening it, to hexane. Additionally the user can interact with the atoms of the side chain and add additional attachments. For example, by adding an Oxygen atom to the methyl side chain in 3-methylpentane the user can create 3-(hydroxymethyl)pentane.

Support is also now in place for molecules containing Sulfur atoms and CoEnzyme A. Similar to Phosphate, CoEnzyme A is represented as a single atom for simplicity.

In light of support for molecules with simple side chains, molecules with Sulfur, and molecules with CoEnzyme A, the Tricarboxylic/Citric acid cycle has now been modeled and added to the Biochemical Pathways page. Additionally, the second portion of the Glycolysis reactions has been added. Finally, the intermediate step, the conversion of the pyruvate resulting from Glycolysis to AcetylCoA for entry into the TCA cycle, has also been modeled and added.

In fact, an exciting result of support for parts or all of 4 different biochemical pathways is that we are now able to find a COMPLETE metabolic pathway for Ribulose-5-phosphate, the precursor of the molecule with which plants fixate Carbon Dioxide, all the way to Oxaloacetate, the molecule left over after energy has been captured from the initial Carbon Dioxide molecule via the Calvin cycle, Glycolysis, and the Citric acid cycle. A completely modeled pathway for everything that happens in one of the main pathways of a plant converting Carbon Dioxide to energy!

Standards - Per usual, standard IUPAC naming of molecules containing simple side chain rules apply. Of particular interest is rule P-65.1.2.2.1, concerning molecules with 3 or more carboxylic acid substituents: P-65.1.2.2.1 If an unbranched chain is linked to more than two carboxy groups, all carboxy groups are named from the parent hydride by substitutive use of the suffix ‘carboxylic acid’, preceded by the appropriate numerical prefix ‘tri’, ‘tetra’ etc. and appropriate locants. This is particularly relevant for Citric Acid/Citrate, the product of Acetyl CoA and Oxaloacetate that enters the Tricarboxylic acid cycle. The systematic IUPAC name of Citrate is 2-hydroxypropane-1,2,3-tricarboxylic acid, reflecting a primary chain of propane rather than pentane as the outer Carbons are considered part of the substituents only. This is furthermore relevant for other tricarboxylic acids in the TCA cycle.

Controls - The controls have fundamentally not changed. As mentioned previously, creation of a side chain is possible by first adding a Carbon to a skeleton as an attachment, and then adding attachments to that Carbon. CoEnzymeA functional groups can be created by adding a CoEnzyme A attachment to a Sulfur atom. Of note, restrictions have been placed to NOT allow molecules more complex than those currently supported to be created. For example, ethers, esters, and anhydrides are not YET supported, so an Oxygen atom cannot be bivalent.

Future considerations - Thus far, the creation process has been iterations of 1) building the infrastructure supporting the interface and pathway search engine, 2) adding functionality, supported pathways, and supported molecules 3) refining the infrastructure as better ways of modeling the molecules and pathways as well as interacting with the interface were discovered/imagined. Since adding support for molecules with side chains is a major step, I expect there to be plenty of refinements on the infrastructure in the near future. More excitingly, many new metabolic pathways are now supported and will shortly be added including fatty acid oxidation and some amino acid pathways. I also expect to soon add modeling of the first part of glycolysis, including representation of the ring form of D-glucose in the interface.

Quick Bug Fix

Release 2.2.2

A quick bug fix to the interface for when the user adds an addition to the molecule that causes the parent hydrocarbon chain of the molecule to change. An example of this case is when adding a Carbon (methyl group) to the 5th Carbon in pentan-1-ol. This will change the parent hydrocarbon chain from a pentane to a hexane chain. The new molecule will be named hexan-1-ol. Previously, there was a bug when attempting to modify the newly added Carbon by either attaching an addition to it, changing the charge, or modifying one of its attachments. As a note, anytime an interaction with the molecule causes the name of the molecule to change (for now the IUPAC name, though this will extend to common/other names as well), that name will be updated accordingly. This includes modifications of the parent hydrocarbon chain. This bug fix is of high priority in order to aid in the ongoing work to expand support for more complex molecules.

Implementation of support for EZ nomenclature, bug fix, and global site stereochemistry mode

Release 2.2.1

EZ nomenclature support has been implemented. Now in addition to the RS stereochemistry designations for atoms with chirality, attachment ordering around double bonds will be designated according to EZ nomenclature conventions. Similar to RS stereochemistry, the EZ nomenclature may be turned on and off, depending on the user's preferences. In off mode, any stereochemistry resulting from double bonds will not be named and enantiomers will not be considered separate molecules. Reactions will not target molecules with specific EZ stereochemistry. In on mode, double bonds that generate EZ stereochemistry WILL result in separate molecules, and these separate molecules will be targeted when considering reactions.

For this iteration, chiral stereochemistry generated by an addition reaction to an alkene will ONLY result in one enantiomer to be considered in the pathway generator. This generally results in S stereocenters, but that is not guaranteed, as a counter-example can likely be found. Nevertheless, for demonstration this can be seen by the generator successfully finding a pathway between (2E)-but-2-ene and (2S,3S)-2,3-dichlorobutane yet unsuccessfully finding a pathway between (2E)-but-2-ene and (2S,3R)-2,3-dichlorobutane. Furthermore, for this iteration, when a double bond is generated as a result of a reaction in the pathway generator and the double bond has alkyl segments protruding from both sides, ONLY the trans formation result will be considered. That is, (2S)-butan-2-ol to (2E)-but-2-ene will be successful, but (2S)-butan-2-ol to (2Z)-but-2-ene will not.

On a related note, the toggle stereochemistry button (previously toggle chirality) in the workspace will now be applied globally. When it is set to "hide stereochemistry" ALL molecules in the workspace will ignore stereochemistry (both RS and EZ) and vice versa. When the stereochemistry mode is off, the reaction butan-2-ol to but-2-ene will have a pathway found.

Finally this particular reaction previously caused an error when run in hide stereochemistry mode. This has been fixed.

Standards - IUPAC nomenclature will be followed. Cahn Ingold Prelog priority rules are followed for assigning E/Z designation of arrangements around double bonds. No further drawing changes were applied. As a note, trans isomerism (generally E, but not always) will not be considered for cyclical skeletons of length less than 10 for torsional strain reasons. As such, we will not consider any EZ stereochemistry for double bonds in a cyclical alkene of length less than 10.

Controls - Stereochemistry support mode may be toggled on and off by clicking on the hide/show stereochemistry button. This will control all aspects of stereochemistry support: nomenclature, molecule display, and reaction pathways. Stereochemistry for a specific stereocenter may be toggled by clicking on the stereocenter. In the case of a chiral stereocenter, toggling will alter the arrangements of the first 2 child attachments. This will result in a toggle of R -> S stereochemistry and vice versa. In the case of clicking on one of the Carbon atoms of a double bond, the arrangements of the attachments NOT involved in the double bond will be altered. This will result in a toggle of the E/Z nomenclature associated with that double bond.

Future considerations - I am interested in coming up with an alternative way to toggle stereochemistry, similar to having different methods to toggle bond size. Also, ALL products of stereochemistry generating reactions will be considered in the pathway generator. That is, the addition of Cl2 to but-2-ene will result in (2S,3S)-2,3-dichlorobutane, (2R,3R)-2,3-dichlorobutane, and (2S,3R)-2,3-dichlorobutane. (Not (2R,3S)-2,3-dichlorobutane as that is a meso isomer of (2S,3R)-2,3-dichlorobutane).

Restyling of inspector and introduction of common molecule names

Release 2.1.3

Restyled inspector to make properties of atoms and interactions clearer. Added common names for certain molecules, specifically parts of the Calvin Cycle. This will make the visualization clearer and more closely resemble pathway illustrations elsewhere such as Wikipedia and biochemistry textbooks. The IUPAC name is still present if the user hovers over the question mark icon next to the molecule name.

Quick bug fix and breadcrumbs

Release 2.1.2

A quick bug fix on interface interactions. Click detects were off following a zoom in or zoom out of the molecule. Also added basic breadcrumb navigation for pathways section.

Introduction of Persistent User-Generated Pathways

Release 2.1.1

I'm actually quite excited about this update. The user will now be able to save a generated pathway for both further reference to view/share and will be able to incorporate the generated pathway in other future pathway searches. The pathways page now contains both an index view of biochemical pathways (for now the same portion of the Calvin Cycle) and an index view of the user generated pathways. The user generated pathways index view will show the name and graphic representation of the start and end molecules of the pathway and a description of the pathway. The user may save/approve a new pathway after the pathway has been generated by clicking the "Approve" button and filling in any desired Notes. The primary benefit of this new feature is that it will allow the pathway generator to grow. As more pathways are discovered (be it from a third party reaction database, new reactions introduced to the local database, etc.) the pathway search will become more powerful and have more data points from which to generate better/more efficient pathways.

A very simple example of using the new persistence of generated pathways is to look at a pathway search for the reaction of converting cyclohexanol to cyclohexanone. Exploiting the ability to search the online Rhea DB for a reaction, we are able to find that the reaction Cyclohexanol Dehydrogenase will work. We are now given the option to approve the reaction. Once we do it will be saved and we may add it to the reactions we can query locally, using the MolGen Reactions search. We will then no longer need to query the Rhea DB for this particular reaction. Once the pathway is approved it will also show up in the index view of My Pathways.

Standards - At this stage room has been left for any standards deemed necessary in the future for approving proposed/generated pathways. I am anticipating a plethora of requirements, so obviously the approval process may be redesigned multiple times.

Controls - Pathways may now be approved and added to the library of known pathways by clicking the "Approve" button on a generated pathway. They may then be viewed in the My Pathways link on the Pathways page. Options for which source(s) to use for a pathway search may now be defined at the URL level by adding the parameter "?options=" followed by one or more of "Calc" (for Pathway Calculations), "Reac" (for local MolGen Reactions), and "RheaDB" (to use the Rhea DB).

Future considerations - It is evident that a tutorial and instructional documentation are becoming increasingly necessary. Also, I hope to add a more complex example of combining different sources used in a pathway search soon. The pathways index view will be expanded to allow more sophisticated navigation as well as search. Finally, the User Pathways section of the Pathways index view will be expanded to include pathways created by other users as well.