Reaction Design Tool

The new Reaction Design Tool is live, and we have a puzzle headed your way! First a little bit about the tool itself. You all have been amazing in the realm of protein design, and now its time to step into the world of small molecule design. One approach in small molecule design is to modify or individually place each atom. This is a great approach, but it can have some short comings like the creation of chemically infeasible molecules, and the last thing we want is to create a wonderfully scoring small molecule that wouldn’t be possible in the real world, or worse would explode! So, the way around this is to use a reaction-based approach. With this approach you will be given fragments of a small molecule and its up to you to find the best way to combine them. The great thing about these fragments, or reactants as they will be known in the game, is that they are already determined to be synthesizable. Meaning that the small molecules you create can be produced in a lab, and possibly used for therapeutics.

The layout of the tool is in three major parts. First, at the top of the tool is the Reaction Panel. This panel allows you to choose the base of your new small molecule, or ligand as it will be known in game. These reaction options are the center of you new ligand. The reactions are surrounded by black spheres. Let’s call these linking atoms. These linking atoms are simply there to denote where your chosen fragments will connect to your reaction base. Note: linking atoms will mostly appear this way, but not always. The second major part of the tool is the Reactant Panel. The reactant panel is where each of the fragments are stored. In some puzzles you will only have one reactant to choose from, while in others you will be able to combine two or three. These reactants also display linking atoms so this way you can see how the reactant you choose will connect with the reaction base. The last part of the tool is the Accept Button. The accept button allows you to realize your creation in the context of the protein. Once you have selected your reaction base and your reactants, you will notice that not only is your ligand glowing blue, but it is now in the shape of the ligand you are trying to create. Once you are satisfied, click the accept button, and you will have created your new ligand! To get the best results you will need to optimize your newly created ligand, just like you would optimize a rebuilt/remixed loop. Wiggle, shake, and move your ligand to discover if it really is the best design for the protein.

Here are some tips to get you started. Just like the Genie from Aladdin, ligands have “phenomenal cosmic power!” Ok well maybe not, but they are quite powerful when it comes to their inactions with proteins. However, just like the Genie they have itty bitty living spaces. This living space is known as the activity pocket. You will need to design a ligand that best fits in this activity pocket. One way to do this is to look for hydrogen bonding. Hydrogen bonds help the ligand bind to the protein and therefore are immensely important. If after wiggling, the ligand gets pushed out of the pocket, or if it appears to be bending and stretching in odd ways, try lowering the wiggle power. A little nudge can go a long way. Also, the Reaction Design Tool tries its best to fit your newly designed ligand to its starting structure. This means that a different starting structure could produce a better resulting ligand, because it is oriented differently in the activity pocket.
We really hope you all enjoy working with this new tool and are extremely excited to see what you all come up with. Expect more small molecule/ligand design puzzles in the future.

Be sure to check out the new Reaction Design tutorial in the Campaign Menu.


Happy folding everyone!

( Posted by  jtscott 171 16006  |  Wed, 06/24/2020 - 20:03  |  6 comments )
1
nspc's picture
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Good idea

Very good idea ! But it is hard to use in the new puzzle for my first try. It will be better with more practice ^^.

I think it will be very usefull, congrats :) !

LociOiling's picture
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typo patrol

"they are quite powerful when it comes to their inactions with proteins"

should be "interactions"

jeff101's picture
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I found the Tutorial difficult.

I tried the Tutorial for this new tool.
It took me over 2 hours to complete,
but I do think it helped me prepare
well for Puzzle 1855.

Having more options in the Tutorial
like the clashing importance, wiggle
power, and bands would have helped.
I also think being able to see
negative scores and thousandths of
points would have helped.

jeff101's picture
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Groups: Go Science
Lower the score to pass

It would also help if the score needed to pass
this Tutorial were lower, perhaps by 100-200
points.

spmm's picture
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how does this work?

Mac OS10 - Did the tutorial - finally got the puzzle open without crashing - opened the ligand interface - one box at the top and three columns of boxes below with slide bars.

Click a lower box - nothing is added or altered in the top box but the ligand in the puzzle changes - no apparent addition or subtraction? Is there a secret key combo?

so is this just 'pick one of the boxes' wiggle and shake etc and repeat until you get lucky or are bored?
Sorry not getting how to do anything resembling design with it? Especially as I can barely see the ligand.

LociOiling's picture
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combinations...

A little late for 1855, but coming soon to the wiki and then video, but here's the words-only version.

Puzzle 1855 starts with arginine, one of our favorite amino acids, as the ligand.

The arginine is not part of a peptide chain, so the amino end (N terminal) and the acid end (C terminal) are available for chemistry. (Several arginine sidechain atoms are available for hydrogen bonds in the usual manner as well.)

In the reaction design panel, the horizontal box at the top gives the starting ligand. There's only one option for 1855, but there are two options in the intro puzzle.

It's very hard to see what's selected, but you'll notice a faint gray-blue outline when you click on a choice. It's thin, and is very close to the elevator bars in color, so hard to distinguish at a glance. A bright red or yellow outline would be easier to see.

The three vertical columns work on the starting ligand selected in the box at the top.

In 1855, the leftmost column lets you select the molecule that attaches to the N terminal of the arginine. The center column lets you select the molecule that attaches to the C terminal. You'll see a glowing preview of the results at you make selections. I found it helpful to pull the ligand out of the protein at zoom in on it while making selections.

The rightmost column in 1855 lets you select the "chirality", or left-handed versus right-handed form. This column may not be present on all puzzles. On 1855, the right column shows the two possible forms of arginine, one with the sidechain on the "left", one with it on the "right".

The effect of the chirality selection on the arginine is a little hard to see, but it has a big impact on the overall shape of the molecule. The arginine doesn't change as you make you're selection. Once you apply the selection, you can see a double-bonded oxygen migrate from one side of the backbone to the other. (Pictures on the wiki, soon.)

So you have to make selections for the box at the top and all three columns, then click on the "accept reaction result" beaker and test tubes icon at the bottom.

It's hard to see, but the initial default selections are made when you open the reaction design panel. So no clicking is required.

Once you made a choice, you can shake, wiggle (wiggle sidechains in particular), and move the ligand around as desired.

The reaction design panel doesn't have a cancel button, but if you close it using the "x", the starting ligand isn't changed.

(Edit: cleared up my own confusion over chirality after further research, fixed typos, and clarified a few points.)

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Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
Supported by: DARPA, NSF, NIH, HHMI, Amazon, Microsoft, Adobe, RosettaCommons