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 60 733 | Wed, 06/24/2020 - 20:03 | 7 comments )