Water/Fragment Map Simulations

What are Water/Fragment Map Simulations?

Much discussion is given to the theory of water and fragment simulations in the Compound Design section. 

For the purposes of summary: Water and Fragment simulations are performed using the Simulated Annealing of Chemical Potentials methodology to lower the chemical potential of the fragments or water in the cell until only the strongest interacting/binding components remain. For water, a common solvent in biological systems, the presence of strongly binding waters on a protein is often indicative of stable water retained on the surface that may prevent drug/ligand interactions. Possessing the chemical potentials or interaction energies of the ligand or water then becomes very important for determining the competitive equilibrium for interacting/binding with that site on the protein.

BMaps currently possesses almost 500 proteins pre-computed with 136 fragments with ~100 snapshot conformations per fragment giving billions of fragment poses. BMaps currently contains ~3500 fragments, and custom fragments may also be added. If you have a fragment/protein combination not currently pre-computed then you will need to run a fragment or water simulation to explore hotspot analysis, retained water positions, fragment based drug design, etc. In the following section we will detail the practical steps to do this. See the Workflows section for how fragment/water map simulations can fit into a larger drug design pipeline.

Water/Fragment Map Simulation Access

To access the water and fragment map simulation setups, go to the right hand tool bar and click "Modeling Tasks" followed by either "Run Water Sim." or "Run Frag. Sim.".

Water Map Simulation Setup Menu

Simulation Type

From any of the water, fragment, or hot spot simulation menus, you can switch to the other simulation menus using the radio buttons under the Simulation Type header.

Simulation System

Under the Simulation System header, there is either the name of the protein in your workspace if you only have one loaded in, or else a dropdown from which you can select from the proteins in your protein selector menu. Note that the protein does not need to be active in the 3D workspace in order to show up in this menu.

After a protein is selected, two more sections will appear. The first is a compound selector drop-down. From here you can add a compound associated with the selected protein to be included as part of the environment for the simulation. Note that only one compound can currently be added to the environment using this drop-down. See Advanced Parameters for how to add additional compounds at once.

The second section that appeared, Target Chains/Ions, allows you to select which chains of the protein you wish to have included in the simulation. You need to select at least one chain or else a warning will appear and you will not be able to prepare the system.

Advanced Parameters

Add Binding Site Specification

This will focus the simulation to only occur around the binding site, which will allow the simulation to finish faster. This is generally only useful for fragment simulations. 

Filter out low confidence AlphaFold residues

If a protein is imported from Alphafold, then the low confidence residues will be removed from the simulation if this box is selected. This is especially important for sections that are low confidence due to high mobility as the static protein within the simulation may not be representative of the actual water/fragment interaction with that portion. Thus, removing the low confidence portion, which is often quite big, can save a lot of simulation time without removing useful meaning.

Use Selection

If you had selected part of the system before opening the Simulation Setup menu, then you can select this checkbox to use all selected atoms as part of the environment. Note that this is how you can include multiple compounds as part of the environment of a simulation.

System Name

Target Protein Name will group all structures and simulations data under your chosen name in the Protein Selector menu after simulation. 

Structure Name will group all fragment/water data under your chosen name in the Fragments Selector menu after simulation.

Clicking the button will prepare the simulation to be run. Preparing the system performs some backend validation and file creation. It is important to note that currently we have a limit on simulation runs to 500 residues. If you need to use a system that is bigger than that, please contact us to setup your simulation. 

After the system is prepared for simulation, you will see a new button, , which will open up a separate page dedicated to the simulation shopping cart where you can see the expected cost of this simulation run.

Simulation Shopping Cart

Currently users receive 20 free fragment simulations a month. Additional water or fragment simulation costs are shown in the shopping cart page. More on the Simulation Shopping Cart is discussed below. 

Checking Simulation Status

From the Simulation Setup menu, you can select the hyperlink View simulation status at the bottom of the menu to check on current simulation progress. This will by default open a separate tab in your browser that shows current runs, completed runs, and provides the option to archive runs to clean up your window space. From this menu, you can also use the hamburger button in the upper right to switch to the fragment manager, simulation shopping cart, or fragment search. 

Fragment Library Search 

This page has a bunch of unique features for fragment management that are especially useful if you are considering whether or not to add your own fragment set.

When you first arrive to the Library search page,  the default library selected in the Search Library box will be the BMaps Fragments. From this box you can select any of the already existing fragment sets or select custom fragments to see the fragment you have added into BMaps. "pick fragment set" will allow you to select subsets from the BMaps Fragments library. 

After selecting the library in which you wish to search, you can also filter by molecule name or substring of the name, or else chemical properties. The potential properties have both upper and lower bounds options and include Molecular Weight (Mol. wt.), Heavy Atom Count (HAC), LogP, Hydrogen bond doner count (HBD), Hydrogen bond acceptor (HBA) , Topological Surface Area (TPSA), and Rotatable Bond Count (RBC). Required Elements can also be listed with commas in between them.

Alternatively, you can also open the sketch menu and select to use the similarity or substructure search of the drawn compound. 

Finally, after your search is setup, click the magnifying glass search button to update the right panel with fragments matching the filter criteria.

If you scroll over or click on a fragment in the right side panel you will see the properties fir that fragment. If you click on the fragment, four buttons appear in the selection bar at the top.

The first allows you to edit the selected fragment in the sketcher. The seconds allows you to search for the selected fragment in PubChem. The third adds the fragment to the simulation shopping cart. The fourth allows you to save the fragment to a new or existing custom fragment library.

If you select more than one fragment, the first two options will disappear. Left and right arrows in the selection bar at the top allow you to flip between fragment pages.

Fragment Map Simulation Setup Menu

Much of the Simulation Setup menu is the same for fragment maps as it is for water map simulations. However, here we will detail the differences.

Simulation System

In place of a compound selector, the simulation will let you know if there is already a simulation setup for your protein. If you choose to keep this setup, then you do not need to select which chains of the protein or System Names you wish to use. The only parameters you will be able to change are the advanced parameters if there are any relevant.

If however you select "Specify a new simulation setup", then the chain, name, and advanced parameters unlock and you will need to prepare the system again. Preparing the system performs some backend validation and file preparation.

Simulation Shopping Cart

In the simulation shopping cart you will be able to add fragments by scrolling over the dropdown to select a fragment library, perform a fragment search, or import fragments you wish to use. After selecting your method of fragment addition and returning to the Simulation shopping cart, you will see the fragments in the left side box. You can select them all with the checkbox at the top of this box and then either remove selected, save the selected for later, and/or specify how many simulations you want run with each fragment selected. You can also perform these actions for each fragment independently under their name.

Note that either Remove selected or Remove from cart need to be selected to update the Job Summary on the right. Deselecting the fragments in the left hand panel will not update the cart. Also note that both waters and fragments can be added to the cart simultaneously by clicking the Waters checkbox and selecting how many water map runs you wish to do.

On the right side is the Job Summary. It will outline how many fragment and water maps are being run and how many times. It will also note the balance of free simulation runs as well as home many you will need to purchase. Your payment method may be added through the Add Card button which will take you to your account management page. 

Below the cost box is also the option to add a phone number to receive notifications when simulations start and stop so you can monitor your jobs without being at your desk. If you are running water simulations, the advanced simulations menu also offers the solvation model checkbox one more time.

Hitting submit will start your simulations and bring your window to the Fragment runs page where you can monitor your job status. Note that if you log out the submitted jobs will continue and can be revisited through this menu.