Ibuprofen Cyclodextrin Inclusion Complexes with the Martini Coarse-Grained Force Field

Tutorial Created with Software Release: 2026-1
Topics: Pharmaceutical Formulations
Methodology: Coarse-Grained Modeling
Products Used: Desmond, MS CG, MS Maestro

Tutorial files

0.3 GB
This tutorial is written for use with a 3-button mouse with a scroll wheel.
Words found in the Glossary of Terms are shown like this: Workspacethe 3D display area in the center of the main window, where molecular structures are displayed

 

Tip: You can hover over a glossary term to display its definition. You can click on an image to expand it in the page.
Abstract:

 

In this tutorial we will prepare and simulate a coarse-grained formulation containing ibuprofen and beta-cyclodextrin with the Martini force field. The self-aggregating system is analyzed with cluster analysis and radial distribution function tools.

 

Tutorial Content

  1. Introduction

  1. Creating Projects and Importing Structures

  1. Generating Coarse-Grained Inputs

  1. Building the Simulation Box and Assigning the Force Field

  1. Performing a Multistage Simulation Workflow

  1. Performing Cluster Analysis

  1. Analyzing the Radial Distribution Function

  1. Conclusion and References

  1. Glossary of Terms

1. Introduction

Drug molecules with poor water solubility can be solubilized with prudent formulation. For example, cyclodextrins (CD), a family of macrocyclic oligosaccharides, are commonly added to pharmaceutical formulations to solubilize hydrophobic compounds. In particular, alpha, beta and gamma cyclodextrin, characterized by the count of glucose subunits, 6, 7 and 8, respectively, are common benign additives which can form inclusion complexes with small molecules. Ibuprofen, a prototypical API (active pharmaceutical ingredient) is well-known to have poor water solubility, demonstrated computationally in the Molecular Dynamics Simulations for Active Pharmaceutical Ingredient (API) Miscibility tutorial. In this tutorial, we will study the aggregation of ibuprofen and beta-cyclodextrin (β-CD), and their tendency to form inclusion complexes.

Figure 1: β-cyclodextrin, ibuprofen and an inclusion complex

All-atom simulation can struggle to reach the length and time scales necessary for observing self-assembly in complex formulations. Coarse-grained methods can more easily access these length and time scales. A coarse-grained model represents molecules or fragments of molecules using coarse-grained particles (sometimes referred to as beads or sites), each of which corresponds to a set of atoms. Particles may represent a molecular fragment, a whole molecule or a set of molecules. An appropriate mapping from an all-atom system to a coarse-grained one can be determined based on the underlying molecular system and the physical phenomena taking place. To build coarse-grained models, the mapping must be determined, as well as all of the parameters that describe the interactions between particles.

In this tutorial, we employ the Martini force field. The Martini force field is one of the most widely used coarse-grained force fields. Martini force field parameters can be obtained or adapted for many molecules from the literature (there are 1000's of articles). If novel molecules are being used as an initial step, it is often helpful to assign initial guesses for appropriate Martini particle types using experimental logP (partition coefficient) values. Please consult Selecting Martini Parameters in the help documentation for suggestions on how to proceed. In the end, comparison of simulation results for small systems with experimental behaviors of interest is a good way to check parametrization and gain insight into what refinements may be needed.

For Martini models, one tries to have particles that represent 2 to 4 heavy atoms along with their bound hydrogen atoms. In addition, ideally, we do not want to split functional groups. All of the potential terms can be obtained based on relation to known parameters (Guess), an average of bonded atomistic interaction (Average), user input based on supplied information (Edited) or from a database of known parameters (Database). This tutorial will use a mix of Guess, Edited and Database parameters.

The model system that we will construct and study herein will consist of β-CD, deprotonated ibuprofen, sodium cations and water. Materials Science Maestro has importable Martini models for β-CD, sodium cation and water components. For ibuprofen, we will learn to map particles and assign force field parameters. Once we have defined all of the parameters, we will perform molecular dynamics (MD) simulations to study the aggregation of the system, and use the cluster analysis and radial distribution function tools to analyze the simulation results. The overall workflow is summarized in the following schematic:

In this tutorial, we will use various panels in the Materials Science (MS) Maestro interface. For the corresponding help documentation, see Coarse-Grained Sketcher, Disordered System Builder, Coarse-Grained Force Field Assignment, MD Multistage Workflow, Cluster Analysis and Radial Distribution Function.

In addition to the panel help documentation, we recommend visiting the overview of Coarse-Grained Modeling in the Materials Science Suite. For this tutorial, it is recommended to read Potentials and Simulation Types for Coarse-Grained Modeling, Coarse-Grained Modeling with the Martini Force Field, and Selecting Martini Parameters.

2. Creating Projects and Importing Structures

At the start of the session, change the file path to your chosen Working Directorythe location where files are saved. in MS Maestro to make file navigation easier. Each session in MS Maestro begins with a default Scratch Projecta temporary project in which work is not saved, closing a scratch project removes all current work and begins a new scratch project., which is not saved. A MS Maestro project stores all your data and has a .prj extension. A project may contain numerous entries corresponding to imported structures, as well as the output of modeling-related tasks. Once a project is saved, the project is automatically saved each time a change is made.

Structures can be built in MS Maestro or can be imported using File > Import Structures (or drag-and-dropped), and are added to the Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion. and Project Tabledisplays the contents of a project and is also an interface for performing operations on selected entries, viewing properties, and organizing structures and data.. The Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion. is located to the left of the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed.. The Project Tabledisplays the contents of a project and is also an interface for performing operations on selected entries, viewing properties, and organizing structures and data. can be accessed by Ctrl+T (Cmd+T) or Window > Project Table if you would like to see an expanded view of your project data.

  1. Double-click the Materials Science icon

Figure 2-1. Change Working Directory option.

  1. Go to File > Change Working Directory
  2. Find your directory, and click Choose
  3. Pre-generated files are included for running jobs or examining output. Download the zip file here: schrodinger.com/sites/default/files/s3/release/current/Tutorials/zip/ibuprofen_martini.zip
  4. After downloading the zip file, unzip the contents in your Working Directorythe location where files are saved. for ease of access throughout the tutorial

Figure 2-2. Saving the project.

  1. Go to File > Save Project As
  2. Change the File name to ibuprofen_martini and click Save
    • The project is now named ibuprofen_martini_tutorial.prj

3. Generating Coarse-Grained Inputs

In this section, we will use the Import Coarse-Grained Structures and Coarse-Grained Sketcher panels to prepare input models for the system.

Figure 3-1. Choosing structures in the Import Coarse-Grained Structures panel.

  1. Go to Tasks > Materials > Classical Mechanics > Coarse Grain Models > Import Coarse-Grained Structures
  2. From the Select structures to import list, choose WF_water, W_water, Na_ion and BCD_betacyclodextrin
    • WF_water is not shown in the figure, but is found higher up on the scrolled list
  3. Click Add
    • BCD_betacyclodextrin, Na_ion WF_water and W_water are displayed in is displayed in the Structures to import dialog box
  4. Click Import

Figure 3-2. The entry list after importing. The BCD_cg molecule is shown in CPK representation.

  1. Close the Import Coarse-Grained Structures panel

 

The entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion. is updated to include four entries: BCD_cg, Na_ion, WF_water and W_water. Feel free to stylize the molecules however you like. In the tutorial, we use the CPK representation.

These imported molecules are provided in the Schrödinger installation for use with the Martini force field. Force field parameters are available for these molecules, which we will see in Section 4.

BCD_betacyclodextrin is represented using three types of particles, which correspond to the molecular fragments shown in the image below (left). The connectivity of the CG particles is shown in the figure below (right). This mapping scheme was adopted from a literature model (Lopez et al., 2013; see References).

W_water and WF_water are a commonly used option in the Martini force field of using two types of water particles (W and WF, for water and antifreeze water, respectively) to reduce the chance that the solvent particles might freeze. Typically WF water particles are used to represent ~10% of water molecules to avoid water crystallization. W_water and WF_water each represent four water molecules.

Na_ion is used to represent a single sodium ion and three water molecules in solution.

Figure 3-3. The Coarse-Grained Sketcher panel.

Unlike water, sodium and β-CD, ibuprofen is not provided as an importable Martini molecule. So, we will have to sketch a coarse-grained representation:

  1. Go to Tasks > Materials > Classical Mechanics > Coarse Grain Models > Coarse-Grained Sketcher

 

The coarse-grained sketcher is a tool for drawing a coarse-grained structure in 2D and saving it as a project entry. Note that the structure is strictly 2D - unlike the 2D Sketcher - no conversion to 3D is done when the structure is saved, and the placement of particles with their interparticle distances is preserved.

Figure 3-4. Adding a particle.

  1. Click the Add Particle button ()
    • The Set Particle Properties panel opens
  2. For Name input IB1
  3. For Color choose magenta
  4. Click Use martini defaults
    • The Radius and Mass update to the Martini defaults
  5. Click OK
    • A magenta particle is added under the Add Particle button, which can now be used in the sketcher

Figure 3-5. The Sketcher after adding four additional particles (5 total).

  1. Repeat the previous steps for four additional particles: IB2 (green), IB3 (blue), IB4 (orange) and IB5 (purple)
    • Ensure to click Use Martini defaults each time
    • The Sketcher is updated to include four additional particles down the right side of the panel

 

Note: To edit or delete a particle, right-click on the particle

Figure 3-6. Sketching, naming and creating the ibuprofen representation.

  1. Sketch the ibuprofen molecule (as shown in the Figure)
    • Be sure to connect the IB3 particles down the middle
  2. Change the Title to ibuprofen
  3. Click Create Project Entry
    • A new entry is added to the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion., titled ibuprofen
  4. Close the Coarse-Grained Sketcher

This mapping was designed to map 2-3 heavy atoms to each particle while maintaining the major structural features of the ibuprofen molecule. The mapping scheme between the CG particles and their corresponding molecular fragments is shown in the image below. The connectivity of the CG model was sketched in Figure 3-7, and includes all of the bonds that exist between fragments in the image below, as well as one additional bond between the two IB3 particles. This bond is used to ensure that the structural rigidity of the aromatic ring is preserved in the CG model.

Figure 3-7. The entry list with the five needed entries. The ibuprofen molecule is shown in the workspace.

The entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion. now contains the five entries needed to construct our system.

4. Building the Simulation Box and Assigning the Force Field

Next, we will use the Disordered System Builder to construct our simulation box. Then, the Martini force field can be applied to the coarse-grained unit cell using the Coarse-Grained Force Field Assignment panel.

Figure 4-1. Opening the Disordered System Building and clearing the Warning.

  1. Selectthe entry is chosen in the Entry List (and Project Table), the row is highlighted; project operations are performed on all selected entries. all five entries from the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.
  2. Go to Tasks > Materials > Structure Builders > Disordered System
  3. Click OK if a Warning appears
    • The warning indicates that the force field is not yet applied - we will do this after constructing the disordered system

Coarse-graining facilitates access to larger length and time scales. Here we will construct our simulation box with 25,069 coarse-grained molecules, which actually represents 100,069 molecules and 304,923 total atoms. The composition corresponds to 1.8% β-CD by weight and 560 μg/mL ibuprofen.

This system size is sufficient to observe the formation of clusters and inclusion complexes at the composition of interest with reasonable computation times (~12 hours). We would be motivated to increase the system size if we were interested in answering a more complex question, like "what is the average cluster size at equilibrium?" To address this question, we would have to look at systems that allow for the formation of larger clusters.

Figure 4-2. Setting the component table in the Disordered System Builder.

  1. Change the Number of molecules to 25069
  2. For Molecules for each Component, input the following (as shown in the Figure)
    • BCD_cg = 29
    • Na_ion = 20
    • WF_water = 2500
    • W_water = 22500
    • ibuprofen = 20

 

To compute weight percentages, we must calculate the compositions externally using the molecular weights for each molecule.

 

  1. Change the Initial state to Tangled chain
  2. Change the Job name to disordered_system_bcd_ib
  3. Adjust the job settings () as needed. This job requires a CPU host. The job can be completed in about 30 minutes.
  4. If you would prefer not to run the job, import Section_04 > disordered_system_bcd_ib > disordered_system_bcd_ib_amorphous.maegz from the provided tutorial files via File > Import Structures. Otherwise, click Run
  5. Close the Disordered System Builder panel

 

Note: For general practice with the Disordered System Builder and more information about the various parameters, see the Disordered System Building and Molecular Dynamics Multistage Workflows tutorial

Figure 4-3. Selecting and including the output.

  1. When the job is finished or after importing, selectthe entry is chosen in the Entry List (and Project Table), the row is highlighted; project operations are performed on all selected entries. and includethe entry is represented in the Workspace, the circle in the In column is blue. disordered_system_bcd_ib_all_components_amorphous

Figure 4-4. Opening the Coarse-Grained Force Field Assignment panel.

The last necessary step before running the MD simulation is to perform the force field assignment.

  1. Ensure that the disordered_system_bcd_ib_all_components_amorphous entry is selectedthe entry is chosen in the Entry List (and Project Table), the row is highlighted; project operations are performed on all selected entries. and includedthe entry is represented in the Workspace, the circle in the In column is blue. and go to Tasks > Materials > Classical Mechanics > Coarse Grain Models > Coarse-Grained Force Field Assignment

Figure 4-5. Importing the Martini force field from the Schrödinger Installation.

  1. Choose Installation for the Location
  2. Choose Martini for Import force field
  3. Click Import
    • Click OK if a Question appears regarding enumeration
    • It may take a few moments for the panel to load
    • The panel is populated to match the Figure

 

Note: Importing Martini will automatically load the standard Martini parameters for water (W,WF) and the sodium ion (Na_ion).  The parameters for β-CD (BCD_B1-3) will load as well, which are based on a literature model (Lopez et al., 2013; see References), with slight modifications.

Figure 4-6. Setting Martini types.

  1. Set the Mass, Charge and Martini Type for the five ibuprofen particles (IB1, IB2, IB3, IB4 and IB5) according to the Figure  

The particle types were chosen based on the fragment that each molecule represents. Qa, which is the proton acceptor type, was chosen for carboxylate-containing IB1 particles. SC2, which is appropriate for aliphatic hydrocarbon fragments of 2-3 carbons, was chosen for IB2, IB4 and IB5. SC5, which is used to represent fragments with 2 aromatic carbons, was chosen for IB3.

 

Standard masses were used based on the particle types. Qa is a standard type particle and was therefore assigned a mass of 72 g/mol. SC2 and SC5 and small (or “S”) type particles and were therefore assigned masses of 45 g/mol.

 

The only charged types are IB1 and Na_ion, which have a charge of -1 due to the carboxylate group and +1 due to the sodium cation, respectively.

 

  1. Go to the Bond tab

Figure 4-7. Setting Bond parameters.

  1. Set the Req/Å and k/(kcal mol-1Å-2) for the five ibuprofen particle bonds according to the Figure

 

The equilibrium bond lengths were chosen based on average values from a mapped MD simulation of bulk ibuprofen. A standard value of the bond force constant (50 kJ mol-1Å-2) was used for all bonds in ibuprofen.

 

  1. Go to the Angle tab

Figure 4-8. Adding the angle parameters.

The β-CD angles are imported, but the ibuprofen angles need to be added to the table:

 

  1. Click Add Row 5 times to add rows for five additional angles
  2. Click Choose a type for each, and select the angles are shown in the Figure

Figure 4-9. Setting Angle parameters.

  1. Set the Θ/Å and k/(kcal mol-1) for the five angles defined in the previous step

 

The equilibrium angles were chosen based on average values from a mapped MD simulation of bulk ibuprofen. A standard value of the angle force constant (25 kJ mol-1) was used for all angles in ibuprofen.

 

The defaults for the Dihedrals, Improper Dihedrals and Non-bonds are sufficient and can be left unchanged.

Figure 4-10. Saving the force field file and running the job.

  1. For Force field name input martini_bcd_ib
  2. Uncheck Merge with imported force field
    • This will prevent merging force field parameters which are not included in this system
  3. Click Save
    • Saving is not absolutely necessary, but is a good practice in case you want to edit the force field later
  4. Click Run
    • The Coarse-Grained Force Field Assignment panel automatically closes, and a new entry is added to the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.. The entry is selectedthe entry is chosen in the Entry List (and Project Table), the row is highlighted; project operations are performed on all selected entries. and includedthe entry is represented in the Workspace, the circle in the In column is blue. by default

Figure 4-11. The disordered system in the entry list and workspace, now containing force field parameters

The new entry is the same disordered system as we built originally, but now all of the defined force field parameters are associated with the various components. This system is now ready for molecular dynamics simulation.

5. Performing a Multistage Simulation Workflow

Now that we have force-field typed our system, we are ready to proceed to a molecular dynamics (MD) simulation using the MD Multistage Workflow panel. For a more in-depth explanation of building and equilibrating disordered systems, see the Disordered System Building and Molecular Dynamics Multistage Workflows tutorial.

Figure 5-1. Preparing the MD Multistage Workflow.

  1. In the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion., selectthe entry is chosen in the Entry List (and Project Table), the row is highlighted; project operations are performed on all selected entries. and includethe entry is represented in the Workspace, the circle in the In column is blue. the new entry disordered_system_bcd_ib_all_components_amorphous
  2. Go to Tasks > Materials > Classical Mechanics > MD Simulations > MD Multistage Workflow
    • The MD Multistage Workflow panel opens
    • The panel can also be conveniently accessed using the Workflow Action Menu button () directly from the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.

Figure 5-2. Setting the stages for the MD Multistage Workflow.

  1. Check Relaxation protocol and ensure Martini is chosen from the dropdown menu
  2. Change the next stage (Stage 7) to Martini Molecular Dynamics
  3. Set the Simulation time (ns) to 1000
  4. Set the Trajectory Recording interval (ps) to 5000
  5. Set the Energy Recording interval to 500
  6. Set the Time step to 10 fs
  7. Click Advanced Options

Figure 5-3. Ensemble Advanced options.

  1. In the Ensemble tab, maintain Langevin ensemble for both Thermostat and Barostat
  2. Set the Relaxation time to 3 ps for the Thermostat
  3. Set the Relaxation time to 6 ps for the Barostat
  4. Go to the Interaction tab

Figure 5-4. Interaction Advanced options.

  1. Ensure that the Cutoff radius to 12.0 Å
  2. Click Apply
  3. Click OK

Figure 5-5. Naming and running the job.

  1. Change the Job name to multistage_simulation_bcd_ib
  2. Adjust the job settings () as needed
    • This job requires a GPU host. The job can be completed in about 12 hours on a GPU host
  3. If you would like to run the job yourself, click Run. Otherwise, import the pre-generated Section_05 > multistage_simulation_bcd_ib > multistage_simulation_bcd_ib-out.cms file from the provided tutorial files via File > Import Structures
  4. Close the MD Multistage Workflow panel

Regarding the choices for the MD parameters:

  • From performing a few trials, 1000 ns proved to be sufficient for the system to reach a steady state  
  • The recording interval settings are pragmatic to keep the file sizes relatively small
  • The time step is the minimal time step size that is ‘safe’ for Martini 
    • Martini systems, particularly during equilibration, can change size quickly in NPT. This can cause numeric problems and crashes if the time step is larger than 10 fs
    • Langevin dynamics is more robust to large energy inflows than Martyna-Tobias-Klein, so that is suggested here
    • Setting the Thermostat to a larger Tau value helps a bit (and lets the system evolve faster); however, setting the barostat relaxation time to a larger value (50 ps may be even better here) slows the volume change rate down. Together these settings usually permit stable simulations
  • As compared to typical all-atom molecular dynamics simulation, the key differences in protocol are the larger time step and the Langevin thermostat and barostat

Figure 5-6. The output after running or importing the job.

  1. When the job is finished or after importing, selectthe entry is chosen in the Entry List (and Project Table), the row is highlighted; project operations are performed on all selected entries. and includethe entry is represented in the Workspace, the circle in the In column is blue. the new disordered_system_bcd_ib_all_components_amorphous entry from the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.

 

Proceed to visualize the trajectory if you are interested. For a reminder on how to visualize trajectories, see the Disordered System Building and Molecular Dynamics Multistage Workflows or Building, Equilibrating and Analyzing Amorphous Polymers tutorials.

 

Note: Recall that the simulation employs periodic boundary conditions (PBCs). In this case, at a first glance, the clusters may look separate, but actually all of the β-CD and ibuprofen are clustered into a single aggregate. We will see this more clearly in Section 6

6. Performing Cluster Analysis

One excellent way to analyze the aggregation is to perform Cluster Analysis calculations. Doing so will allow us to study the aggregation over the course of the simulation.

Figure 6-1. Opening the Cluster Analysis panel and loading the simulation output.

  1. With the output of the MD simulation, disordered_system_bcd_ib_all_components_amorphous, selectedthe entry is chosen in the Entry List (and Project Table), the row is highlighted; project operations are performed on all selected entries. in the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion. and includedthe entry is represented in the Workspace, the circle in the In column is blue. in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed., go to Tasks > Materials > Classical Mechanics > Trajectory Analysis > Cluster Analysis Calculations
  2. Click Load from Workspace
    • Be patient, loading can take a few seconds depending on the size of the trajectory
    • disordered_system_bcd_ib appears next to the load button

 

Note: Use the Trajectory Frames button if you wish to only perform the cluster analysis on a subset of the data. In this case, we can analyze all 201 frames.

Figure 6-2. Defining the cluster constituents.

  1. Change the Maximum neighbor distance at 9.00 Å
    • This is the radius for defining a neighbor in the cluster-defining algorithm. 6.00 - 9.00 Å works well for Martini type coarse-grained systems

Use the Cluster constituents section of the panel to decide which components can qualify as part of a cluster.

  1. From the Molecular species dropdown, deselect Na_ion, W and WF (maintain the selection of BCD and IB)
    • This ensures that the water molecules and sodium ions are excluded from the cluster analysis calculation
    • Alternatively, use the a Molecular weight range to discriminate components

Figure 6-3. Naming and running the job.

  1. Keep the remaining defaults and set the Job name to cluster_analysis_bcd_ib
  2. Adjust Job settings () as needed, and click Run
    • The job takes ~10 minutes on a CPU host

Figure 6-4. Visualizing the Cluster Analysis output in the workspace.

  1. Close the Cluster Analysis panel
  2. Once the job is incorporated, selectthe entry is chosen in the Entry List (and Project Table), the row is highlighted; project operations are performed on all selected entries. and includethe entry is represented in the Workspace, the circle in the In column is blue. the new output file: disordered_system_bcd_ib_all_components_amorphous
    • The output in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed. is the last frame in the trajectory range
    • The clusters are automatically colored. In this case, there is exactly one cluster containing all the β-CD and ibuprofen molecules

 

Note: The final number of clusters may vary depending on the initial conditions of the simulation. 

Figure 6-5. Coloring the coarse-grained particles.

It will be easier to visualize the cluster and the inclusion complexes with a different styling:

  1. Select all of the particles in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed. (there are many ways to do so, including using the button in the toolbar)
  2. Use the Style palette () and set Color Atoms to Coarse Grain Particle (under Other Schemes)
    • The particles are now colored by clearer coloring schemes

Figure 6-6. Visualizing the aggregates.

Zooming in on the workspacethe 3D display area in the center of the main window, where molecular structures are displayed., we can nicely visualize the cluster and several of the inclusion complexes.

Figure 6-7. Cluster analysis results.

  1. To analyze the results panel for the calculation, use the Workflow Action Menu (WAM) button () or go to Tasks > Materials > Classical Mechanics > Trajectory Analysis > Cluster Analysis Results
    • The Cluster Analysis Viewer panel opens
    • If the graphs are not populated by default, use the Load from Workspace button

 

The top graph shows the number of clusters over time. We can choose to display the average cluster size over time as well.

 

The bottom graph shows the number of molecules in a given cluster over time. The blue line is the largest cluster, the orange line is the second largest cluster. Additional clusters can be displayed or hidden by toggling the Plot for largest counter.

 

Use the Property dropdown to view additional properties of the cluster(s). In this study, we are mainly interested in the first plot, Number of Clusters vs Time, which indicates that the self-assembly is complete after ~500 ns.

For a complete description of the properties available in the cluster analysis results panel, visit the Cluster Analysis tutorial.

 

While the cluster analysis tells us about the aggregation, it does not specifically indicate whether or not inclusion complexes are forming within the cluster. For this analysis, we turn to the radial distribution function in the next section.

 

  1. After you are done analyzing the clustering, close the panel

7. Analyzing the Radial Distribution Function

To better probe the formation of inclusion complexes, we can use the Radial Distribution Function tools.

Figure 7-1. Opening the Radial Distribution Function and loading a file.

  1. Selectthe entry is chosen in the Entry List (and Project Table), the row is highlighted; project operations are performed on all selected entries. and includethe entry is represented in the Workspace, the circle in the In column is blue. the output of the MD simulation disordered_system_bcd_ib_all_components_amorphous
  2. Go to Tasks > Materials > Classical Mechanics > Trajectory Analysis > Radial Distribution Function

Figure 7-2. Loading the .cms file.

  1. Make sure that the Trajectory source points to Workspace (included entry) and click Load.

Figure 7-3. Defining the selections and running the calculation.

  1. In the Atom Selection section of the panel, for Set 1, choose Group by Molecules Calculate using Center of mass
  2. For Selection 1 atoms, input the following ASL: (atom.name "BCD_B1") OR (atom.name "BCD_B2") OR (atom.name "BCD_B3")
  3. Check the box next to Set 2
  4. Choose Group by Molecules Calculate using Center of mass
  5. For Selection 2 atoms, input the following ASL: (atom.name IB1) OR (atom.name IB2) OR (atom.name IB3) OR (atom.name IB4) OR (atom.name IB5)
  6. Change the Job name to rdf_bcd_ib
  7. Adjust Job settings () as needed, and click Run
    • The job takes ~2 minutes on a CPU host
  8. Do not close the Radial Distribution Function panel. We will use the same panel for viewing the results

 

Note: The Selection inputs are ASL representations for the ibuprofen and β-CD molecules. There are other ways to represent these molecules. One straightforward way to generate ASL representations is from Select > Define from the main menu

Figure 7-4. Viewing the radial distribution function output.

When the job is finished, the panel will automatically switch to the View Results tab.

If it does not do so, go to the View Results tab, click Import Results File and load the rdf_bcd_ib.dat file

 

The radial distribution function indicates that the center of mass of most of the ibuprofen molecules are within 2 Å of the center of mass of the cyclodextrin molecules, corresponding to the formation of inclusion complexes.

8. Conclusion and References

In this tutorial, we learned to prepare and simulate a Martini coarse-grained pharmaceutical formulation containing ibuprofen and beta-cyclodextrin. The self-aggregating output was studied with cluster analysis and radial distribution function tools.

For further learning:

For introductory content, focused on navigating the Schrödinger Materials Science interface, an Introduction to Materials Science Maestro tutorial is available. Please visit the materials science training website for access to 70+ tutorials. For scientific inquiries or technical troubleshooting, submit a ticket to our Technical Support Scientists at help@schrodinger.com.

For self-paced, asynchronous, online courses in Materials Science modeling, including access to Schrödinger software, please visit the Schrödinger Online Learning portal on our website.

For some related practice, proceed to explore other relevant tutorials:

For further reading:

9. Glossary of Terms

Coarse-Grained Particle - a single particle that represents multiple atoms in an all-atom model; occasionally referred to as beads or sites in addition to particles

Coarse-Grained Molecule - a molecule or group of molecules represented by one or more coarse-grained particles

Entry List - a simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.

Included - the entry is represented in the Workspace, the circle in the In column is blue.

Project Table - displays the contents of a project and is also an interface for performing operations on selected entries, viewing properties, and organizing structures and data.

Scratch project - a temporary project in which work is not saved, closing a scratch project removes all current work and begins a new scratch project.

Selected - the entry is chosen in the Entry List (and Project Table), the row is highlighted; project operations are performed on all selected entries.

Working Directory - the location where files are saved.

Workspace - the 3D display area in the center of the main window, where molecular structures are displayed.