Replica Exchange Panel

This panel allows you to set up and run Desmond temperature replica exchange simulations.

To open this panel: click the Tasks button and browse to Classical Simulation → Replica Exchange.

Overview
Using
Features
Additional Resources

Overview of Replica Exchange

Many molecular systems have conformations that are separated by significant free energy barriers. It can be difficult to sample such conformations if they differ by concerted or collective shifts of many atoms. This commonly occurs in protein-ligand complexes. Random methods such as Monte Carlo conformational searches have trouble generating such collective changes, while thermal methods such as molecular dynamics have trouble surmounting the free energy barriers. Replica exchange simulations [27, 28] attempt to tackle this problem by allowing the system to spend some time at elevated temperatures in addition to the temperature of interest. Time spent at elevated temperatures permits the system to evolve faster, in part by more readily crossing free energy barriers.

Desmond supports replica exchange simulations in which multiple copies of the system are simulated at different temperatures, which usually range from the temperature of interest up to 700 K or more. This is known as temperature replica exchange. Periodically during the simulation, attempts are made to exchange the coordinates of copies that are at different temperatures. The exchange is processed in a Monte Carlo-like process: select the systems to attempt to exchange and then use a Metropolis-like criterion to decide whether to accept the change [27]. The exchange acceptance ratio satisfies the detailed balance or balance condition so that each replica remains in equilibrium after the exchange. When many such exchanges are accepted over the course of an extended simulation, multiple systems with very different histories can visit the temperature of interest. While systems spend time at higher temperatures they explore conformational space significantly more rapidly than if they remained at the target temperature. Thus the composite trajectory at the temperature of interest may contain a more diverse collection of conformations than if multiple simulations were performed at the target temperature.

For systems such as protein-ligand complexes, where the focus of attention is on the ligand and its immediate surroundings, an alternative is the use of replicas in which only the atoms of interest are sampled with the potential energy adjusted to allow a greater range of motion: the REST (Replica Exchange with Solute Tempering) method [32,34]. The restriction to a small part of the system decreases the time taken to achieve the desired result.

Since the simulation of each replica proceeds independently between exchange attempts the additional level of parallelization achieved by running multiple replicas is highly efficient. Time slicing is used to advance replicas at the same rate.

Using the Replica Exchange Panel

The replica exchange simulation produces one trajectory for each replica, labeled jobname_replicanum_trj, where num is the index of the replica, starting from 0.

When the calculation finishes, you can review the results in the Replica Exchange Review panel, which you can open with Classical Simulation → Replica Exchange.

To write out the input file and a script for running the job from the command line, click the arrow next to the Settings button and choose Write. For information on command usage and options, see multisim Command Help.

Model system section

In this section, you select the model system that you will use for the simulation. A valid model system must contain both the coordinates of the particles and the force field parameters. A file of a valid model system normally has the .cms extension. You can use the System Builder Panel to prepare the model system for any structure that you have. If you want to build an amorphous structure from scratch, you can use the Disordered System Builder Panel to create a model system.

The option menu offers two choices for the source of the model system:

Load from Workspace—Load the model system from the Workspace. When you choose this option, the Load button is displayed to the right of the menu. Click this button to load the model system.
Import from file—Import the model system from a file. When you choose this option, a text box and Browse button are displayed to the right of the menu. You can enter the name of the file in the text box, or click Browse and navigate to the file.

You can choose to import a model system file (.cms) or a checkpoint file (.cpt).

If you import a model system file, it must contain a model system that has already been prepared. When the file is imported, a message about the system is displayed below the option menu.

If you import a checkpoint file, most of the panel controls are unavailable. The purpose of the checkpoint file is to restart an interrupted simulation, so the parameters of the simulation cannot be altered. You can change the total simulation time, and then start the job.

Replica section

In this section you set up the parameters of the simulation.

Tempering method options

Select an option for the tempering method. The settings shown in the Replica section depend on the option you choose.

Parallel (REMD)—Use the standard method in which parallel calculations are performed on the entire system at different temperatures.
Solute (REST)—Use solute tempering, in which the potential energy is adjusted for just the critical part of the system [32,34].

Number of replicas text box

Specify the number of replicas to use. The default is 2. Each replica is simulated at a different temperature (REMD) or with different potential energy adjustments (REST).

Temperature range text boxes

Specify the range of temperatures to be used. The defaults are 300 K for the low temperature and 310 K for the high temperature. For REST, only the Low text box is available, to specify the temperature of the system.

Hot region text box and Get from Selection button

Atom selection for the region that is simulated with adjusted potential energy. To define the atoms, you can type in an ASL expression or select the atoms in the Workspace and click Get from Selection. These settings are only available if you chose Solute (REST) for the tempering method.

Temperature profile options

Specify the temperature profile for the replicas. These options are only available if you chose Parallel (REMD) for the tempering method. The options are:

Quadratic—Set the temperatures by quadratic interpolation between the minimum and maximum, with the high temperature at the maximum of the quadratic curve.
Linear—Set the temperatures by linear interpolation between the maximum and minimum.
Auto—Automatically set the number of replicas and the temperature schedule so that the acceptance ratio is approximately 30%.
Manual—Set the temperatures manually, by editing the temperatures in the replica table. When you select this option the table becomes editable. Some guidance on selecting temperatures is available in Ref. [29].

Predicted average acceptance ratio text

This text displays the predicted average acceptance ratio, and can be used to ensure a high enough ratio when you set the temperature profile.

Replica table

This table displays the temperatures for each replica, which is only relevant for Parallel (REMD) simulations. You can edit the temperatures by selecting manual for the temperature profile.

Simulation section

In this section you set up the parameters of the simulation.

Simulation time text boxes

Specify the total time of the simulation, in ns, in the total text box. Changing the total simulation time changes the trajectory recording interval, to maintain a maximum of 1000 frames in the trajectory.

The elapsed text box displays the amount of time the simulation has already run, if you are restarting a simulation. For new simulations it should contain zero. This text box cannot be edited.

Recording interval text boxes

Specify the recording interval for the energy and the trajectory, in ps, in the energy and trajectory text boxes. Values entered in these text boxes are rounded to an integer multiple of the far time step size. By default, the far time step size is 0.006 ps. This time step size is set in the Integration tab of the Molecular Dynamics - Advanced Options Dialog Box, in the RESPA integrator section. If you adjust the trajectory recording interval, the number of frames is updated.

Approximate number of frames text box

Specify the approximate number of frames in the trajectory. This value is coupled with the recording interval for the trajectory and the simulation time: the number of frames times the trajectory recording interval is the total simulation time. If you adjust the number of frames, the recording interval is modified.

Ensemble class option menu

Choose the ensemble class from this option menu. The following classes are available:

NVE—constant particle number (N), volume (V) and energy (E). This class represents the microcanonical ensemble.
NVT—constant particle number (N), volume (V) and temperature (T). This class represents the canonical ensemble.
NPT—constant particle number (N), pressure (P) and temperature (T). This class is an isothermal-isobaric ensemble, the common experimental conditions.
NPAT—constant particle number (N), pressure (P), lateral surface area (A), and temperature (T). This class is an isothermal-isobaric ensemble with constant normal pressure and lateral surface area i.e. the pressure coupling is nonisotropic.
NPγT—constant particle number (N), pressure (P), lateral surface tension (γ), and temperature (T). This class represents an isothermal-isobaric ensemble with constant normal pressure and lateral surface tension, i.e. the pressure coupling is nonisotropic.

The last two ensembles are often used for membrane-containing systems. Fixing the surface area or surface tension helps to ensure that the simulation box does not deform significantly in the plane of the membrane while the pressure is applied normal to the membrane surface.

Pressure text box

Specify the pressure to be used, in bar. Not available for the NVE and NVT ensemble classes.

Surface tension text box

Specify the surface tension to be used, in bar angstroms. Only available for the NPγT ensemble class.

Relax model system before simulation option

When selected, a series of minimizations and short molecular dynamics simulations are performed to relax the model system before performing the simulation you set up (see Relaxing a Model System). If the system contains a membrane, the option text reads Relax membrane model system before simulation, and relaxation protocols suitable for a membrane-bound system are used (see Relaxing a Membrane-Containing Model System).

Normally, this option is needed only for model systems that have just been prepared with the System Builder Panel or the Disordered System Builder Panel, and have not been relaxed. This option is selected by default for a new simulation, but is deselected and unavailable if you are starting from a checkpoint file.

Relaxation protocol text box and Browse button

Specifiy a custom protocol to be used for the relaxation. You can specify a protocol by clicking Browse and selecting the appropriate .msj file for the relaxation. The text box shows the name of the file you selected.

Advanced Options button

Opens the Replica Exchange - Advanced Options dialog box, in which you can control many more of the detailed settings for the simulation than are available in the Replica Exchange panel.

Job toolbar

Manage job submission and settings. See Job Toolbar for a description of this toolbar.

The Job Settings button opens the Replica Exchange - Job Settings Dialog Box, where you can make settings for running the job.

Status bar

The status bar displays information about the current job settings and status for the panel. The settings includes the job name, task name and task settings (if any), number of subjobs (if any) and the host name and job incorporation setting. The job status can include messages about job start, job completion and incorporation.

Use the Reset button to reset the panel to its default settings and clear any data from the panel. You can also reset the panel from the Job toolbar.

The status bar also contains the Help button , which opens the help topic for the panel in your browser. If the panel is used by one or more tutorials, hovering over the Help button displays a button, which you can click to display a list of tutorials (or you can right-click the Help button instead). Choosing a tutorial opens the tutorial topic.