Random acceleration molecular dynamics simulations

The ``lib/ramd" directory stores the tcl scripts and the example files for the implementation of the Random Acceleration Molecular Dynamics (RAMD) simulation method in NAMD. The RAMD method can be used to carry out molecular dynamics (MD) simulations with an additional randomly oriented acceleration applied to the center of mass of one group of atoms (referred to below as ``ligand") in the system. It can, for example, be used to identify egress routes for a ligand from a buried protein binding site. Since its original implementation in the ARGOS [59,103] program, the method has been implemented in AMBER 8 [82], and CHARMM [17]. The first implementation of RAMD in NAMD using a tcl script (available as supplementary material in [96]) provided only limited functionality compared to the AMBER 8 implementation and was followed with an implementation of RAMD and RAMD-MD in NAMD [24,9]. Recently the RAMD method was improved in speed by using NAMD vector implementations and streamlining the code. The current implementation is now focused on the RAMD simulation and was used in the $\tau$ RAMD procedure for the estimation of relative drug-target residence times [51].

Additional information is found in the README file in the ``lib/ramd" directory. The user is encouraged to carefully read this information before starting production runs.

The two required scripts are stored in ``lib/ramd/scripts": (i) ramd-5.tcl defines the simulation parameters and passes them from the NAMD configuration file to the main script, (ii) ``ramd-5_script.tcl" adds the randomly oriented force and performs all related computations.

Two examples for running RAMD are included in the directory ``lib/ramd/example/". The examples can be started using the RAMD-force.sh shell scripts.

The specific RAMD simulation parameters to be provided in the NAMD configuration file (listed below) should be preceded by the keyword ``ramd". The default values for these parameters are only given as guidance. They may not to be suitable for other systems.

Mandatory parameter settings:

• ramd lastProtAtom $<$ Last index of protein atom $>$
  Acceptable Values: positive integer
  Description: Specifies the index of the last protein atom.

• ramd firstRamdAtom $<$ First index of ligand atom $>$
  Acceptable Values: positive integer
  Description: Specifies the index of the first ligand atom.

• ramd lastRamdAtom $<$ Last index of ligand atom $>$
  Acceptable Values: positive integer
  Description: Specifies the index of the last ligand atom.

• ramd ramdfilename $<$ Name of ramd output file $>$
  Acceptable Values: Valid file name
  Description: Specified the name of the file where the ramd logs are written.

Optional parameter settings with a default. Depending on your simulation system, you might want to change these settings:

• ramd firstProtAtom $<$ First index of protein atom $>$
  Acceptable Values: positive integer
  Default Value: 1
  Description: Specifies the index of the first protein atom.

• ramd ramdSteps $<$ Set number of steps in RAMD block $>$
  Acceptable Values: positive integer
  Default Value: 50
  Description: Specifies the number of steps in 1 RAMD block; the simulations are evaluated every `ramdSteps' steps.

• ramd forceRAMD $<$ Set acceleration force $>$
  Acceptable Values: positive decimal
  Default Value: 16.0
  Description: Specifies the force to be applied. Replaces the acceleration (accel) specified in previous releases. Defaults to 16 kcal/mol/Angstrom

• ramd rMinRamd $<$ Set threshold for distance travelled RAMD $>$
  Acceptable Values: positive decimal
  Default Value: 0.01
  Description: Specifies a threshold value for the distance in Angstroms travelled by the ligand in 1 RAMD block. In RAMD simulations the direction of the acceleration is changed if the ligand has travelled less than `rMinRamd' Å in the evaluated block.

• ramd forceOutFreq $<$ Set frequency of RAMD forces output $>$
  Acceptable Values: positive integer, Must be divisor of ramdSteps
  Default Value: 10
  Description: Every `forceOutFreq' steps, detailed output of forces will be written.

• ramd maxDist $<$ Set center of mass separation $>$
  Acceptable Values: positive decimal
  Default Value: 50
  Description: Specifies the distance in Angstroms between the the centers of mass of the ligand and the protein when the simulation is stopped.

• ramd ramdSeed $<$ Set RAMD seed $>$
  Acceptable Values: positive integer
  Default Value: 14253
  Description: Specifies seed for the random number generator for generation of RAMD force directions. Change this parameter if you wish to run different trajectories with identical parameters.

• ramd debugLevel $<$ Set debug level of RAMD $>$
  Acceptable Values: integer value
  Default Value: 0
  Description: Activates verbose output if set to an integer greater than 0. Should be used only for testing purposes because the very dense output is full of information only relevant for debugging.

• ramd namdVersion $<$ Set the NAMD version $>$
  Acceptable Values: float value
  Default Value: 2.13
  Description: After NAMD version 2.10 a call to enabletotalforces is done to enable tcl processing in NAMD

Note: In the current RAMD implementation, combined RAMD-MD simulations, where RAMD blocks alternate with standard MD blocks are not available. In case you are are interested in this feature, please contact the RAMD developers at mcmsoft@h-its.org

Scripts for using RAMD in the $\tau$ RAMD procedure for computing residence times are available at: https://www.h-its.org/downloads/ramd/.