Locally enhanced sampling

Locally enhanced sampling (LES) [92,101,102] increases sampling and transition rates for a portion of a molecule by the use of multiple non-interacting copies of the enhanced atoms. These enhanced atoms experience an interaction (electrostatics, van der Waals, and covalent) potential that is divided by the number of copies present. In this way the enhanced atoms can occupy the same space, while the multiple instances and reduces barriers increase transition rates.

Structure generation

To use LES, the structure and coordinate input files must be modified to contain multiple copies of the enhanced atoms. psfgen provides the multiply command for this purpose. NAMD supports a maximum of 255 copies, which should be sufficient.

Begin by generating the complete molecular structure and guessing coordinates as described in Sec. 4. As the last operation in your script, prior to writing the psf and pdb files, add the multiply command, specifying the number of copies desired and listing segments, residues, or atoms to be multiplied. For example, multiply 4 BPTI:56 BPTI:57 will create four copies of the last two residues of segment BPTI. You must include all atoms to be enhanced in a single multiply command in order for the bonded terms in the psf file to be duplicated correctly. Calling multiply on connected sets of atoms multiple times will produce unpredictable results, as may running other commands after multiply.

The enhanced atoms are duplicated exactly in the structure--they have the same segment, residue, and atom names. They are distinguished only by the value of the B (beta) column in the pdb file, which is 0 for normal atoms and varies from 1 to the number of copies created for enhanced atoms. The enhanced atoms may be easily observed in VMD with the atom selection beta != 0.

Simulation

In practice, LES is a simple method used to increase sampling; no special output is generated. The following parameters are used to enable LES:

• les $<$ is locally enhanced sampling active? $>$
  Acceptable Values: on or off
  Default Value: off
  Description: Specifies whether or not LES is active.

  lesFactor $<$ number of LES images to use $>$
  Acceptable Values: positive integer equal to the number of images present
  Description: This should be equal to the factor used in multiply when creating the structure. The interaction potentials for images is divided by lesFactor.

• lesReduceTemp $<$ reduce enhanced atom temperature? $>$
  Acceptable Values: on or off
  Default Value: off
  Description: Enhanced atoms experience interaction potentials divided by lesFactor. This allows them to enter regions that would not normally be thermally accessible. If this is not desired, then the temperature of these atoms may be reduced to correspond with the reduced potential. This option affects velocity initialization, reinititialization, reassignment, and the target temperature for langevin dynamics. Langevin dynamics is recommended with this option, since in a constant energy simulation energy will flow into the enhanced degrees of freedom until they reach thermal equilibrium with the rest of the system. The reduced temperature atoms will have reduced velocities as well, unless lesReduceMass is also enabled.

• lesReduceMass $<$ reduce enhanced atom mass? $>$
  Acceptable Values: on or off
  Default Value: off
  Description: Used with lesReduceTemp to restore velocity distribution to enhanced atoms. If used alone, enhanced atoms would move faster than normal atoms, and hence a smaller timestep would be required.

• lesFile $<$ PDB file containing LES flags $>$
  Acceptable Values: UNIX filename
  Default Value: coordinates
  Description: PDB file to specify the LES image number of each atom. If this parameter is not specified, then the PDB file containing initial coordinates specified by coordinates is used.

• lesCol $<$ column of PDB file containing LES flags $>$
  Acceptable Values: X, Y, Z, O, or B
  Default Value: B
  Description: Column of the PDB file to specify the LES image number of each atom. This parameter may specify any of the floating point fields of the PDB file, either X, Y, Z, occupancy, or beta-coupling (temperature-coupling). A value of 0 in this column indicates that the atom is not enhanced. Any other value should be a positive integer less than lesFactor.