Peptide-Based Drug Design

120 Copps et al.
10. In accordance with NVT conditions, the temperature of the system must be
coupled to a virtual heat bath, with reference temperature (typically 300 K) set
by the user. Solvent, solute, and ions should be coupled separately to a bath of
the same reference temperature using Berendsen coupling (10), with the same
time constant (frequency of coupling, typically 0.1 ps) for each. Pressure is not
coupled and held constant during the NVT simulation, in order to keep the box
rigid and the volume constant. Dielectric constant and isothermal compressibility
of the solvent are also important parameters to set here. Finally, enable generation
of velocities for solvent atoms and ions. GROMACS will generate velocities
using a Maxwell distribution at a user-defined temperature, which should be
the same as the coupled temperature. Generate a run-input file using the grompp
program as in the energy minimization step, input to the mdrun program, and start
the simulation. A positionally restrained simulation of 100 ps with a time step of
2 fs is typical. Choose the number of processors on which to run the simulation,
and if using more than one, use the MPI program described in the GROMACS
manual (11) (see Note 11).
11. For the full NPT (constant pressure, temperature, and number of molecules)
simulation run, the parameter file is unchanged from the NVT simulation, except
that generation of velocities as well as position restraints should be turned off.
Along with temperature coupling, pressure coupling should be enabled (and the
system volume allowed to scale), with a reference pressure of typically 1 bar and
a 1 ps time constant for coupling (10). Dispersion corrections for the cut-off of
the long-range Lennard-Jones potential should also be enabled for both energy
and pressure. Once again, generate the final run-input file using grompp, input
to mdrun and start the simulation. The user should specify a full simulation time
and a time step (again, typically 2 fs). The number of processors used for the full
simulation should be the same as used for the NVT simulation and optimal for
speed and efficient use of computational resources (see Note 11).
12. When the simulation is complete, check the fidelity of the final trajectory
file using the gmxcheck program and, if desired, convert to the less memoryconsuming
.xtc format. Subset group trajectories based on groups listed in the
index file can also be written.
3. Replica Exchange Molecular Dynamics (REMD)
With standard MD simulations at low temperatures, an explicitly solvated
protein or peptide generally becomes trapped in any of many local energy
minima, prohibiting a representative sampling of the entire range of conformations.
Of a few suggested solutions, REMD is least time-consuming, easiest to
implement, and theoretically sound (12–14). In REMD, multiple independent
simulations (“replicas”) are conducted, each at a different temperature in a
limited range. At user-defined time steps, the trajectory coordinates of simulations
of “neighboring” temperatures are either randomly exchanged or not