Extensive Molecular Dynamics Simulations of Peptides

All MD simulations were
performed with NAMD^{40 (link)} employing CHARMM-formatted
parameter files^{41 (link)} for all force fields
tested, which are provided in the Supporting Information. For all simulations, a temperature of 300 K and pressure of 1 atm
were maintained with a Nose–Hoover Langevin piston barostat
with a piston period of 100 fs and a piston dampening time scale of
50 fs and a Langevin thermostat with a damping coefficient of 1 ps^–1. Nonbonded cutoffs were employed at 11 Å with
a smoothing function starting at 9 Å, with particle mesh Ewald
used to treat long-range electrostatics. The systems were solvated
in cubic water boxes with edge lengths ranging from 25 to 58 Å.
Sodium and chloride ions were added to neutralize the charges in the
system and provide approximately a 150 mM concentration of salt. A
2 fs time step was employed with the use of SHAKE and SETTLE.
Triplicate 205 ns simulations were run for an unblocked alanine pentapeptide
(Ala₅) with and glycine tripeptide (Gly₃) with
protonated C-termini with the first 5 ns discarded as equilibration.
The remaining amino acids, with the exception of proline, were simulated
for 205 ns as blocked dipeptides, again in triplicate with the first
5 ns discarded as equilibration. Values and error bars throughout
the paper represent the mean and standard deviation of the calculated
quantities from the triplicate runs. Ala₅ and Gly₃ simulations were run with each of the four weighting temperatures
examined in this work, as well as the previous OPLS-AA and OPLS-AA/L
force field. Dipeptide simulations were performed with OPLS-AA, OPLS-AA/L,
and the new parameters optimized at 2000 K. As each system was studied
for 600 ns with at least three different force fields, over 50 μs
of validating simulations have been executed. In analyzing the molecular
dynamics simulations for the short alanine and glycine peptides, the
definitions of secondary structure, the three sets of Karplus parameters
for calculating J couplings, and the experimental
error values used to calculate χ² from Best et al.^{42 (link)} were employed. For the dipeptide simulations,
only the first set of Karplus parameters, that of Hu and Bax,⁴³ was employed. χ₁ rotamer populations
were determined by dividing the range of χ₁ values
into three equal sized bins, corresponding to the p (+60°), t
(180°) and m (−60°) conformers. Definitions of p,
t, and m for valine, isoleucine, and threonine were adopted from the
work of Dunbrak and co-workers^{27 (link)} and are
depicted in Figure 1.
The proteins ubiquitin and GB3 were started from the PDB
structures 1UBQ(44 (link)) and 1P7E(45 (link)) and gradually
heated to 300 K over
400 ps before 205 ns simulations were run. Both the heating period
and the first 5 ns were discarded as equilibration, and simulations
were performed in triplicate for each protein. All other simulation
parameters were identical to those used for the dipeptides. For calculation
of backbone J couplings of the full protein, both
the 1997 empirical Karplus parameters⁴³ used for the dipeptides and another empirical model developed from
work with GB3^{46 (link)} are employed. Side chain J couplings were calculated for couplings to methyl side
chains with the set of Karplus parameters developed by Vögeli
et al.,^{46 (link)} while all other couplings employed
Karplus parameters from Perez et al.^{48 (link)}