Secondary structure propensities in peptide folding simulations: a systematic comparison of molecular mechanics interaction schemes

Abstract

We present a systematic study directed toward the secondary structure propensity and sampling behavior in peptide folding simulations with eight different molecular dynamics force-field variants in explicit solvent. We report on the combinational result of force field, water model, and electrostatic interaction schemes and compare to available experimental characterization of five studied model peptides in terms of reproduced structure and dynamics. The total simulation time exceeded 18 mus and included simulations that started from both folded and extended conformations. Despite remaining sampling issues, a number of distinct trends in the folding behavior of the peptides emerged. Pronounced differences in the propensity of finding prominent secondary structure motifs in the different applied force fields suggest that problems point in particular to the balance of the relative stabilities of helical and extended conformations.

Figure 1

RMSD of the main-chain and C_β atoms with respect to the NMR reference structure as function of the simulation time for Chignolin, Mbh12, and Tc5b. RMSD curves for the simulations CHI (A), CHI.REF (B), MBH (C), MBH.REF (D), TC5B.REF −250 ns (E), and TC5B.REF −30 ns (F) were smoothed.

Figure 2

Percentage of α-helical segments present in the trajectories of Fs₂₁ and Agd1 peptides as function of simulation time. Helical content curves for the simulations FS21 (A), FS21.REF (B), AGD1 (C), and AGD1.REF (D) were smoothed.

Figure 3

Comparison of the conformational space sampled in the simulations of the Chignolin peptide with ff03 (A), ff99SB (B), 43A1-RF (C), 43A1-PME (D), 53A6-RF (E), 53A6-PME (F), OPLS-Cutoff (G), and OPLS-PME (H). The individual trajectories were projected onto the first two common eigenvectors obtained from the PCA of the combined simulation runs for each force field, respectively. The location of the NMR reference structure and the completely extended starting conformation is indicated by a dot. Snapshots from each trajectory are shown with open circles.

Figure 4

Conformational space sampled in the simulations of the Mbh12 peptide. Projections of the NMR reference structure, extended starting conformation, and snapshots from each trajectory are denoted according to Fig. 3.