Are current molecular dynamics force fields too helical?

Abstract

Accurate force fields are essential for the success of molecular dynamics simulations. In apparent contrast to the conformational preferences of most force fields, recent NMR experiments suggest that short polyalanine peptides in water populate the polyproline II structure almost exclusively. To investigate this apparent contradiction, with its ramifications for the assessment of molecular force fields and the structure of unfolded proteins, we performed extensive simulations of Ala(5) in water ( approximately 5 micros total time), using twelve different force fields and three different peptide terminal groups. Using either empirical or density-functional-based Karplus relations for the J-couplings, we find that most current force fields do overpopulate the alpha-region, with quantitative results depending on the choice of Karplus relation and on the peptide termini. Even after reweighting to match experiment, we find that Ala(5) retains significant alpha- and beta-populations. In fact, several force fields match the experimental data well before reweighting and have a significant helical population. We conclude that radical changes to the best current force fields are not necessary, based on the NMR data. Nevertheless, experiments on short peptides open the way toward the systematic improvement of current simulation models.

FIGURE 1

Secondary structure populations. Ternary diagrams on the left (A, C, and E) and right (B, D, and F) show the relative populations before and after reweighting for (A and B) the original Karplus parameters (19), (C and D) DFT1, and (E and F) DFT2 (24), respectively. Symbol areas are proportional to 1/χ²: (blue) blocked termini, (red) zwitterionic, (yellow) protonated C-terminus without ions, (green) protonated C-terminus with ions. Arrows indicate the direction in which each axis should be read, and colors indicate the corresponding scale and isolines.

FIGURE 2

Secondary structure populations for C-terminally protonated (blue) and blocked (red) peptides after re-weighting using (A) the original Karplus equation (19), (B) DFT1, and (C) DFT2 (24). Axes are as in Fig. 1.