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.

Bayesian Energy Landscape Tilting: Towards Concordant Models of Molecular Ensembles

“…2a, red). Low P P II populations and inconsistency between force fields have been previously noted (9,11,14,19)…”

“…Short peptides provide crucial tests for evaluating and optimizing molecular dynamics force fields (9,11,14,19,40). Such peptides offer a window into the intrinsic conformational propensities of amino acids, free from the secondary structure bias found in statistical surveys of protein structures (41).…”

“…This weights the measurements differently and will lead to quantitative differences in estimated populations. Different choices of Karplus coefficients also may lead to different predicted properties, as has been discussed elsewhere (9,58). Finally, the prior method's choice of state decomposition may cause slight differences in estimated conformational populations.…”

Is there an en route folding intermediate for cold shock proteins?

“…For example, several commonly used force fields could be too helical. [30][31][32] In the recent study by Nettels et al, 33 the Rg of unfolded Csp measured in simulations using AMBER ff03/ TIP4P-Ew and OPLS-AA/L force field are around 14 Å , which is significantly smaller than the value inferred from single-molecule FRET experiments, 23 Å . 33 In this case, the unfolded/denatured states of Csp are not correctly modeled by these force fields.…”

Lipid composition influences the release of Alzheimer's amyloid β‐peptide from membranes

“…17,18 We have applied that same force field model in this study. It is important to note, however, that all force fields have some inherent limitations and biases that must be taken into account, 42,43 and that studies on structurally dynamic proteins such as Ab 40 require great care in interpreting results. We note that, despite our efforts to comprehensively sample conformations that Ab 40 may adopt through relatively long simulations (100 ns) and several replicates, our data reflect the considerable heterogeneity intrinsic to the peptide.…”