Are Current Molecular Dynamics Force Fields too Helical?

¹ University of Cambridge
² University College Dublin
³ NIH

^* To whom correspondence should be addressed. E-mail: gerhard.hummer{at}nih.gov.

Submitted on March 4, 2008
Revised on March 28, 2008
Accepted on 8 April 2008

	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 (Graf et al., J. Am. Chem. Soc. 2007, 129, 1179-1189) suggest that short poly-alanine 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 have performed extensive simulations of Ala₅ in water (~5 µs 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 region, with quantitative results depending on the Karplus relation and on the peptide termini. Even after re-weighting to match experiment, we find that Ala₅ retains significant and 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, the experiments of Graf et al. open the way toward the systematic improvement of current simulation models, such that they quantitatively reproduce the conformational equilibria of peptides.

Key Words: Karplus relation, NMR, alpha-helix, molecular dynamics simulations, protein folding