Three Force Fields' Views of the 310 Helix

Abstract

Slowly but steadily bibliographic evidence is accumulating that the apparent convergence of the various biomolecular force fields as evidenced from simulations of proteins in the folded state does not hold true for folding simulations. Here we add one more example to the growing list of peptides and proteins for which different force fields show irreconcilable differences in their folding predictions, even at such a fundamental level as that of a peptide's secondary structure. We show that for an undecamer peptide that is known from two independent NMR structure determinations to have a mainly 3(10)-helical structure in solution, three mainstream biomolecular force fields give completely disparate predictions: The CHARMM force field (with the CMAP correction) predicts an outstandingly stable α-helical structure, in disagreement not only with the experimental structures, but also with experimental evidence obtained from circular dichroism. OPLS-AA shows an almost totally disordered peptide with the most frequently observed folded conformation corresponding to a β-hairpin-like structure, again in disagreement with all available experimental evidence. Only the AMBER99SB force field appears to qualitatively agree with not only the general structural characteristics of the peptide (on the account of both NMR- and CD-based experiments), but to also correctly predict some of the experimentally observed interactions at the level of side chains. Possible interpretations of these findings are discussed.

Aggregation propensity of Aib homo‐peptides of different length: an insight from molecular dynamics simulations

“…This effect should stabilize the N-H not involved in intramolecular H-bonds near the N-terminus, and in turn, it is expected to favor the α-helical conformation. Despite a bias from the conditions we used in the simulations cannot be completely ruled out, in particular the choice of the force field [79][80][81][82][83] and, in a few simulations, the simultaneous presence of six peptides in the box, we can reasonably conclude that Z-U 6 -N differs from its longer homologous peptides for its conformational and dynamic features even in very diluted solutions. To investigate the relation between these differences and the diverging propensity to aggregate, we performed MD simulations with six replicas of the peptide (Figures 8-11).…”

Enhanced molecular dynamics simulation of the transformation between α-helix and β-hairpin structures for peptide

“…Note that although the larger population of α-helix state has been obtained, there is still located considerable amount of folded β-hairpin state. The difference of the results between the theoretical simulation and experiment might be due to secondary structure preference of the force fields [24][25][26][27][28]. However, it is worthy to note that the widely applicable ITS method, which is as well as the HSREMD method developed for sampling structure transformation processes, can also deal with the same processes efficiently and reliably.…”

Characterizing a partially ordered miniprotein through folding molecular dynamics simulations: Comparison with the experimental data

“…To our knowledge, there is not a single example of a stably folded peptide for which the combination of the AMBER99SB‐ILDN (or AMBER99SB‐STAR‐ILDN) force field with TIP3P water model and full electrostatics has failed to correctly identify the peptide's native state. To the contrary, the aforementioned combination has been shown to be able to accurately predict the structure and dynamics of peptides ranging from very stable folders, to marginally stable peptides, and for all structural motifs from mainly helical to almost exclusively β‐hairpin like . It should be noted, however, that recent studies have indicated the presence of a tendency of these force fields to produce overly compact structures in the case of disordered peptide systems which are known to be rather difficult systems to study with empirical force fields .…”