title: Force-field dependence of chignolin folding and misfolding: comparison with experiment and redesign.
abstract: We study the folding of the designed hairpin chignolin, using simulations with four different force fields. Interestingly, we find a misfolded, out-of-register, structure comprising 20-50% of the ordered structures with three force fields, but not with a fourth. A defining feature of the misfold is that Gly-7 adopts a β(PR) conformation rather than α(L). By reweighting, we show that differences between the force fields can mostly be attributed to differences in glycine properties. Benchmarking against NMR data suggests that the preference for β(PR) is not a force-field artifact. For chignolin, we show that including the misfold in the ensemble results in back-recalculated NMR observables in slightly better agreement with experiment than parameters calculated from a folded ensemble only. For comparison, we show by NMR and circular dichroism spectroscopy that the G7K mutant of chignolin, in which formation of this misfold is impossible, is well folded with stability similar to the wild-type and does not populate the misfolded state in simulation. Our results highlight the complexity of interpreting NMR data for small, weakly structured, peptides in solution, as well as the importance of accurate glycine parameters in force fields, for a correct description of turn structures.
authors: Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky University, Olomouc, Czech Republic.
authors: Petra
authors: P
authors: Kührová
authors: Alfonso
authors: A
authors: De Simone
authors: Michal
authors: M
authors: Otyepka
authors: Robert B
authors: RB
authors: Best
mesh_terms: D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012984:Software
chemical_list: D009842:Oligopeptides; C506175:chignolin