Molecular dynamics simulations of intrinsically disordered peptides (IDPs) can provide high resolution structural ensembles if the force field is accurate enough and if the simulation sufficiently samples the conformational space of the IDP with the correct weighting of sub-populations. Here, we investigate the combined force field–sampling problem by testing a number of standard as well as newer fixed charge force fields, the latter specifically motivated for better description of unfolded states and IDPs, as well as testing them using a standard temperature replica exchange (TREx) protocol and a non-equilibrium Temperature Cool Walking (TCW) sampling algorithm recently applied to large systems. The force field and sampling combinations are used to characterize the structural ensembles of the amyloid-beta peptides Aβ42 and Aβ43, which should both be random coils, with only short- and medium-range amino acid contacts and exhibit at most very small differences in the C-terminus, as shown recently by experimental NMR and 2D FRET. The results illustrate the key importance of the sampling method: once the deficiencies of TREx are overcome with the TCW method, the standard force fields appear no worse than the recently optimized protein-water force field combinations, based on their agreement with standard random coil models and comparison to NMR, and to a lesser extent, 2D FRET data.

Combined force-field sampling problem in simulations of disordered amyloid-β peptides

2019 Spring National Meeting

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