Comparison of Structure Determination Methods for Intrinsically Disordered Amyloid-β Peptides

Abstract

Intrinsically disordered proteins (IDPs) represent a new frontier in structural biology since the primary characteristic of IDPs is that structures need to be characterized as diverse ensembles of conformational substates. We compare two general but very different ways of combining NMR spectroscopy with theoretical methods to derive structural ensembles for the disease IDPs amyloid-β 1–40 and amyloid-β 1–42, which are associated with Alzheimer’s Disease. We analyze the performance of de novo molecular dynamics and knowledge-based approaches for generating structural ensembles by assessing their ability to reproduce a range of NMR experimental observables. In addition to the comparison of computational methods, we also evaluate the relative value of different types of NMR data for refining or validating the IDP structural ensembles for these important disease peptides.

Structural Ensembles of Intrinsically Disordered Proteins Depend Strongly on Force Field: A Comparison to Experiment

“…Consistent with earlier reports, 17,94,95 we find that the ensembles in all force fields are in poor agreement with RDCs (see Figure S19). It has been suggested that the conformational ensembles of IDPs may be affected by the presence of alignment media used in measurements of RDCs.…”

“…Ensembles consistent with experimental data have also been selected from conformations obtained using MD simulations. [16][17][18] Ball et al compared knowledge-based ensemble selection approaches to ensembles obtained using de novo MD simulations. 17 Because IDP ensembles are severely underdetermined (that is, there are many degrees of freedom and relatively few experimental observables), cross-validation and care in avoiding overfitting are essential to these approaches.…”

“…[16][17][18] Ball et al compared knowledge-based ensemble selection approaches to ensembles obtained using de novo MD simulations. 17 Because IDP ensembles are severely underdetermined (that is, there are many degrees of freedom and relatively few experimental observables), cross-validation and care in avoiding overfitting are essential to these approaches. 16,19,20 Computational methods of the second type have been used extensively to obtain ensembles of IDPs de novo.…”

Quarterly intrinsic disorder digest (April–May–June, 2014)

“…63 Ball et al compare 2 different ways of combining NMR spectroscopy with theoretical methods and apply them to determining the structural ensembles for amyloid b. 64 Finally, Sara et al demonstrate the use of novel NMR and EPR techniques to characterize weak protein-protein complexes, such as those seen in IDP interactions. 65 Single-molecule force spectroscopy as a method to study IDPs was also covered this quarter.…”

Emergence of order in self-assembly of the intrinsically disordered biomineralisation peptide n16N

“…IDPs are defined by their lack of a single stable tertiary structure [11,12], and often have a function for which their disorder is essential [13]. It has been suggested that biomineralisation proteins are the most disordered functional protein class [14], perhaps owing to required adaptability for multi-stage matrix assembly [13], interaction with ions [15] and selectivity of chemical environment in which assembly occurs [16].…”