Comparing atomistic molecular mechanics force fields for a difficult target: a case study on the Alzheimer’s amyloid β-peptide

Abstract

Macromolecular function arises from structure, and many diseases are associated with misfolding of proteins. Molecular simulation methods can augment experimental techniques to understand misfolding and aggregation pathways with atomistic resolution, but the reliability of these predictions is a function of the parameters used for the simulation. There are many biomolecular force fields available, but most are validated using stably folded structures. Here, we present the results of molecular dynamics simulations on the intrinsically disordered amyloid β-peptide (Aβ), whose misfolding and aggregation give rise to the symptoms of Alzheimer's disease. Because of the link between secondary structure changes and pathology, being able to accurately model the structure of Aβ would greatly improve our understanding of this disease, and it may facilitate application of modeling approaches to other protein misfolding disorders. To this end, we compared five popular atomistic force fields (AMBER03, CHARMM22 + CMAP, GROMOS96 53A6, GROMOS96 54A7, and OPLS-AA) to determine which could best model the structure of Aβ. By comparing secondary structure content, NMR shifts, and radius of gyration to available experimental data, we conclude that AMBER03 and CHARMM22 + CMAP over-stabilize helical structure within Aβ, with CHARMM22 + CMAP also producing elongated Aβ structures, in conflict with experimental findings. OPLS-AA, GROMOS96 53A6, and GROMOS96 54A7 produce very similar results in terms of helical and β-strand content, calculated NMR shifts, and radii of gyration that agree well with experimental data.

Conformational Transitions of the Amyloid‐β Peptide Upon Copper(II) Binding and pH Changes

“…QM calculations were employed to derive OPLS‐AA/L force‐field parameters for the Aβ 1–42 /Cu 2+ complex, based on the fully optimized truncated copper center (Figure ). It has been shown that OPLS‐AA/L produces results for Aβ in terms of helical and β‐strand contents, calculated NMR coupling constants and chemical shifts, and radii of gyration that agree well with experimental data . Details about the parameterization procedure are presented in the supporting information (SI).…”

“…However, lower (∼3 % and ∼6 %) and higher (∼15 % and ∼30 %) β‐propensities have also been reported. These differences result from different force fields used, as: 1) a previous MD studies testing force fields for Aβ 1–40 also produced different β‐strand populations;, and 2) an REMD study comparing three force fields for Aβ 16–22 dimers and trimers also produced different α‐ and β‐propensities . However, the different force‐field results agree, by demonstrating that the helical propensity is the highest between residues 10 and 20, while β‐structures are preferentially adopted by C‐terminal residues.…”

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

“…[23][24][25]27,28,42,[44][45][46] On the other hand, the accuracy of unfolded state and IDP structural ensembles obtained using several widely-used force fields has been called into question. [25][26][27]43,[46][47][48][49][50][51][52][53] Piana et al suggested that modern force fields, including Amber ff99sb*-ildn and CHARMM 22* in particular, produce IDP and unfolded state ensembles that are on average too compact. 48 It has also been suggested that Amber force fields systematically underestimate chain dimensions of IDPs and unfolded states.…”

“…A variety of simulation methods (MD, Monte Carlo, metadynamics, replica exchange) and different levels of representation (coarse-grained, implicit solvent, all-atom with explicit water) have been used to obtain IDP ensembles. 7,[21][22][23][24][25][26][27][28][29] There are two main challenges encountered in de novo simulations.…”

Resveratrol interferes with the aggregation of membrane-bound human-IAPP: A molecular dynamics study

“…The GROMOS 53A6 force field [35,36] was used. This forcefield has been shown to perform well in simulating proteineprotein and membrane-protein systems [37,16]. The SPC (simple point charge) water model [38] was used.…”