Effects of force fields on the conformational and dynamic properties of amyloid β(1‐40) dimer explored by replica exchange molecular dynamics simulations

Abstract

The conformational space and structural ensembles of amyloid beta (Aβ) peptides and their oligomers in solution are inherently disordered and proven to be challenging to study. Optimum force field selection for molecular dynamics (MD) simulations and the biophysical relevance of results are still unknown. We compared the conformational space of the Aβ(1-40) dimers by 300 ns replica exchange MD simulations at physiological temperature (310 K) using: the AMBER-ff99sb-ILDN, AMBER-ff99sb*-ILDN, AMBER-ff99sb-NMR, and CHARMM22* force fields. Statistical comparisons of simulation results to experimental data and previously published simulations utilizing the CHARMM22* and CHARMM36 force fields were performed. All force fields yield sampled ensembles of conformations with collision cross sectional areas for the dimer that are statistically significantly larger than experimental results. All force fields, with the exception of AMBER-ff99sb-ILDN (8.8 ± 6.4%) and CHARMM36 (2.7 ± 4.2%), tend to overestimate the α-helical content compared to experimental CD (5.3 ± 5.2%). Using the AMBER-ff99sb-NMR force field resulted in the greatest degree of variance (41.3 ± 12.9%). Except for the AMBER-ff99sb-NMR force field, the others tended to under estimate the expected amount of β-sheet and over estimate the amount of turn/bend/random coil conformations. All force fields, with the exception AMBER-ff99sb-NMR, reproduce a theoretically expected β-sheet-turn-β-sheet conformational motif, however, only the CHARMM22* and CHARMM36 force fields yield results compatible with collapse of the central and C-terminal hydrophobic cores from residues 17-21 and 30-36. Although analyses of essential subspace sampling showed only minor variations between force fields, secondary structures of lowest energy conformers are different.

On the Conformational Dynamics of β-Amyloid Forming Peptides: A Computational Perspective

“…The dimer structures are classified by cluster analysis and the inter-chain interactions are mainly located in the regions of residues 5-12, 16-23, and 30-40. Another work studied the dimerization of the Aβ polypeptide using REMD, with each replicate lasting for 300 ns (Watts et al, 2018). The analysis of intra-and inter-chain residue distances showed that although the individual chains were highly flexible, the dimeric system stays in a loosely packed antiparallel β-sheet configuration with contacts between two CHC regions.…”

“…The results obtained using both the force fields were comparable with the chemical shift values determined by performing NMR experiments. Watts et al (2018) performed an REMD simulation on the Aβ40 dimer using a series of force fields in the AMBER and CHARMM families. The conformational spaces were classified by cluster analysis and projected the energy landscapes in the first 3 dihedral principle components ( Figure 5A).…”

Molecular Dynamics Simulation for Mechanism Elucidation of Food Processing and Safety: State of the Art

“…Chen et al (2018) was corrected to Chen et al (2018a) and Chen et al (2018b) in the reference list after initial online publication.] that define the atoms, residues, and their masses, charges, types, and so on involved in a system under study (Cheng et al, 2018;Couallier, Riaublanc, David, & Rousseau, 2018;Foley, Tessier, & Woods, 2012;Watts, Gregory, Frisbie, & Lovas, 2018). They also include bonded and nonbonded parameters involved in bonded and nonbonded interactions.…”

“…The development of force fields, an essential component of MD software, was widely expanded over the years (Table ). Force fields provide parameters that define the atoms, residues, and their masses, charges, types, and so on involved in a system under study (Cheng et al., ; Couallier, Riaublanc, David, & Rousseau, ; Foley, Tessier, & Woods, ; Watts, Gregory, Frisbie, & Lovas, ). They also include bonded and nonbonded parameters involved in bonded and nonbonded interactions.…”

Activation of G-protein coupled receptors is thermodynamically linked to lipid solvation

“…The lipid mixture (0.55:0.15:0.30 DPPC:DOPC:Chol) is in the liquid-liquid coexistence region of the phase diagram. The protein and lipids were modeled with the CHARMM36 force field (Klauda et al, 2010;Huang et al, 2017;Watts et al, 2018), and the ligand was modeled with the CHARMM general force field (Vanommeslaeghe et al, 2010) with atoms typed by the ParamChem server (Vanommeslaeghe & MacKerell, 2012).…”