Is the Conformational Ensemble of Alzheimer’s Aβ10-40 Peptide Force Field Dependent?

Abstract

By applying REMD simulations we have performed comparative analysis of the conformational ensembles of amino-truncated Aβ10-40 peptide produced with five force fields, which combine four protein parameterizations (CHARMM36, CHARMM22*, CHARMM22/cmap, and OPLS-AA) and two water models (standard and modified TIP3P). Aβ10-40 conformations were analyzed by computing secondary structure, backbone fluctuations, tertiary interactions, and radius of gyration. We have also calculated Aβ10-40 3JHNHα-coupling and RDC constants and compared them with their experimental counterparts obtained for the full-length Aβ1-40 peptide. Our study led us to several conclusions. First, all force fields predict that Aβ adopts unfolded structure dominated by turn and random coil conformations. Second, specific TIP3P water model does not dramatically affect secondary or tertiary Aβ10-40 structure, albeit standard TIP3P model favors slightly more compact states. Third, although the secondary structures observed in CHARMM36 and CHARMM22/cmap simulations are qualitatively similar, their tertiary interactions show little consistency. Fourth, two force fields, OPLS-AA and CHARMM22* have unique features setting them apart from CHARMM36 or CHARMM22/cmap. OPLS-AA reveals moderate β-structure propensity coupled with extensive, but weak long-range tertiary interactions leading to Aβ collapsed conformations. CHARMM22* exhibits moderate helix propensity and generates multiple exceptionally stable long- and short-range interactions. Our investigation suggests that among all force fields CHARMM22* differs the most from CHARMM36. Fifth, the analysis of 3JHNHα-coupling and RDC constants based on CHARMM36 force field with standard TIP3P model led us to an unexpected finding that in silico Aβ10-40 and experimental Aβ1-40 constants are generally in better agreement than these quantities computed and measured for identical peptides, such as Aβ1-40 or Aβ1-42. This observation suggests that the differences in the conformational ensembles of Aβ10-40 and Aβ1-40 are small and the former can be used as proxy of the full-length peptide. Based on this argument, we concluded that CHARMM36 force field with standard TIP3P model produces the most accurate representation of Aβ10-40 conformational ensemble.

Structure of APP-C991-99and Implications for Role of Extra-Membrane Domains in Function and Oligomerization

“…All simulations were performed using CHARMM version c41b1 [73] using the CHARMM36 force field, [74] likely to be the most accurate force field for simulation of Aβ. [75] The GBSW implicit membrane solvent model was used, [69] employing a 0.004 kcal mol -1 Å -2 surface tension, 5 Å smoothing length from the membrane core-surface boundary, and 0.6 Å smoothing length at the water-membrane surface boundary, using 24 radial and 38 angular integration points to 20 Å.…”

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

“…The shared primary structural feature of Aβ peptides is a central hydrophobic core (CHC) from residues Leu to Ala and a C‐terminal hydrophobic core from Ala to Val with an N‐terminal hydrophilic region from Asp to Lys and central hydrophilic region from Glu to Gly. X‐ray diffraction, solid state NMR, other spectroscopic methods and molecular dynamics (MD) simulations have demonstrated that collapse of CHC and residues 30–36, leads to the formation of a β‐strand‐loop‐β‐strand motif that is important for oligomerization and fibril formation .…”

Effects of Force Fields on the Conformational and Dynamic Properties of Amyloid β(1-40) Dimer Explored by Replica Exchange Molecular Dynamics Simulations

“…The predominance of A fibrils in cerebral cortical tissue does not necessarily correlate with causation of AD or CAA given the finding that A(1-40) is ten times more abundant in cerebrospinal fluid than A(1-42). [14][15][16] The shared primary structural feature of A peptides is a central hydrophobic core (CHC) from residues Leu 17 to Ala 21 and a C-terminal hydrophobic core from Ala 30 to Val 36 with an N-terminal hydrophilic region from Asp 1 to Lys 16 and central hydrophilic region from Glu 22 to Gly 29 . X-ray diffraction, solid state NMR, other spectroscopic methods and molecular dynamics (MD) simulations have demonstrated that collapse of CHC and residues 30-36, leads to the formation of a -strand-loop--strand motif that is important for oligomerization and fibril formation.…”

“…29 This behavior may also hold for other forms of A monomers given a recently published MD simulation of A(10-40) using the CHARMM22/cmap and CHARMM36 force fields demonstrated a similar helical motif with excellent agreement with the previously published 3 JHNH  -coupling and RDC constants from the 2LFM solution structure. 30 The lowest order A oligomer that appears to be biologically active is the dimer having been identified in the cerebral tissue of AD patients. 16 Covalently linked synthetic A dimers have also been used to demonstrate rapid oligomerization and fibril formation as well as the development of hyper-phosphorylated tau protein in the cerebral cortex tissue of animal models.…”

“…34 This phenomenon of increased L-helical sampling was not observed in our previous study and it is unclear if the highly polar nature of RS, (AAQAA)3, and HEWL19 peptides played a significant role in the findings of Rauscher et al 34 Despite multiple MD simulations on A peptides, it is neither clear what force field should be used for simulations nor how to compare and interpret the results of simulations completed utilizing different force fields. 30,[35][36][37][38][39] Herein, we utilize statistically robust methodologies comparing the conformational and dynamic properties of A(1-40) dimer as a function of force field selection using REMD simulations in TIP3P water with the AMBER-ff99sb-ILDN, AMBER-ff99sb*-ILDN, AMBER-ff99sb-NMR, and CHARMM22* force fields. [40][41][42][43][44][45][46][47][48] Comparisons are made to existing circular dichroism spectropolarimetry (CD), IM-MS collision cross section measurements (CCS), and the previously published dimer simulation of Tarus and colleagues 23 using the CHARMM22* force field and our previous results with CHARMM36 force fields.…”