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

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.Author Summary: Dependence of protein conformational ensembles on force field parameterizations limits the predictive power of molecular dynamics simulations. To address this problem, we evaluated five all-atom force fields for their consistency in reproducing the conformational ensemble of Alzheimer’s Aβ10-40 peptide. To generate conformational ensembles, we have used replica exchange molecular dynamics and computed Aβ10-40 secondary and tertiary structures. We found that, although all force fields predict Aβ10-40 unfolded structure, they strongly disagree on helix and β propensities and tertiary structure distributions. We have also calculated Aβ10-40 J-coupling and residual dipolar coupling constants and compared them with the experimental data for the full-length Aβ1-40 peptide. Unexpectedly, we determined that in silico Aβ10-40 and experimental Aβ1-40 constants are in better agreement than these quantities computed and measured previously for identical peptides, such as Aβ1-40 or Aβ1-42. We then concluded that the conformational ensembles of Aβ10-40 and Aβ1-40 are similar and on this basis argue that CHARMM36 force field with standard TIP3P water model provides the most accurate description of Aβ10-40. Although our objective was not to evaluate the biomolecular force fields in general, our study is expected to facilitate their proper selection for the simulations of Alzheimer’s peptides.