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 A β 10-40 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). A β 10-40 conformations were analyzed by computing secondary structure, backbone fluctuations, tertiary interactions, and radius of gyration. We have also calculated A β 10-40 3 J HNHα -coupling and RDC constants and compared them with their experimental counterparts obtained for the full-length A β 1-40 peptide. Our study led us to several conclusions. First, all force fields predict that A β adopts unfolded structure dominated by turn and random coil conformations. Second, specific TIP3P water model does not dramatically affect secondary or tertiary A β 10-40 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 A β 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 3 J HNHα -coupling and RDC constants based on CHARMM36 force field with standard TIP3P model led us to an unexpected finding that in silico A β 10-40 and experimental A β 1-40 constants are generally in better agreement than these quantities computed and measured for identical peptides, such as A β 1-40 or A β 1-42. This observation suggests that the differences in the conformational ensembles of A β 10-40 and A β 1-40 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 A β 10-40 conformational ensemble.