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.
Highlights
Aβ peptides linked to the development of Alzheimer’s disease (AD) are produced, through a normal cellular proteolysis, in a variety of alloforms, which differ with respect to sequence length and the extent of amino- or C-terminal truncation [1,2,3]
We have investigated four all-atom protein force fields and two explicit water models [37, 38] resulting in five simulation systems, which utilized CHARMM36 [39] with modified TIP3P water model, CHARMM36 with standard TIP3P water model (C36s), CHARMM22Ã with modified TIP3P water model (C22Ã) [40], CHARMM22 with CMAP corrections and modified TIP3P water model (C22cmap) [41], and OPLS-AA with modified TIP3P water model (OPLS-AA) [42]
Unique features of OPLS-AA force field are moderate β-structure propensity and extensive, but flickering long-range tertiary interactions leading to Aβ collapse
Summary
Aβ peptides linked to the development of Alzheimer’s disease (AD) are produced, through a normal cellular proteolysis, in a variety of alloforms, which differ with respect to sequence length and the extent of amino- or C-terminal truncation [1,2,3]. All Aβ peptides are highly amyloidogenic [5, 6] and play a central role in amyloid cascade hypothesis, which explains AD pathogenesis on the basis of multi-stage aggregation of Aβ species. In this process, Aβ monomers represent initial species involved in spontaneous aggregation. Aβ peptides display a high level of cytotoxicity [2, 8,9,10], which is related to their ability to readily bind to cellular lipid bilayers and disrupt their structure [11]. The mechanism of binding to lipid bilayers is likely to be concentration dependent, Aβ peptides predominantly bind as monomers rather than oligomers at nanomolar concentrations [12, 13]
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