RESUMO
Extensive experimental and computational studies have suggested that multiple Zn(2+) binding modes in amyloid ß (Aß) peptides could exist simultaneously. However, consistent results have not been obtained for the effects of Zn(2+) binding on Aß structure, dynamics, and kinetics in particular. Some key questions such as why it is so difficult to distinguish the polymorphic states of metal ions binding to Aß and what the underlying rationale is, necessitate elucidation. In this work, two 3N1O Zn(2+) binding modes were constructed with three histidines (His(6), His(13), and His(14)), and Asp(1)/Glu(11) of Aß40 coordinated to Zn(2+). Results from molecular dynamics simulations reveal that the conformational ensembles of different Zn(2+)-Aß40 complexes are nonoverlapping. The formation of turn structure and, especially, the salt bridge between Glu(22)/Asp(23) and Lys(28) is dependent on specific Zn(2+) binding mode. Agreement with available NMR observations of secondary and tertiary structures could be better achieved if the two simulation results are considered together. The free energy landscape constructed by combining both conformations of Aß40 indicates that transitions between distinct Aß40 conformations thar are ready for Zn(2+) binding could be possible in aqueous solution. Markov state model analyses reveal the complex network of conformational space of Aß40 modeulated by Zn(2+) binding, suggesting various misfolding pathways. The binding free energies evaluated using a combination of quantum mechanics calculations and the MM/3D-RISM method suggest that Glu(11) is the preferred oxygen ligand of Zn(2+). However, such preference is dependent on the relative populations of different conformations with specific Zn(2+) binding modes, and therefore could be shifted when experimental or simulation conditions are altered.
