Molecular Dynamics Simulations On The Polymorphic Properties Of Amyloid β Peptides

Alzheimer’s disease (AD) has become one of the leading neurodegenerative disorders which seriously threaten the health of the aged worldwide. The misfolding and abnormal aggregations of amyloid β(Aβ) peptides are usually believed as one of contributing factors to the pathology of AD. Investigating the underlying mechanism of amyloid protein aggregation and designing appropriate inhibitors have been considered as a promising approach to advance the clinical treatment of these diseases. AP belongs to intrinsically disordered proteins, whose conformational space is highly polymorphic. It has been shown that a number of single point mutations at residues A21, E22, D23, and M35 of Aβ can increase or decrease aggregation tendency of Aβ. Although the effects of point mutations on the structural properties of Aβ peptides have been intensively studied, how single point mutation affects the kinetics of Aβ remains unknown. Also, metal ions have been suggested to be associated with the pathogenesis of Alzheimer’s disease. Understanding the interactions between Aβ and metal ions at the molecular level is a key step in investigating the role of metal ions in the aggregation of Aβ to form neurotoxic oligomers. Recent studies of Aβ indicate that formation of toxic and soluble oligomers may be an important contribution to the onset of AD. The toxicity of Aβ oligomers depends on their structure. Detailed information about the structure of Aβ in atomistic level and the thermodynamic property of assembly of monomeric AP into oligomeric structures is rather important for pathogenesis of AD. Therefore, the main content of the study in this paper are as follows:(1) Molecular dynamics simulations were performed to investigate the polymorphic property of Aβ and its mutants. We used dihedral dynamics analyses, which combine dihedral principle component analysis (dPCA), potential of mean force (PMF) calculations, and Markov state models (MSMs), to elucidate the different global free energy landscapes, the PMF of individual dihedral angle, microstates, and dynamic properties for a number of Aβ42 and its mutants (A21G, E22G, E22K, E22Q, D23N, E22A, and Met35OX). Our simulation results show that one point mutation is sufficient to change the rugged free energy landscape of Aβ42 by altering the energy barriers around basins. This alteration was also observed in the potential of each dihedral angle to varying degrees, although most minima of PMF do not shift. MSMs further reveal that E22 mutants (E22△, E22G, E22K, and E22Q) and D23N generate more hub-like microstates than wild type Aβ42, thus creating diverse alternative pathways for conformational transitions and increasing subsequent aggregation. In contrast, transitions are more preferred within the same microstate of A21G and Met35OX. Mapping MSM to free energy landscape suggests that transitions between different sets of microstates are kinetically feasible but thermodynamically difficult.(2) Molecular dynamics simulations were carried out to study the effects of Zn2+ on the polymorphic states of Aβ40 and Aβ42. We used dihedral dynamics analyses which combine the potential of PMF to calculate the free energies of individual dihedral angles of Zn2+ bound Aβ40(Aβ40-Zn2+) and Aβ42 (Aβ42-Zn2+) using a coarse-grained model, dihedral principle component analysis to characterize the free energy landscapes of Aβ40-Zn2+ and Aβ42-Zn2+. Then, we establish Markova state models to show the dynamic misfolding network of Aβ40-Zn2+ and Aβ42-Zn2+. Our simulation results show that the dihedral free energies of Zn2+bound AP40 and AP42 are similar, with significant difference being observed for the dihedral consisting of Val24, Gly25, Ser26, and Asn27 residues. Both free energy landscapes are less rugged, indicating that no high energy barrier has to be crossed for conformational transitions of Aβ. Furthermore, the Markov state model suggests that each microstate containing a number of similar structures serves as a hub in the network, and multiple alternative misfolding pathways are available if that node is blocked, indicating the kinetic feasibility of conformational transitions of Zn2+ bound Aβ. In particular, the role of the β-strand structure in the kinetic network is negligible, consistent with the experimental result that little β-strand structure was identified in Zn2+ bound Aβ.(3) We studied the process of two kinds of Aβ40-Zn2+ monomers aggregate to Ap40-Zn2+ dimer and the role of Zn2+ in Zn2+-Aβ40 monomer or oligomers by MD simulations in an explicit solvent environment. At the same time, we used MM-PBSA method to survey the thermodynamic properties of (Aβ40-Zn2+)2 and (Aβ40-Zn2+)4. Our simulation results show that β-hairpins of Aβ40-Zn2+ monomer is relatively less stable in aqueous solution; Two identical Aβ40-Zn2+ monomers can directly self-assembly into one dimer (Aβ40-Zn2+)2 without altering the β-hairpins structures significantly:Two Aβ40 monomers of (Aβ40)2 was found to deviate from its original arrangement and become disordered, the results suggest that Zn2+can stabilize β-hairpins of (Aβ40-Zn2+)2 and relative alignment. The results of MM-PBSA illustrate that the Aβ40-Zn2+ dimer are soluble in an aqueous solution; the association of two (Aβ40-Zn2+)2 into [(Aβ40-Zn2+)n>2] is thermodynamically favorable; the (Aβ40-Zn2+)2 structure may be a building unit for oligomers.In summary, MD simulations were applied to characterize the effects of point mutations, metal ions, and aggregation on the polymopric nature of Aβ. It was found that point mutation can alter the microdynamic of Aβ significantly; metal ions like Zn2+ lower the energy barrier of conformational conversion, and make β-strand structures less important in kinetic network; and aggregation seems favorable for Aβ monomers in β-hairpin conformations. Our present results provide valuable insights into the aggregation mechanism induced by metal ions.