Effect of mutation on Aß1-42-Heme complex in aggregation mechanism: Alzheimer's disease.

Amyloid ß (Aß) peptide aggregation is one of the root causes for Alzheimer's disease. Recently, experimental studies show that three active binding sites (His6, His13 and His14) of Aß peptides were bound with heme to form Aß-Heme complex, which leads to inhibit the aggregation process. We apply molecular dynamic simulation to investigate the aggregation pathways of Aß-Heme peptides. The above three binding sites were mutated by Glycine residue individually and generate three complex systems such as Aß(His6Gly)-Heme, Aß(His13Gly)-Heme and Aß(His14Gly)-Heme. These complexes were simulated in explicit water using gromos53a6 force field for 200ns. We found that the His13Gly mutation increase the ß-sheet contents (75%) in Aß peptide. On the other hand, heme binds with His13 residue of native peptide plays an important role to reduce the formation ß-sheet content (50%) in Aß peptide. This finding is in agreement with experimental study, which showed that the effect of mutation on His6 is not directly involved in ß-sheet formation, but the effect of mutation in His13 and His14 has involved in ß-sheet formation [J. Neurochem. (2009), 110, 1784-1795]. So, our results may be useful to understand the pathway mechanism of aggregation of Aß peptides.

Fe(2+) binding on amyloid ß-peptide promotes aggregation.

The metal ions Zn(2+) , Cu(2+) , and Fe(2+) play a significant role in the aggregation mechanism of Aß peptides. However, the nature of binding between metal and peptide has remained elusive; the detailed information on this from the experimental study is very difficult. Density functional theory (dft) (M06-2X/6-311++G (2df,2pd) +LANL2DZ) has employed to determine the force field resulting due to metal and histidine interaction. We performed 200 ns molecular dynamics (MD) simulation on Aß1-42 -Zn(2+) , Aß1-42 -Cu(2+) , and Aß1-42 -Fe(2+) systems in explicit water with different combination of coordinating residues including the three Histidine residues in the N-terminal. The present investigation, the Aß1-42 -Zn(2+) system possess three turn conformations separated by coil structure. Zn(2+) binding caused the loss of the helical structure of N-terminal residues which transformed into the S-shaped conformation. Zn(2+) has reduced the coil and increases the turn content of the peptide compared with experimental study. On the other hand, the Cu(2+) binds with peptide, ß sheet formation is observed at the N-terminal residues of the peptide. Fe(2+) binding is to promote the formation of Glu22-Lys28 salt-bridge which stabilized the turn conformation in the Phe19-Gly25 residues, subsequently ß sheets were observed at His13-Lys18 and Gly29-Gly37 residues. The turn conformation facilitates the ß sheets are arranged in parallel by enhancing the hydrophobic contact between Gly25 and Met35, Lys16 and Met35, Leu17 and Leu34, Val18 and Leu34 residues. The Fe(2+) binding reduced the helix structure and increases the ß sheet content in the peptide, which suggested, Fe(2+) promotes the oligomerization by enhancing the peptide-peptide interaction. Proteins 2016; 84:1257-1274. © 2016 Wiley Periodicals, Inc.

Study on the inter- and intra-peptide salt-bridge mechanism of Aß23-28 oligomer interaction with small molecules: QM/MM method.

Amyloid ß (Aß) peptides have long been known to be a potential candidate for the onset of Alzheimer's disease (AD). The biophysical properties of Aß42 peptide aggregates are of significant importance for the amyloid cascade mechanism of AD. It is necessary to design an inhibitor using small molecules to reduce the aggregation process in Aß42 peptides. Attention has been given to use the natural products as anti-aggregation compounds, directly targeting Aß peptides. Polyphenols have been extensively studied as a class of amyloid inhibitors. 9,10-Anthraquinone (AQ) is present in abundance in medicinal plants (rhubarb), the Trp-Pro-Tyr (TPT) peptide has been found in the venom of the black mamba snake, and the morin molecule is naturally present in wine and green tea; several other polyphenol derivatives are under clinical trials to develop anti-neurodegenerative drugs. In vitro and in vivo results strongly suggest that AQ and morin molecules are potential inhibitors of Aß aggregation; however, the detailed understanding of the inhibition mechanism remains largely unknown. The formation of Aß fibrils and oligomers requires a conformational change from α-helix to ß-sheet, which occurs due to the formation of a salt-bridge between Asp(23) and Lys(28) residues. The present study focused on investigating the salt-bridge mechanism in the monomer, dimer and oligomer of the Aß23-28 peptide during the interaction with TPT, morin and AQ molecules. Interaction energy and natural bond orbital analyses have been carried out using the ONIOM(M05-2X/6-31++G(d,p):UFF) method. The QM/MM studies have been performed to study the mechanism of salt-bridge formation during the inhibition process of amyloid ß protein aggregation. The TPT molecule, which binds with the Asp(23) and Lys(28) residues of Aß, prevents the salt-bridge formation between Asp(23) and Lys(28) residues and consequently the probability of the formation of Aß fibrils is reduced.

Targeted studies on the interaction of nicotine and morin molecules with amyloid ß-protein.

Alzheimer's disease (AD) is a neurodegenerative disorder that occurs due to progressive deposition of amyloid ß-protein (Aß) in the brain. Stable conformations of solvated Aß1₋42 protein were predicted by molecular dynamics (MD) simulation using the OPLSAA force field. The seven residue peptide (Lys-Leu-Val-Phe-Phe-Ala-Glu) Aß16₋22 associated with AD was studied and reported in this paper. Since effective therapeutic agents have not yet been studied in detail, attention has focused on the use of natural products as effective anti-aggregation compounds, targeting the Aß1₋42 protein directly. Experimental and theoretical investigation suggests that some compounds extracted from natural products might be useful, but detailed insights into the mechanism by which they might act remains elusive. The molecules nicotine and morin are found in cigarettes and beverages. Here, we report the results of interaction studies of these compounds at each hydrophobic residue of Aß16₋22 peptide using the hybrid ONIOM (B3LYP/6-31G**:UFF) method. It was found that interaction with nicotine produced higher deformation in the Aß16₋22 peptide than interaction with morin. MD simulation studies revealed that interaction of the nicotine molecule with the ß-sheet of Aß16₋22 peptide transforms the ß-sheet to an α-helical structure, which helps prohibit the aggregation of Aß-protein.

Molecular dynamics simulations and density functional theory studies of NALMA and NAGMA dipeptides.

Classical molecular dynamics (MD) simulations using fixed charged force field (AMBER ff03) and density functional theory method using the M05-2X/6-31G** level of theory have been used to investigate the plasticity of the hydrogen bond formed between dipeptides of N-Acetyl-Leucine-MethylAmide (NALMA), N-Acetyl-Glycine-MethylAmide (NAGMA), and vicinity of water molecules at temperature of 300 K. We have noticed that 2-3 water molecules contribute to change in the conformations of dipeptides NAGMA and NALMA. The self-assembly of 11 water molecules leads to the formation of water bridge at vicinity of the dipeptides and it constrain the conformations of dipeptides. We have found that the energy balance between breaking of the C = O…H-N H bonds and the formation of the C = O…H-O (wat) H bonds may be one of the determining factors to control the dynamics of the folding process of protein molecules.

Microsolvation and hydrogen bond interactions in Glycine Dipeptide: molecular dynamics and density functional theory studies.

Molecular dynamics (MD) simulations were carried out to study the conformational characteristics of Glycine Dipeptide (GD) in the presence of explicit water molecules for over 10 ns with a MD time step of 2 fs. The density functional theory (DFT) methods with 6-311G** basis set have been employed to study the effects of microsolvation on the conformations of GD with 5-10 water molecules. The interaction energy with BSSE corrections and the strength of the intermolecular hydrogen bond interactions have been analyzed. The Bader's Atoms in Molecules (AIM) theory has been employed to investigate H-bonding patterns in water interacting complexes. The natural bond orbital (NBO) analysis has been carried out to analyze the charge transfer between proton acceptor to the antibonding orbital of the XH bond in the hydrated complexes. NMR calculations have been carried out at B3LYP/6-311G (2d, 2p) level of theory to analyse the changes in structure and hydrogen bonding environment that occur upon solvation.