Computational protocol: Molecular Dynamics Study of Zn(Aβ) and Zn(Aβ)2

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Protocol publication

[…] Aβ(1-42) (PDB: 1Z0Q) models were created for all molecular dynamics simulations. In general, the initial structures for Zn(Aβ)n (where n = 1 or 2) complexes were created by using the experimental data and our aforementioned DFT calculations. The initial structure for Zn(Aβ) was created by using the NMR structure for Zn(Aβ(1-16)) (PDB: 1ZE9) as the N-terminus and combining it with residues 17-42 from Aβ(1-42) (PDB: 1Z0Q) . The Zn(II) was covalently bound to His6, 13, 14 and Glu11 as found by NMR, using the force-constants obtained from our DFT calculations. For the Zn(Aβ)2 complexes, quantum mechanics calculations revealed that the ligand combinations (2 Glu and 2 His) and 4 His are relatively stable dimeric cross linkages (at pH 7.0). Thus, there are six different possible dimeric structures (Glu11/His6, Glu11/His13, Glu11/His14, His6/His13, His6/His14 and His13/His14). To model the His6/His13 and His6/His14 combinations would have required changing the backbone from what was observed in the NMR. Therefore, the His6/His13 and His6/His14 combinations were not included in this study. Control models were built by removing the Zn(II) from the Zn-bound complexes, thereby keeping the same initial structures (prior to minimization) for the peptides. In this manner, it is possible to show how zinc's effect on the peptide can persist even after dissociation. Ten models were built and simulated. We used all-atom simulations with explicit water solvent (TIP3P) for the systems with our augmented CHARMM 22/CMAP force field (). We performed conjugate gradient energy minimization on the solvated system, followed by 1.5 ns simulation during which thermal energy was added to the systems gradually, which increased the temperature from 0 to 300 K. Next, we performed 200 ns simulations in triplicate for each complex at constant temperature and pressure (NPT, 1 atm, 300 K) using the program NAMD 2.7 . All data analysis was done using VMD 1.9 .Root mean square deviations (RMSD) of the Cα atoms were measured () for all simulations to evaluate the extent of equilibration. To compare the flexibilities of different regions of Aβ, root mean square fluctuations (RMSF) were measured () for the Cα atoms after the simulations equilibrated. Secondary structure changes over time were measured (using the STRIDE plugin as implemented in VMD ) for all peptide species in terms of total percentage secondary structure composition within each peptide chain. Also, we measured the percentage of time each residue exhibited either helix or β-sheet structures after equilibration. The radius of gyration was measured over time in each simulation to determine how binding to zinc affects how compact the peptides are. Salt bridges () over time were measured to reveal certain intra-chain and inter-chain interactions. […]

Pipeline specifications

Software tools CHARMM, NAMD, VMD, STRIDE
Application Protein structure analysis
Diseases Alzheimer Disease, Neurotoxicity Syndromes, Genetic Diseases, Inborn
Chemicals Zinc