مجال التميز | تميز دراسي وبحثي |
البحوث المنشورة |
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البحث (1): | |
عنوان البحث: |
Can ionic effects induce α-sheet conformation of Peptides? |
رابط إلى البحث: |
https://www.sciencedirect.com/science/article/abs/pii/S0009261421007788 |
تاريخ النشر: |
30/09/2021 |
موجز عن البحث: |
We report coupled cluster, MP2 and DFT data on the relative energy and geometry of α-sheet and β-strand conformations of model peptides. We show that ionic effects have a strong effect on energy balance through formation of multiple cation-oxygen contacts in the α-sheet form. Such effects are markedly dependent on both sequence and ion: two peptides considered favour α-sheet in the presence of cations, whereas a third, non-polar one favours β-strand in the same conditions. |
البحث (2): | |
عنوان البحث: |
Computational study of copper binding to DAHK peptide |
رابط إلى البحث: |
https://www.sciencedirect.com/science/article/abs/pii/S0020169321003455?dgcid=rss_sd_all |
تاريخ النشر: |
27/08/2021 |
موجز عن البحث: |
Ligand Field Molecular Mechanics (LFMM), Density Functional Theory (DFT) and Semi-Empirical methods are used to study Cu(II) binding to the tetrapeptide Asp-Ala-His-Lys (DAHK). Two conformational searching tools, LFMM/AMBER and CREST/xTB, are used to predict the energy and geometry of Cu-DAHK, using DFT as a benchmark. In addition, DFT-predicted electronic spectra are used to evaluate the binding modes found. LFMM and DFT reproduce the experimentally determined coordination, a distorted square planar arrangement of 4 nitrogen ligands with axial coordination to a fifth, oxygen ligand. However, CREST conformational search was unsuccessful in predicting the coordination mode of Cu-DAHK, changing the bonding equatorial ligands from 4 N to 3N1O. |
البحث (3): | |
عنوان البحث: |
Forcefield evaluation and accelerated molecular dynamics simulation of Zn(II) binding to N-terminus of amyloid-β |
رابط إلى البحث: |
https://www.sciencedirect.com/science/article/abs/pii/S1476927121001079 |
تاريخ النشر: |
08/07/2021 |
موجز عن البحث: |
We report conventional and accelerated molecular dynamics simulation of Zn(II) bound to the N-terminus of amyloid-β. By comparison against NMR data for the experimentally determined binding mode, we find that certain combinations of forcefield and solvent model perform acceptably in describing the size, shape and secondary structure, and that there is no appreciable difference between implicit and explicit solvent models. We therefore used the combination of ff14SB forcefield and GBSA solvent model to compare the result of different binding modes of Zn(II) to the same peptide, using accelerated MD to enhance sampling and comparing the free peptide simulated in the same way. We show that Zn(II) imparts significant rigidity to the peptide, disrupts the secondary structure and pattern of salt bridges seen in the free peptide, and induces closer contact between residues. Free energy surfaces in 1 or 2 dimensions further highlight the effect of metal coordination on peptide’s spatial extent. We also provide evidence that accelerated MD provides improved sampling over conventional MD by visiting as many or more configurations in much shorter simulation times. |
البحث (4): | |
عنوان البحث: |
Theoretical study of copper binding to GHK peptide |
رابط إلى البحث: |
https://www.sciencedirect.com/science/article/abs/pii/S1476927120302000 |
تاريخ النشر: |
22/04/2020 |
موجز عن البحث: |
We report ligand field molecular mechanics, density functional theory and semi-empirical studies on the binding of Cu(II) to GlyHisLys (GHK) peptide. Following exhaustive conformational searching using molecular mechanics, we show that relative energy and geometry of conformations are in good agreement between GFN2-xTB semi-empirical and B3LYP-D DFT levels. Conventional molecular dynamics simulation of Cu-GHK shows the stability of the copper-peptide binding over 100 ps trajectory. Four equatorial bonds in 3N1O coordination remain stable throughout simulation, while a fifth in apical position from C-terminal carboxylate is more fluxional. We also show that the automated conformer and rotamer search algorithm CREST is able to correctly predict the metal binding position from a starting point consisting of separated peptide, copper and water. |
البحث (5): | |
عنوان البحث: |
Molecular dynamics simulations of copper binding to N-terminus mutants of amyloid-β |
رابط إلى البحث: | |
تاريخ النشر: |
02/04/2020 |
موجز عن البحث: |
We report results of molecular dynamic (MD) simulations on N-terminus mutants of the copper-bound, amyloid-β (Aβ) peptide. Eight structures of Aβ were modelled, including seven mutant peptides in addition to the unaltered wild-type (WT). Trajectories analysed for each individual system were all approximately 1.4 μs in length, yielding a total of over 11 μs in total. The impact of these mutations are marked and varied compared to the wild-type peptide, including effects on secondary structure, stability and conformational changes. Each system showed differing levels of stability with some showing consistent, compact conformations whereas others displayed more flexible structures. Contrasts between comparable mutations at similar sites, such as A2T/A2V and D7H/D7N, show the location as well as the type of mutation have effects on protein structure observed in Ramachandran plots. We also report notable changes in peptide structure at residues remote to the site of substitution showing these mutations influence the entirety of Aβ. Salt-bridge profiles show this most clearly: addition or removal of charged residues affecting all salt-bridge interactions present in WT, even those remote from the site of mutation. Effects on secondary structure differ between mutations, most notably a change in incidence of β-strand, which has been linked to enhanced aggregational properties for the peptide. GFN2-xTB semi-empirical calculations show clear differences in binding energies of the copper-centre for each system. Communicated by Ramaswamy H. Sarma. |
المؤتمرات العلمية |
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المؤتمر (1): | |
عنوان المؤتمر: |
4th CCPBioSim / CCP5 Multiscale Modelling Conference |
تاريخ الإنعقاد: |
29/03/2021 |
مكان الإنعقاد: |
UK |
طبيعة المشاركة: |
Poster presentation |
عنوان المشاركة: |
Modelling the Interaction of Cu(II) with Peptides Associated with Alzheimer’s Disease |
ملخص المشاركة: |
Cu(II) acts as an accelerant for aggregation & as a source of reactive oxygen species (ROS) involved in the formation of cross-links between Aβ peptides forming species associated with Alzheimer’s disease. GHK, is protective to neurons by chelating strongly to Cu(II), thus interfering with Aβ aggregation. In conjunction with its small size, GHK is an effective benchmark for modelling Cu(II) interactions with larger peptides such as Aβ. |
ناديه محسن عياده الشمري
دكتوراه
العلوم والتقنية
Cardiff University