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SPS Seminar - Atomistic Modelling in Alzheimer’s Disease

Thursday, June 15, 2023 - 14:00 to 15:00

When:   Thursday 15 June at 14.00

Where:  Microsoft Teams – Robert Hooke/Online

Speaker:  Shaun T Mutter (LHCS)

Hosted by: Andrew James


Amyloid-β peptides are a major constituent of the senile plaques observed in the brains of patients

with Alzheimer's disease. Naturally occurring metals in the brain, such as copper, can coordinate at the N-terminus of amyloid-β and it has long been suggested that they contribute to aggregation and therefore play a role in the onset of Alzheimer’s disease.[1] Non-natural metals, such as platinum, can also coordinate to similar sites, as such they have shown potential as anti-Alzheimer's agents through a disruption of the native metal coordination.[2] Ligand field molecular mechanics (LFMM) offers a powerful tool to study systems such as these by utilising a small number of transferable parameters that capture the key d-orbital effects, and is an alternative for expensive quantum simulations or molecular mechanics with ad hoc metal parameters.
The accuracy of LFMM, benchmarked against density functional theory and semi empirical approaches

is reported. Results are also reported using LFMM as a molecular dynamics tool to study copper and platinum binding to the 42-residue variant of amyloid-β monomer. The structure and dynamics of the transition metal bound systems are compared to those of the free peptide to show that secondary structure and salt bridge networks are significantly altered under coordination. Significant differences are observed not only between the metal bound and free peptides but also between the copper and platinated systems.[3]

[1] A. Rauk, Chem. Soc. Rev. 2009, 38, 2698.

  1. M. Turner, J. A. Platts, R. J. Deeth, J. Chem. Theory Comput. 2016, 12, 1385.
  2. S. T. Mutter, R. J. Deeth, M. Turner, J. A. Platts, ACS Chem. Neuro. 2018, 9, 2795


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