Abstract
Ligand field molecular mechanics simulation has been used to model the interactions of copper(II) and platinum(II) with the amyloid-β1-42 peptide monomer. Molecular dynamics over several microseconds for both metalated systems are compared to analogous results for the free peptide. Significant differences in structural parameters are observed, both between Cu and Pt bound systems as well as between free and metal-bound peptide. Both metals stabilize the formation of helices in the peptide as well as reducing the content of β secondary structural elements compared to the unbound monomer. This is in agreement with experimental reports of metals reducing β-sheet structures, leading to formation of amorphous aggregates over amyloid fibrils. The shape and size of the peptide structures also undergo noteworthy change, with the free peptide exhibiting globular-like structure, platinum(II) system adopting extended structures, and copper(II) system resulting in a mixture of conformations similar to both of these. Salt bridge networks exhibit major differences: the Asp23-Lys28 salt bridge, known to be important in fibril formation, has a differing distance profile within all three systems studied. Salt bridges in the metal binding region of the peptide are strongly altered; in particular, the Arg5-Asp7 salt bridge, which has an occurrence of 71% in the free peptide, is reduced to zero in the presence of both metals.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative condition, currently affecting more than 30 million people worldwide,[1,2] for which there is no cure
Brains show oxidative stress caused by reactive oxygen species (ROS)[9,10] and increased concentrations of metal ions, such as copper,[11] zinc,[4,12] iron,[13] and calcium.[14]
We have shown the suitability of Ligand field molecular mechanics (LFMM) for description of binding of Cu(II)[66] and Pt(II) with fragments of Aβ.[67−69]. We extend this LFMM approach to examine the dynamical behavior of Cu(II)− and Pt(II)(phen)−Aβ complexes using molecular dynamics simulations and LFMM description of metal coordination coupled with conventional molecular mechanics (MM) for the peptide
Summary
Alzheimer’s disease (AD) is a neurodegenerative condition, currently affecting more than 30 million people worldwide,[1,2] for which there is no cure. Common symptoms of AD include short-term memory loss, mild cognitive impairment, confusion and aggression. Cognitive function degrades and control of bodily functions is lost, eventually leading to death. AD is the fourth most common cause of death in Western countries.[3]. The causes and development of the condition are not well understood, but AD is associated with damage to specific brain regions, the hippocampus and cerebral cortex,[4] involved in memory and cognition. Brains show oxidative stress caused by reactive oxygen species (ROS)[9,10] and increased concentrations of metal ions, such as copper,[11] zinc,[4,12] iron,[13] and calcium.[14]
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