Computer simulation of metal-amyloid interaction and its role in plaque formation

Alzheimer's disease is one of the greatest healthcare challenges facing 21st century society. Characterised by progressive loss of brain function, especially memory, the human, social and financial costs of this disease are already huge, and are forecast to become even more so in the coming decades. AD is associated with formation of fibrils and plaques (dense, mostly insoluble deposits of protein and cellular material outside and around neurons) in brain tissue that impair proper functioning of neurons. Plaques are formed by aggregation of amyloid-beta peptides that are soluble in isolation, but insoluble when bound to one another. The presence of metals, notably copper, zinc and iron, is a vital part of the aggregation and subsequent toxicity of amyloid beta peptides: increased levels of Cu and Zn are found in plaque regions of diseased brain, and those plaques which do not contain metal ions have been found to be non-toxic. Moreover, different metals such as platinum and ruthenium have been shown to inhibit aggregation, opening new avenues for treatment and diagnosis.

Experiments to determine how metals might bind to amyloid beta peptides are difficult and costly to perform: the peptides themselves are inherently highly flexible, and tend to aggregate into an insoluble mass that cannot be studied using conventional means such as spectroscopy. Moreover, they can be expensive and problematic to synthesise in pure form. In this light, using computers to simulate how metals bind to amyloid beta peptides and affect their structure and aggregation is an attractive proposition. Computer models are used in all walks of modern life, and computer-aided molecular design plays a vital role in the discovery of new drugs, agrochemicals, catalysts, dyes and materials, to name but a few.

This project will use modern simulation methods to describe in detail how metals can bind to the peptides that cause Alzheimer's, and the effect different metals have on their structure and aggregation characteristics. To do this in a reliable manner, we need methods that are capable of using supercomputers to describe the motions of hundreds or thousands of atoms, while also properly describing the particular chemistry of metal atoms in different environments. We have identified ligand field molecular mechanics (LFMM) as the ideal candidate for this task, as it efficiently and transferably captures the behaviour of metals, and has been used previously to examine processes such as the dynamics and spectroscropy of copper-containing proteins and the binding of platinum- based drugs to DNA. We will test this method for the specific case of metal-amyloid interactions by comparing against slower but more rigorous quantum mechanical and hybrid quantum-molecular mechanical (QM/MM) methods, since experimental structures are scarce. Having done so, we will use LFMM within molecular dynamics simulations to explicitly allow the peptide to change its shape in response to different metals. Crucially, the speed of LFMM coupled with the supercomputing resources available to us means that we can simulate the behaviour of two or more peptides together, and hence to examine the effect of metal on the initial stages of aggregation.

In this project, we will investigate how transition metals interact and bind with amyloid-beta peptides, using modern simulation methods. EPSRC recognises the continuing importance and demand for advances in tools and techniques which underpin many other research areas including Chemical Biology, and Catalysis. Molecular simulation is already a well established technique and a noted strength of UK Chemistry, but this will be the first application of these approaches to study metal-amyloid interactions in a manner that combines the efficiency required for long timescale dyanmic simulation of biomolecules with the theoretical rigour necessary to describe transition metals as diverse as iron, copper, ruthenium and platinum. Hence the academic community working in this field will be the primary beneficiaries.

Looking forward, metal complexes are also used for a variety of biological targets including as contrast agents in MRI and radiopharmaceuticals in the treatment of arthritis, ulcers and cancer chemotherapy. Despite this potential, few coordination compounds are actually implemented as drugs, since the pharmaceutical industry continues to focus on organic synthetic procedures. Apart from the cisplatin family, only a few compounds have undergone clinical trial while others, such as the Ru(II) arenes, have shown tremendous promise. By providing another enabling tool to probe metal-biomolecule interactions, this research may potentially create an opportunity to study in greater detail new families of active metal complexes, leading to new applications. The impact of this work reaches beyond the UK scientific community, being of significance to the international research community within both academic and industrial strands of pharmaceutical and medicinal chemistry.

Different approaches will be employed to ensure that the various beneficiaries outlined above are identified and engaged with from an early stage of the project. In the short term, the academic community will benefit directly from the development and applications of the advanced computational techniques utilised in the project. As noted above, we will provide atomic level detail that is difficult to access otherwise, and will enable the community to explore the possibilities of utilising metal complexes to examine and control amyloid peptides and their aggregations. The case for overall societal benefits is also compelling, as results arising from the project should contribute to ongoing developments in treatment and diagnosis of Alzheimer's disease. This is a massively debilitating condition and without treatment to even retard its onset, never mind actually cure the disease, the prognosis for sufferers is bleak. New insights provided by this research could, in the long term, contribute to the search for new therapeutic or diagnostic agents.

Outreach activities (also outlined in the Pathways to Impact) will also aim to engage the general public and school age children. Dr. Mason as a STEM Ambassador will facilitate the opportunities for public engagement on this project. Although the project as described is technically ambitious, there are general concepts that easily translate to a general audience or under-16 age group. Training opportunities and collaborations on use of computational facilities could be provided , while targeted public lectures and exhibitions will be delivered throughout the lifetime of the project, as detailed in the Pathways to Impact.