Aluminium modulation of the dynamics of short disordered peptides

PhD Program

Speaker

David Silva Brea

When

2025/07/24
10:30

Place

CFM Auditorium (Donostia / San Sebastían)

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PhD Thesis defense by David Silva Brea

Supervisors: Xabier López  (DIPC Associate Researcher) & David de Sancho (DIPC Associate Researcher) 

Biochemistry: Metal-protein interactions

Proteins and metals are two biological elements with many essential functions in organisms. While they often work together for shared purposes, their aberrant interaction typically leads to the development of disorders.
In the case of intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs), a type of proteins that move away from the traditional structure-function paradigm, the abnormal metal coordination alters the natural accessible conformation distributions of the protein. The resultant metal-IDP/IDR complex has been linked to medical conditions multiple times, including Alzheimer’s Disease (AD), Parkinson’s Disease (PD) or Huntington’s Disease (HD). Understanding their interactions can pave the way for improved treatments and prevention strategies, ultimately enhancing public health and quality of life. In this thesis, we have focused on studying two key processes involving the coordination of peptides displaying intrinsically disordered behaviour to an aluminium cation (Al3+):
(i) the potential of de novo mimosine-containing peptides as aluminium chelator agents for metal overload, and (ii) the role of aluminium in protein aggregation mechanisms of AD, including his integration in the Metal Ion Hypothesis (MIH), a hypothesis proposed to explain the formation of pathological aggregates in AD due to the presence of metal ions. These two processes present opposing natures as the problem and the solution to their related medical conditions. Therefore, an adequate understanding of the metal-peptide interaction is fundamental to our capacity to take advantage of this duality. We have used a combination of quantum mechanical and molecular dynamics techniques to address our systems’ multi-scaling nature, allowing us to simultaneously evaluate both the statistical ensembles of conformations and the specific molecular interactions governing them.
Our analysis of the metal-peptide interactions across the evaluated systems shows that aluminium cation presents remarkable affinity with the proteins, especially towards residues with oxygen atoms —such as phosphoserines or mimosines— forming strongly coordinated complexes. Factors such as the peptide length, the coordinated residue types, the intra-chain protein interactions, or the system charge distribution can modulate the interactions between the metal and the peptide, having a non-negligible impact on the energetics of the systems, particularly through the entropic contribution.
Our results suggest that these structural factors can offset the entropic cost associated with the metal binding to the peptide. In the case of mimosine containing peptides, the entropic penalty is a contribution that could be modified by design to achieve suitable chelation affinities. However, in the aggregation mechanisms of AD, the character of the interactions would naturally reduce this entropic cost, resulting in unfortunate favourable metal coordination and subsequent aggregate growth. Leveraging the duality of metal-protein interaction systems, these results could be utilized to design efficient chelating agents and to understand the molecular mechanisms of protein aggregation, potentially leading to the development of therapeutic strategies.