Phosphorylation promotes Al(iii) binding to proteins: GEGEGSGG as a case study

Area of Science:

• Biochemistry
• Computational Chemistry
• Neuroscience

Background:

• Aluminum exposure is linked to neurodegenerative diseases like Alzheimer's.
• Aluminum's role in forming neurofilament tangles and amyloid plaques is known.
• Experimental characterization of in vivo aluminum speciation is challenging.

Purpose of the Study:

• To develop a theoretical protocol for characterizing aluminum binding to peptides.
• To investigate the impact of phosphorylation on aluminum-peptide interactions.
• To interpret experimental data and thermodynamic quantities related to aluminum binding.

Main Methods:

• Molecular dynamics simulations
• Structure clustering
• Density functional theory (DFT)
• Comparison with NMR experimental data

Main Results:

• Phosphorylation shifts aluminum binding from the C-terminal to S6(P) in the octapeptide GEGEGSGG.
• Binding affinity increases by approximately 15 kcal mol(-1) due to phosphorylation.
• Phosphorylation can alter peptide secondary structure and stiffness, especially with bidentate binding.

Conclusions:

• Phosphorylation plays a critical role in modulating aluminum-peptide interactions.
• The theoretical protocol provides a framework for interpreting experimental findings on aluminum speciation.
• Understanding these interactions may elucidate aluminum's contribution to neurodegenerative disease pathogenesis.