Theoretical characterization of Al(III) binding to KSPVPKSPVEEKG: Insights into the propensity of aluminum to interact with key sequences for neurofilament formation.

Classical molecular dynamic simulations and density functional theory are used to unveil the interaction of aluminum with various phosphorylated derivatives of the fragment KSPVPKSPVEEKG (NF13), a major multiphosphorylation domain of human neurofilament medium (NFM). Our calculations reveal the rich coordination chemistry of the resultant structures with a clear tendency of aluminum to form multidentate structures, acting as a bridging agent between different sidechains and altering the local secondary structure around the binding site. Our evaluation of binding energies allows us to determine that phosphorylation has an increase in the affinity of these peptides towards aluminum, although the interaction is not as strong as well-known chelators of aluminum in biological systems. Finally, the presence of hydroxides in the first solvation layer has a clear damping effect on the binding affinities. Our results help in elucidating the potential structures than can be formed between this exogenous neurotoxic metal and key sequences for the formation of neurofilament tangles, which are behind of some of the most important degenerative diseases.