title: Phosphorylation promotes Al(iii) binding to proteins: GEGEGSGG as a case study.
abstract: Aluminum, the third most abundant element in the Earth's crust and one of the key industrial components of our everyday life, has been associated with several neurodegenerative diseases due to its ability to promote neurofilament tangles and β-amyloid peptide aggregation. However, the experimental characterization of aluminum speciation in vivo is a difficult task. In the present study, we develop a theoretical protocol that combines molecular dynamics simulations, clustering of structures, and density functional theory for the characterization of the binding of aluminum to the synthetic neurofilament analogue octapeptide GEGEGSGG and its phosphorylated variant. Our protocol is tested with respect to previous NMR experimental data, which allows for a full interpretation of the experimental information available and its relationship with key thermodynamic quantities. Our results demonstrate the importance of phosphorylation in the ability of a peptide to bind to aluminum. Thus, phosphorylation: (i) changes the binding pattern of aluminum to GEGEGSGG, shifting the preferential binding site from the C-terminal to S6(P); (ii) increases the binding affinity by a factor of around 15 kcal mol(-1) in free energy; and (iii) may cause significant changes in the secondary structure and stiffness of the polypeptide chain, specially in the case of bidentate binding modes. Our results shed light on the possibility of aluminum to induce aggregation of β-amyloid proteins and neurofilament tangles.
authors.affiliation: Kimika Fakultatea, Euskal Herriko Unibertsitatea (UPV/EHU) and Donostia Internacional Physics Center (DIPC), P.K., 1072, 20080 Donostia, Euskadi, Spain. xabier.lopez@ehu.es.
authors.forename: Rafael
authors.initials: R
authors.lastname: Grande-Aztatzi
authors.affiliation: Kimika Fakultatea, Euskal Herriko Unibertsitatea (UPV/EHU) and Donostia Internacional Physics Center (DIPC), P.K., 1072, 20080 Donostia, Euskadi, Spain. xabier.lopez@ehu.es.
authors.forename: Elena
authors.initials: E
authors.lastname: Formoso
authors.affiliation: Kimika Fakultatea, Euskal Herriko Unibertsitatea (UPV/EHU) and Donostia Internacional Physics Center (DIPC), P.K., 1072, 20080 Donostia, Euskadi, Spain. xabier.lopez@ehu.es.
authors.forename: Jon I
authors.initials: JI
authors.lastname: Mujika
authors.affiliation: Kimika Fakultatea, Euskal Herriko Unibertsitatea (UPV/EHU) and Donostia Internacional Physics Center (DIPC), P.K., 1072, 20080 Donostia, Euskadi, Spain. xabier.lopez@ehu.es.
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Ugalde
authors.affiliation: Kimika Fakultatea, Euskal Herriko Unibertsitatea (UPV/EHU) and Donostia Internacional Physics Center (DIPC), P.K., 1072, 20080 Donostia, Euskadi, Spain. xabier.lopez@ehu.es.
authors.forename: Xabier
authors.initials: X
authors.lastname: Lopez
mesh_terms: D000535:Aluminum / Q000737:chemistry*; D000595:Amino Acid Sequence; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010766:Phosphorylation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*
chemical_list: D011506:Proteins; D000535:Aluminum