Molecular Mechanisms and Aspects on the Role of Neuropeptide Y as a Zn²⁺ and Cu²⁺ Chelator

Abstract

The concept of metal chelation is based on simple coordination chemistry. The development of an ideal metal chelator that completely and selectively removes toxic metals from a specific metal binding site in proteins is required to prevent and or inhibit a variety of diseases, among them neurodegenerative diseases. This work examines neuropeptide Y (NPY) as a Zn 2+ and Cu 2+ chelator agent. NPY is a natural peptide that is produced in the human body; therefore, it is not a toxic agent and the complex that it forms is not toxic as well. Our simulations reveal that NPY has an efficient Zn 2+ chelation activity but is less effective in chelating Cu 2+ . Moreover, while NPY demonstrates several conformations, the metal chelation occurs more efficiently in its native structure. Beyond the exploration of the activity of NPY as a Zn 2+ and Cu 2+ chelator agent, this work provides an insight into the molecular mechanisms of the chelation of these metals at the molecular level. The outcomes from this work may guide future experimental studies to examine NPY in metal chelation therapy for neurodegenerative diseases.

Neuropeptides: Roles and Activities as Metal Chelators in Neurodegenerative Diseases

“…The first Zn 2+ binding site consists of the residues Asp6, Glu10, Asp11, and Asp16, while the second Zn 2+ binding site contains His26 and water molecules that complete the coordination mode. 135 Our simulations also showed that NPY can bind Cu 2+ , but only along the N-terminal domain, containing the following residues: Asp6, Glu10, Asp11, and Asp16 ( Figure 7 ). Our simulations, therefore, suggested that NPY can selectivity bind Cu 2+ ions, while a competition between two binding sites may occur when NPY binds Zn 2+ ions.…”

“…Recently, our simulations demonstrated that NPY could bind Zn 2+ ion in two domains along the sequence of NPY (Figure ). The first Zn 2+ binding site consists of the residues Asp6, Glu10, Asp11, and Asp16, while the second Zn 2+ binding site contains His26 and water molecules that complete the coordination mode . Our simulations also showed that NPY can bind Cu 2+ , but only along the N-terminal domain, containing the following residues: Asp6, Glu10, Asp11, and Asp16 (Figure ).…”

“…Neuropeptides comprise numerous subfamilies of groups, e.g., hypothalamic and other hormones, tachykinin, opioid peptides, and pancreatic polypeptides . Only a few neuropeptides were investigated as metal chelators by in vitro (reviewed elsewhere in Section ) and by in silico studies. , There are still large number of neuropeptides that need to be investigated for their ability to bind metal ions both by in vitro and in silico studies. Moreover, to date, in vivo studies have not been completed to investigate the neuropeptides as metal chelators in neurodegenerative diseases.…”