Molecular Dynamics Studies of Cu(II)-Bound α-Synuclein(αS) Complexes

Abstract

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. The aggregation of α-Synuclein (αS) is thought to be one of the key pathological events in the pathology of PD. Elevated Cu(II) concentrations have been reported in the cerebrospinal fluid of PD patients and many in vitro studies show that Cu(II) bonds to αS on different sequences either promotes or prevents the aggregation process . However, there is disagreement over which residues preferentially bind Cu(II) and how Cu(II) affects the aggregation process. Residues Met1, Asp2, 119, 121, His50, Asn120, Glu123 have been suggested as the most stable Cu(II) binding sites. However, research has shown that αS aggregation begins in the NAC region (residues 61-95) where Cu(II) binding could also occur at residues Glu61 and Glu83. To gain more insight into the nature of Cu(II) binding and its role in αS aggregation, single-site binding models of Cu(II) to all the aforementioned suggested residues were created using the NMR solution structure of αS and quantum mechanics calculations on the Cu(II) coordination environment. Also, Cu(II)-bound dimeric structures of just the NAC region were built and compared with those of the Cu(II)-free NAC dimer. Molecular dynamics simulations were performed and the energetics as well as dynamic structures were monitored.