The human prion protein binds Cu+2 ions in the octarepeat domain of the N-terminal tail up to full occupancy at pH = 7,4. Recent experiments show that the HGGG octarepeat sub-domain is responsible for holding the metal bound in a square planar configuration. By using first principle ab initio molecular dynamics simulations of the Car-Parrinello type, the coordination of Cu to the binding sites of the prion protein octarepeat region is investigated. Simulations are carried out for a number of structured binding sites. Results for the complexes Cu(HGGGW)(wat), Cu(HGGG), [Cu(HGGG)]2 and Cu(HGGG) + one imidazole ring are presented. While the presence of a Trp residue and a water molecule does not seem to affect the nature of the Cu coordination, high stability of the bond between Cu and the amide nitrogen of deprotonated Gly's is confirmed in all cases. Actually, it is found that Gly deprotonation is energetically accessible even at low temperatures. For the interesting [Cu(HGGG)]2 complex a dynamically entangled arrangement of the two domains with exchange of amide nitrogen bonds between the two Cu centers emerges, which is consistent with the short Cu-Cu distance observed in experiments at full Cu occupancy. In the presence of multiple imidazole ring (one from the His and one added to the system), it is found that the bond with the amide nitrogens from deprotonated Gly's is favoured. This is a priori surprising given the high affinity of imidazole for Cu.
La proteina prionica umana lega gli ioni Cu+2 nel dominio octarepeat della coda N-terminale fino a raggiungere una occupazione piena ad un pH = 7,4. Recenti esperimenti mostrano che il sotto-dominio HGGG dell'octarepeat é responsabile del mantenere il metallo legato in una configurazione planare quadrata. Utilizzando simulazioni di dinamica molecolare ab initio a partire da principi primi del tipo di Car Parrinello, viene studiata la coordinazione del Cu ai siti leganti della regione degli octarepeat della proteina prionica. Sono state condotte simulazioni per una serie di siti leganti strutturati. Sono presentati risultati per i complessi Cu(HGGGW)(acqua), Cu(HGGG), [Cu(HGGG)]2 and Cu(HGGG) + un imidazolo. Mentre la presenza di un residuo Trp e di una molecola d'acqua non sembra influenzare la natura della coordinazione del Cu, tutte le simulazioni confermano una grande stabilitá del legame fra il Cu e gli azoti amidici delle Gly deprotonate. In effetti si mostra che la deprotonazione della Gly é energeticamente accessibile anche a basse temperature. Nel caso dell'interessante complesso [Cu(HGGG)]2 risulta la formazione di una configurazione intrecciata dei due domini con lo scambio dei legami con gli azoti amidici fra i due centri Cu, in maniera consistente con la corta distanza Cu-Cu osservata sperimentalmente nel caso di piena occupazione. In presenza di piú anelli imidazolici (uno dall'His e uno aggiunto al sistema) si trova che il legame con gli azoti amidici dalle Gly deprotonate é favorito. Questo é a priori sorprendente data l'alta affinitá dell'imidazolo per il Cu.
Computer simulations of biomolecules: the case of the N-terminal PrP Cu binding site
Francesco, Guerrieri
2008
Abstract
The human prion protein binds Cu+2 ions in the octarepeat domain of the N-terminal tail up to full occupancy at pH = 7,4. Recent experiments show that the HGGG octarepeat sub-domain is responsible for holding the metal bound in a square planar configuration. By using first principle ab initio molecular dynamics simulations of the Car-Parrinello type, the coordination of Cu to the binding sites of the prion protein octarepeat region is investigated. Simulations are carried out for a number of structured binding sites. Results for the complexes Cu(HGGGW)(wat), Cu(HGGG), [Cu(HGGG)]2 and Cu(HGGG) + one imidazole ring are presented. While the presence of a Trp residue and a water molecule does not seem to affect the nature of the Cu coordination, high stability of the bond between Cu and the amide nitrogen of deprotonated Gly's is confirmed in all cases. Actually, it is found that Gly deprotonation is energetically accessible even at low temperatures. For the interesting [Cu(HGGG)]2 complex a dynamically entangled arrangement of the two domains with exchange of amide nitrogen bonds between the two Cu centers emerges, which is consistent with the short Cu-Cu distance observed in experiments at full Cu occupancy. In the presence of multiple imidazole ring (one from the His and one added to the system), it is found that the bond with the amide nitrogens from deprotonated Gly's is favoured. This is a priori surprising given the high affinity of imidazole for Cu.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.14242/200048
URN:NBN:IT:UNIROMA2-200048