The interaction landscape of amyloid beta-Zn(II) from molecular dynamics simulations

Abstract

Abstract (English)

Amyloid fibrils are stable forms of misfolded proteins associated with numerous neurode-generative diseases. Among these, Alzheimer’s disease may be the most prevalent, with over 50 million dementia cases reported by the World Health Organization in 2019. The molecular origin of Alzheimer’s is linked to amyloid fibril formation by misfolded ABeta-peptide. These fibrils can form aggregates that are stabilized by the presence of Zn(II) cations. Although many possible structures have been reported in the last few years fort he Zn(II)-Abeta complexes, details about the molecular interactions involved are still lacking.In this work, I present a detailed computational study of the different possible structures that the system could show with their respective weights. I have employed equilibrium classical molecular dynamics simulations and the Hamiltonian replica exchange method in order to characterize these bound states of Zn(II).

Laburpena (Euskaraz)

Amiloide zuntzak hainbat gaixotasun neurodegeneratiboren eragile diren proteina desegi-turatuen egoera egonkorrak dira. Gaixotasun hauen artean, Alzheimerra da nabarmenena. 2019an Osasunaren Munduarteko Erakundeak 50 milioi kasu baina gehiago erregistratu zituen. Alzheimerraren eragilea maila molekularrean Abeta-peptido amiloidearen desegituraren ondorioz sortutako zuntzak dira. Peptido pilaketa hauek Zn(II) katioiarenpresentzian egonkortu egiten dira. Nahiz eta Zn(II)-Abeta sistemaren egitura ugari ezagunak diren, haien arteko interakzio molekularrei buruzko informazio eza oraindik ere handia da. Ikerketa proiektu honetan, egitura ezberdin posibleei buruzko azterketa konputazional detailatua eta bakoitzaren garrantzia aurkezten dut. Oreka klasikoko dinamika molekularrak eta Hamiltonian replica exchange metodoetaz baliatu naiz Zn(II)ak erakusten dituenkoordinazio egoera ezberdinak karakterizatzeko.