Misfolding of the amyloid -protein: A molecular dynamics study

Dagmar Flöck ^{1 *}, Stefano Colacino ², Giorgio Colombo ², Alfredo Di Nola ¹

¹Department of Chemistry, University of Rome La Sapienza, P.le Aldo Moro 5, Rome, Italy
²Istituto di Chimica del Riconoscimento Molecolare, CNR, Milan, Italy

Keywords

Conformational changes • protein aggregation • pH-dependence • terminal charges

Abstract

Amyloid -proteins spontaneously aggregate and build plaques in the brains of Alzheimer's disease patients. The polypeptide has been the subject of extensive in vitro and computational research. Still, the pathway to aggregational forms and their exact conformations remain largely unclear. Here we present an extensive molecular dynamics approach simulating the protein in various temperatures, pH conditions, and with different charge states of the N- and C-termini, thus exploring the conformational space of the protein at large. Our results show that the protein is able to sample different conformations, many of which are rich in structure content, and all characterized by a rapid loss of helix 1 that converts into a -helix, while helix 2 samples random and -rich structures. Moreover, a hydrophobic cluster is observed involving Val18, Phe19, Ala21, and Gly25. The results are carefully compared with recent NMR and spectroscopic data, and are in global agreement with the experimental findings. Proteins 2006. © 2005 Wiley-Liss, Inc.