formation and growth of oligomers a monte carlo study of an amyloid tau fragment寡聚物的形成和生长的蒙特卡罗研究淀粉样τ片段.pdfVIP

Formation and Growth of Oligomers: A Monte Carlo Study of an Amyloid Tau Fragment 1.¤ 2. ¨ 3 1 Da-Wei Li , Sandipan Mohanty , Anders Irback *, Shuanghong Huo * ¨ 1 Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, Worcester, Massachusetts, United States of America, 2 John von Neumann Institut fur ¨ ¨ Computing, Forschungszentrum Julich, Julich, Germany, 3 Computational Biology and Biological Physics Division, Department of Theoretical Physics, Lund University, Lund, Sweden Abstract Small oligomers formed early in the process of amyloid fibril formation may be the major toxic species in Alzheimer’s disease. We investigate the early stages of amyloid aggregation for the tau fragment AcPHF6 (Ac-VQIVYK-NH2) using an implicit solvent all-atom model and extensive Monte Carlo simulations of 12, 24, and 36 chains. A variety of small metastable aggregates form and dissolve until an aggregate of a critical size and conformation arises. However, the stable oligomers, which are b-sheet-rich and feature many hydrophobic contacts, are not always growth-ready. The simulations indicate instead that these supercritical oligomers spend a lengthy period in equilibrium in which considerable reorganization takes place accompanied by exchange of chains with the solution. Growth competence of the stable oligomers correlates with the alignment of the strands i