Multidimensional View of Amyloid Fibril Nucleation in Atomistic Detail

被引:69
作者
Baftizadeh, Fahimeh [1 ]
Biarnes, Xevi [2 ]
Pietrucci, Fabio [3 ]
Affinito, Fabio [4 ]
Laio, Alessandro [1 ]
机构
[1] SISSA, I-34014 Trieste, Italy
[2] Sarria Univ Ramon Llull, Inst Quim, Barcelona, Spain
[3] Ecole Polytech Fed Lausanne, Ctr Europeen Calcul Atom & Mol, CH-1015 Lausanne, Switzerland
[4] CINECA, Bologna, Italy
关键词
PROTEIN AGGREGATION; MONTE-CARLO; FORCE-FIELDS; DYNAMICS; PEPTIDE; OLIGOMERS; A-BETA(16-22); SIMULATIONS; MECHANISM; CONFORMATIONS;
D O I
10.1021/ja210826a
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Starting from a disordered aggregate, we have simulated the formation of ordered amyloid-like beta structures in a system formed by 18 polyvaline chains in explicit solvent, employing molecular dynamics accelerated by bias-exchange metadynamics. We exploited 8 different collective variables to compute the free energy of hundreds of putative aggregate structures, with variable content of parallel and antiparallel beta-sheets and different packing among the sheets. This allowed characterizing in detail a possible nucleation pathway for the formation of amyloid fibrils: first the system forms a relatively large ordered nucleus of antiparallel beta-sheets, and then a few parallel sheets start appearing. The relevant nucleation process culminates at this point: when a sufficient number of parallel sheets is formed, the free energy starts to decrease toward a new minimum in which this structure is predominant. The complex nucleation pathway we found cannot be described within classical nucleation theory, namely employing a unique simple reaction coordinate like the total content of beta-sheets.
引用
收藏
页码:3886 / 3894
页数:9
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