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Structural transitions and oligomerization along polyalanine fibril formation pathways from computer simulations
Author(s) -
Phelps Erin M.,
Hall Carol K.
Publication year - 2012
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.24052
Subject(s) - monomer , fibril , stacking , amorphous solid , crystallography , chemistry , molecular dynamics , protein aggregation , chemical physics , kinetics , polymer , computational chemistry , physics , organic chemistry , biochemistry , quantum mechanics
The results of a computer simulation study of the aggregation kinetics of a large system of model peptides with particular focus on the formation of intermediates are presented. Discontinuous molecular dynamic simulations were used in combination with our intermediate‐resolution protein model, PRIME, to simulate the aggregation of a system of 192 polyalanine (KA 14 K) peptides at a concentration of 5 m M and a reduced temperature of T * = 0.13 starting from a random configuration and ending in the assembly of a fibrillar structure. The population of various structures, including free monomers, beta sheets, amorphous aggregates, hybrid aggregates, and fibrils, and the transitions between the structures were tracked over the course of 30 independent simulations and averaged together. The aggregation pathway for this system starts with the association of free monomers into small amorphous aggregates that then grow to moderate size by incorporating other free monomers or merging with other small amorphous aggregates. These then rearrange into either small beta sheets or hybrid aggregates formed by association between unstructured chains and beta sheets, both of which grow in size by adding free monomer chains or other small aggregates, one at a time. Fibrillar structures are formed initially either by the stacking of beta sheets, rearrangement of hybrid aggregates or association between beta sheets and hybrid aggregates. They grow by the addition of beta sheets, hybrid aggregates, and other small fibrillar structures. The rearrangement of amorphous aggregates into beta sheets is a critical and necessary step in the fibril formation pathway. Proteins 2012. © 2012 Wiley Periodicals, Inc.