Abstract
This study explores the stabilities of single sheet parallel systems of three sequence variants of 1GNNQQNY7, N2D, N2S and N6D, with variations in aggregate size (5–8) and termini charge (charged or neutral). The aggregates were simulated at 300 and 330 K. These mutations decrease amyloid formation in the yeast prion protein Sup35. The present study finds that these mutations cause instability even in the peptide context. The protonation status of termini is found to be a key determinant of stabilities; other determinants are sequence, position of mutation and aggregate size. All systems with charged termini are unstable, whereas both stable and unstable systems are found when the termini are neutral. When termini are charged, the largest stable aggregate for the N2S and N6D systems has 3 to 4 peptides whereas N2D mutation supports oligomers of larger size (5-and 6-mers) as well. Mutation at 2nd position (N2S and N2D) results in fewer H-bonds at the mutated as well as neighboring (Gly1/Gln4) positions. However, no such effect is found if mutation is at 6th position (N6D). The effect of Asn→Asp mutation depends on the position and termini charge: it is more destabilizing at the 2nd position than at the 6th in case of neutral termini, however, the opposite is true in case of charged termini. Appearance of twist in stable systems and in smaller aggregates formed in unstable systems suggests that twist is integral to amyloid arrangement. Disorder, dissociation or rearrangement of peptides, disintegration or collapse of aggregates and formation of amorphous aggregates observed in these simulations are likely to occur during the early stages of aggregation also. The smaller aggregates formed due to such events have a variety of arrangements of peptides. This suggests polymorphic nature of oligomers and presence of a heterogeneous mixture of oligomers during early stages of aggregation.
Highlights
Proteins can self-aggregate into insoluble, fibrillar assemblies called amyloids under conditions that destabilize their native state [1,2]
In the present study, we have investigated the stabilities and dynamics of single sheet parallel systems, consisting of three sequence variants of 1GNNQQNY7 using all-atom molecular dynamics (MD) simulation in explicit solvent
The parallel arrangement of the peptides in a single sheet leads to arraying of like-charges along the termini leading to repulsion
Summary
Proteins can self-aggregate into insoluble, fibrillar assemblies called amyloids under conditions that destabilize their native state [1,2]. These assemblies are associated with a number of neurodegenerative diseases such as Alzheimer’s and Huntington’s. Despite the diversity in sequence, size, function, and native and secondary structures of amyloid-forming proteins, fibrils formed by them share certain features such as tinctorial properties, morphology, X-ray fiber diffraction pattern and a highly organized internal structure. Formation of amyloid fibrils follows a cooperative, nucleation dependent kinetics with a rate-determining lag phase [1,6] and has been suggested to be characterized by reversible association of the constituent monomers [7,8]. Soluble oligomers that form during the early stages of aggregation are toxic [10,11,12], besides the mature fibrils that form in later stages [12,13]
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