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This study explores the stabilities of single sheet parallel systems of three sequence variants of  1 GNNQQNY 7 , 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 2 nd  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 6 th  position (N6D). The effect of Asn→Asp mutation depends on the position and termini charge: it is more destabilizing at the 2 nd  position than at the 6 th  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.

Interplay of Sequence, Topology and Termini Charge in Determining the Stability of the Aggregates of GNNQQNY Mutants: A Molecular Dynamics Study