Oligomer Formation of Toxic and Functional Amyloid Peptides Studied with Atomistic Simulations

Abstract

Amyloids are associated with diseases, including Alzheimer's, as well as functional roles such as storage of peptide hormones. It is still unclear what differences exist between aberrant and functional amyloids. However, it is known that soluble oligomers formed during amyloid aggregation are more toxic than the final fibrils. Here, we perform molecular dynamics simulations to study the aggregation of the amyloid-β peptide Aβ25-35, associated with Alzheimer's disease, and two functional amyloid-forming tachykinin peptides: kassinin and neuromedin K. Although the three peptides have similar primary sequences, tachykinin peptides, in contrast to Aβ25-35, form nontoxic amyloids. Our simulations reveal that the charge of the C-terminus is essential to controlling the aggregation process. In particular, when the kassinin C-terminus is not amidated, the aggregation kinetics decreases considerably. In addition, we observe that the monomeric peptides in extended conformations aggregate faster than those in collapsed hairpin-like conformations.

Comparison of force fields for Alzheimer's A: A case study for intrinsically disordered proteins

“…At every exchange interval, 32768 ( , where is the number of replicas) random exchanges were attempted as suggested by Chodera and Shirts . Virtual sites were used for all protein hydrogens which permitted a time step of 4 fs to be used, a strategy that has been successfully employed before . Protein bonds were constrained using the P‐Lincs algorithm with an expansion order of 6 and water molecules were constrained with the Settle algorithm .…”

“…61 Virtual sites were used for all protein hydrogens 62 which permitted a time step of 4 fs to be used, a strategy that has been successfully employed before. [63][64][65][66] Protein bonds were constrained using the P-Lincs algorithm 67 with an expansion order of 6 and water molecules were constrained with the Settle algorithm. 68 Electrostatic interactions were calculated with the particle mesh Ewald method 69 with a Fourier spacing of 0.12 nm and a short-range cutoff of 1.2 nm.…”

Comparative binding of kaempferol and kaempferide on inhibiting the aggregate formation of mutant (G85R) SOD1 protein in familial amyotrophic lateral sclerosis: A quantum chemical and molecular mechanics study

“…3, the noticeable changes in the secondary structure of β-strand were seen upon binding kaempferol and kaempferide on mutant SOD1. For SOD1, the most abundant β-strand (above 0.75) are formed in regions (1-9), (15)(16)(17)(18)(19)(20)(21)(22), (29)(30)(31)(32)(33)(34)(35)(36), (41)(42)(43)(44)(45)(46)(47)(48), (86-89), (95-100), (116-120), and (143-150). The substitution mutation of R at position G85 in SOD1 has augmented the formation of β-strand in regions (23)(24), (27)(28), (49)(50)(51)(52)(53), (60-63), and (123-128) within the probability of 0.75 as compared to wild type.…”

“…From the chemistry point of view, the influence of amino acid substitution from GLY to ARG at 85th position in SOD1 relates to steric hindrance and altered geometry, owing to a replacement of large polar amino acid with the conformationally flexible small amino acid [19]. Atomistic simulations have been extensively used as a forthright method for investigating the protein aggregation [20,21]. Discrete molecular dynamics (DMD) is a versatile unique event driven MD program, which uses a physics-based simulation technique by discrete energetic potentials rather than traditional continuous potentials, letting microsecond time scale simulations of bio molecular systems to be accomplished on individual computers relatively to that of high-computing workstations or GPU-Graphical Processing Unit clusters.…”

Influence of pH and sequence in peptide aggregation via molecular simulation

“…As a result, most atomistic simulation studies either focus on just a small part of the whole process [7] or a minimal system size [8,9]. Coarse-grained models are, then, an appealing alternative.…”