Probing the mechanisms of fibril formation using lattice models

Abstract

Using exhaustive Monte Carlo simulations we study the kinetics and mechanism of fibril formation using lattice models as a function of temperature ͑T͒ and the number of chains ͑M͒. While these models are, at best, caricatures of peptides, we show that a number of generic features thought to govern fibril assembly are captured by the toy model. The monomer, which contains eight beads made from three letters ͑hydrophobic, polar, and charged͒, adopts a compact conformation in the native state. In both the single-layered protofilament ͑seen for M ഛ 10͒ and the two-layer fibril ͑M Ͼ 10͒ structures, the monomers are arranged in an antiparallel fashion with the "strandlike" conformation that is perpendicular to the fibril axis. Partial unfolding of the folded monomer that populates an aggregation prone conformation ͑N * ͒ is required for ordered assembly. The contacts in the N * conformation, which is one of the four structures in the first "excited" state of the monomer, are also present in the native conformation. The time scale for fibril formation is a minimum in the T-range when the conformation N * is substantially populated. The kinetics of fibril assembly occurs in three distinct stages. In each stage there is a cascade of events that transforms the monomers and oligomers to ordered structures. In the first "burst" stage, highly mobile oligomers of varying sizes form. The conversion to the N * conformation occurs within the oligomers during the second stage in which a vast number of interchain contacts are established. As time progresses, a dominant cluster emerges that contains a majority of the chains. In the final stage, the aggregation of N * particles serve as a template onto which smaller oligomers or monomers can dock and undergo conversion to fibril structures. The overall time for growth in the latter stages is well described by the LifshitzSlyazov growth kinetics for crystallization from supersaturated solutions. The detailed analysis shows that elements of the three popular models, namely, nucleation and growth, templated assembly, and nucleated conformational conversion are present at various stages of fibril assembly.

Computational Studies of Protein Aggregation: Methods and Applications

“…(a) Simple models: the orientable stick model (19) and the sphero-cylindrical model (20). (b) Phenomenological models: the lattice model (21), Caflisch model (22), and Shea model (23). (c) Systematic coarse graining: a coarse-grained polyalanine chain (24).…”

Structure propensities in mutated polyglutamine peptides

“…In addition, the peptides that failed to aggregate demonstrated evidence of a lesser extent of antiparallel β-sheet structure tendency than the peptides that aggregated. Therefore, the localized primary perturbation of peptide structure exerted by the glutamine→proline mutations appears to result in a global secondary perturbation of peptide structural confinement, discouraging random conformational fluctuations which may be involved in the unfavourable transition towards β-sheet structure (Chopra et al, 2008;Bhattacharyya et al, 2005;Li et al, 2008), and so confining the peptide to an existing preference for the coil state. Indeed, introduction of such mutations into the polyQ segments of PGQ 9 would result in mutant polyQ sequences containing glutamine/proline-rich regions, in which intervals of only four or five residues separate consecutive prolines (Table 2).…”

“…Thus, our results provide a structural explanation for the inhibition of aggregation observed for these peptides. Indeed, a recent computational study by Vitalis et al (2008) proposed that a key factor in polyQ chain association is spontaneous conformational fluctuations within the polyQ monomer, and additional computational studies (Chopra et al, 2008;Li et al, 2008) have also suggested that spontaneous conformational fluctuation is involved in the transition toward β-sheet-like structure.…”

Relative stability of de novo four–helix bundle proteins: Insights from coarse grained molecular simulations

“…25 Each bead has mass m (m is the mass unit) and is connected to the neighboring beads in the peptide chain by harmonic ''springs.'' 25,[29][30][31][32] The force field used in our study has the following functional form:…”