What Determines the Structure and Stability of KFFE Monomers, Dimers, and Protofibrils?

Bellesia, Giovanni; Shea, Joan–Emma

doi:10.1016/j.bpj.2008.10.040

Cited by 58 publications

(58 citation statements)

References 43 publications

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“…The self-assembly of peptide KFFE was studied experimentally 20 and theoretically, 9,22,23 but its fibril formation rates have not been estimated. Recent x-ray diffraction analysis by Sawaya et al has shown that NNQQ can form both parallel ␤-sheet fibrils and closely related structured microcrystals.…”

Section: Introductionmentioning

confidence: 99%

Relationship between population of the fibril-prone conformation in the monomeric state and oligomer formation times of peptides: Insights from all-atom simulations

Nam

Kouza²,

Zung³

et al. 2010

The Journal of Chemical Physics

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Despite much progress in understanding the aggregation process of biomolecules, the factors that govern its rates have not been fully understood. This problem is of particular importance since many conformational diseases such as Alzheimer, Parkinson, and type-II diabetes are associated with the protein oligomerization. Having performed all-atom simulations with explicit water and various force fields for two short peptides KFFE and NNQQ, we show that their oligomer formation times are strongly correlated with the population of the fibril-prone conformation in the monomeric state. The larger the population the faster the aggregation process. Our result not only suggests that this quantity plays a key role in the self-assembly of polypeptide chains but also opens a new way to understand the fibrillogenesis of biomolecules at the monomeric level. The nature of oligomer ordering of NNQQ is studied in detail.

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Section: Introductionmentioning

confidence: 99%

Relationship between population of the fibril-prone conformation in the monomeric state and oligomer formation times of peptides: Insights from all-atom simulations

Nam

Kouza²,

Zung³

et al. 2010

The Journal of Chemical Physics

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“…In recent years, molecular dynamics (MD) simulations performed at all-atom resolution and with explicitly treated water have proved to be a valuable tool for studying the mechanisms of aggregation [23][24][25][26][27][28][29] and ligand binding. [30][31][32][33][34][35][36] In our previous study, we have used replica exchange molecular dynamics (REMD) simulations to probe binding of FDDNP ligands to amino-truncated Aβ10-40 monomers.…”

mentioning

confidence: 99%

Molecular Mechanisms of Alzheimer’s Biomarker FDDNP Binding to Aβ Amyloid Fibril

Parikh

Klimov

2015

J. Phys. Chem. B

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Using isobaric-isothermal replica exchange molecular dynamics and the all-atom explicit water model, we examined the binding of FDDNP biomarkers to the Aβ amyloid fibril fragment. Our results can be summarized as follows. First, FDDNP ligands bind with high affinity to the Aβ fibril, and the hydrophobic effect together with π-stacking interactions are the dominant factors governing FDDNP binding. In comparison, electrostatic interactions and hydrogen bonding play a minor role. Second, our simulations reveal a strong tendency of bound FDDNP molecules for self-aggregation. Accordingly, about two-thirds of all bound ligands form aggregated clusters of various sizes, and ligand-ligand interactions make considerable contribution to FDDNP binding. Third, FDDNP ligands bind to two distinct sites on the Aβ fibril. Primary binding sites (NT) are located at the N-terminals of Aβ10-40 peptides, whereas secondary ones (CE) occur on the concave fibril edge near fibril channels. The NT sites are characterized by strong hydrophobic and π-stacking interactions, favorable binding entropy resulting from multiple FDDNP binding orientations and propensity for self-aggregation but relatively weak van der Waals interactions. In contrast, the CE sites offer stronger van der Waals binding interactions but weaker hydrophobic and aromatic interactions and less favorable binding entropy. By comparing our data with previous studies, we suggest that the primary binding locations identified by us are likely to occur in other Aβ fibril polymorphic structures. We also show that FDDNP binds via distinct mechanisms to Aβ fibrils and monomers. We argue that FDDNP binds with stronger affinity to benign Aβ monomers than to the fibrils, raising questions about the ability of FDDNP to selectively label amyloid deposits.

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“…The diphenylalanine (FF) structural motif and its derivatives are among the most widely studied minimal building blocks that allow the formation of ordered polymer-like assemblies at the nano-scale [17][18][19][20] . This class of molecular species exhibits effective self-assembly properties, and has been shown to generate a rich variety of ultrastructures, with functional physical and chemical properties, including piezoelectricity 21,22 , luminescence 23 and robust mechanical characteristics [24][25][26][27][28][29] .…”

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confidence: 99%

Ostwald’s rule of stages governs structural transitions and morphology of dipeptide supramolecular polymers

et al. 2014

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The self-assembly of molecular building blocks into nano-and micro-scale supramolecular architectures has opened up new frontiers in polymer science. Such supramolecular species not only possess a rich set of dynamic features as a consequence of the non-covalent nature of their core interactions, but also afford unique structural characteristics. Although much is now known about the manner in which such structures adopt their morphologies and size distributions in response to external stimuli, the kinetic and thermodynamic driving forces that lead to their transformation from soluble monomeric species into ordered supramolecular entities have remained elusive. Here we focus on Boc-diphenylalanine, an archetypical example of a peptide with a high propensity towards supramolecular self-organization, and describe the pathway through which it forms a range of nano-assemblies with different structural characteristics. Our results reveal that the nucleation process is multi-step in nature and proceeds by Ostwald's step rule through which coalescence of soluble monomers leads to the formation of nanospheres, which then undergo ripening and structural conversions to form the final supramolecular assemblies. We characterize the structures and thermodynamics of the different phases involved in this process and reveal the intricate nature of the transitions that can occur between discrete structural states of this class of supramolecular polymers.

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What Determines the Structure and Stability of KFFE Monomers, Dimers, and Protofibrils?

Cited by 58 publications

References 43 publications

Relationship between population of the fibril-prone conformation in the monomeric state and oligomer formation times of peptides: Insights from all-atom simulations

Relationship between population of the fibril-prone conformation in the monomeric state and oligomer formation times of peptides: Insights from all-atom simulations

Molecular Mechanisms of Alzheimer’s Biomarker FDDNP Binding to Aβ Amyloid Fibril

Ostwald’s rule of stages governs structural transitions and morphology of dipeptide supramolecular polymers

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