Elucidating the reversible and irreversible self-assembly mechanisms of low-complexity aromatic-rich kinked peptides and steric zipper peptides

Lao, Zenghui; Tang, Yiming; Dong, Xuewei; Tan, Yuan; Li, Xuhua; Liu, Xianshi; Li, Le; Guo, Cong; Wei, Guanghong

doi:10.1039/d3nr05130g

Nanoscale

2024

DOI: 10.1039/d3nr05130g

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Elucidating the reversible and irreversible self-assembly mechanisms of low-complexity aromatic-rich kinked peptides and steric zipper peptides

Zenghui Lao,

Yiming Tang,

Xuewei Dong

et al.

Abstract: Many RNA-binding proteins such as fused in sarcoma (FUS) can self-assemble into reversible liquid droplets and fibrils through the self-association of their low-complexity (LC) domains. Recent experiments reveal that SYG-rich...

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Cited by 2 publications

References 81 publications

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Pathogenic Mutation ΔK280 Promotes Hydrophobic Interactions Involving Microtubule‐Binding Domain and Enhances Liquid‐Liquid Phase Separation of Tau

Chen,

Sun,

Tang

et al. 2024

Small

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Liquid‐liquid phase separation (LLPS) of tau protein can initiate its aggregation which is associated with Alzheimer's disease. The pathogenic mutation ΔK280 can enhance the aggregation of K18, a truncated tau variant comprising the microtubule‐binding domain. However, the impact of ΔK280 on K18 LLPS and underlying mechanisms are largely unexplored. Herein, the conformational ensemble and LLPS of ΔK280 K18 through multiscale molecular simulations and microscopy experiments are investigated. All‐atom molecular dynamic simulations reveal that ΔK280 significantly enhances the collapse degree and β‐sheet content of the K18 monomer, indicating that ΔK280 mutation may promote K18 LLPS, validated by coarse‐grained phase‐coexistence simulations and microscopy experiments. Importantly, ΔK280 mutation promotes β‐sheet formation of six motifs (especially PHF6), increases the hydrophobic solvent exposure of PHF6* and PHF6, and enhances hydrophobic, hydrogen bonding, and cation‐π interactions involving most of the motifs, thus facilitating the phase separation of K18. Notably, ΔK280 alters the interaction network among the six motifs, inducing the formation of K18 conformations with high β‐sheet contents and collapse degree. Coarse‐grained simulations on full‐length tau reveal that ΔK280 promotes tau LLPS by enhancing the hydrophobic interactions involving the microtubule‐binding domain. These findings offer detailed mechanistic insights into ΔK280‐induced tau pathogenesis, providing potential targets for therapeutic intervention.

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Pathogenic Mutation ΔK280 Promotes Hydrophobic Interactions Involving Microtubule‐Binding Domain and Enhances Liquid‐Liquid Phase Separation of Tau

Chen,

Sun,

Tang

et al. 2024

Small

View full text Add to dashboard Cite

show abstract

Revisiting the Most Stable Structures of the Benzene Dimer

Czernek,

Brus

2024

IJMS

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The benzene dimer (BD) is an archetypal model of π∙∙∙π and C–H∙∙∙π noncovalent interactions as they occur in its cofacial and perpendicular arrangements, respectively. The enthalpic stabilization of the related BD structures has been debated for a long time and is revisited here. The revisit is based on results of computations that apply the coupled-cluster theory with singles, doubles and perturbative triples [CCSD(T)] together with large basis sets and extrapolate results to the complete basis set (CBS) limit in order to accurately characterize the three most important stationary points of the intermolecular interaction energy (ΔE) surface of the BD, which correspond to the tilted T-shaped (TT), fully symmetric T-shaped (FT) and slipped-parallel (SP) structures. In the optimal geometries obtained by searching extensive sets of the CCSD(T)/CBS ΔE data of the TT, FT and SP arrangements, the resulting ΔE values were −11.84, −11.34 and −11.21 kJ/mol, respectively. The intrinsic strength of the intermolecular bonding in these configurations was evaluated by analyzing the distance dependence of the CCSD(T)/CBS ΔE data over wide ranges of intermonomer separations. In this way, regions of the relative distances that favor BD structures with either π∙∙∙π or C–H∙∙∙π interactions were found and discussed in a broader context.

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Elucidating the reversible and irreversible self-assembly mechanisms of low-complexity aromatic-rich kinked peptides and steric zipper peptides

Abstract: Many RNA-binding proteins such as fused in sarcoma (FUS) can self-assemble into reversible liquid droplets and fibrils through the self-association of their low-complexity (LC) domains. Recent experiments reveal that SYG-rich...

Cited by 2 publications

References 81 publications

Pathogenic Mutation ΔK280 Promotes Hydrophobic Interactions Involving Microtubule‐Binding Domain and Enhances Liquid‐Liquid Phase Separation of Tau

Pathogenic Mutation ΔK280 Promotes Hydrophobic Interactions Involving Microtubule‐Binding Domain and Enhances Liquid‐Liquid Phase Separation of Tau

Revisiting the Most Stable Structures of the Benzene Dimer

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