Dissecting how ALS-associated D290V mutation enhances pathogenic aggregation of hnRNPA2286–291 peptides: Dynamics and conformational ensembles

Yuan, Tao; Chen, Yujie; Liu, Xianshi; Tang, Yuanyan; Lao, Zenghui; Wei, Guanghong

doi:10.1016/j.ijbiomac.2023.124659

Cited by 5 publications

(1 citation statement)

References 82 publications

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“…The effects of familial mutations on secondary structure changes of other amyloid proteins and their correlations with LLPS/fibrillization have also been investigated using computational and experimental methods. ,− Such studies are crucial for understanding the contribution of secondary structure shifts to switching between pathological and potentially benign assembly pathways in amyloidogenesis. For example, an MD simulation study by Derreumaux et al showed that A2V mutation decreases the β-sheet conformation and increases helix and coil conformations of the Aβ 40 dimer, providing an explanation for the protective effects of A2V mutation.…”

Section: Resultsmentioning

confidence: 99%

Dissecting the Effect of ALS Mutation G335D on the Early Aggregation of the TDP-43 Amyloidogenic Core Peptide: Helix-to-β-Sheet Transition and Conformational Shift

Chen

Tang

et al. 2023

J. Chem. Inf. Model.

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The aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) into fibrillary deposits is associated with amyotrophic lateral sclerosis (ALS). The 311–360 fragment of TDP-43 (TDP-43311–360), the amyloidogenic core region, can spontaneously aggregate into fibrils, and the ALS-associated mutation G335D has an enhanced effect on TDP-43311–360 fibrillization. However, the molecular mechanism underlying G335D-enhanced aggregation at atomic level remains largely unknown. By utilizing all-atom molecular dynamics (MD) and replica exchange with solute tempering 2 (REST2) simulations, we investigated influences of G335D on the dimerization (the first step of aggregation) and conformational ensemble of the TDP-43311–360 peptide. Our simulations show that G335D mutation increases inter-peptide interactions, especially inter-peptide hydrogen-bonding interactions in which the mutant site has a relatively large contribution, and enhances the dimerization of TDP-43311–360 peptides. The α-helix regions in the NMR-resolved conformation of the TDP-43311–360 monomer (321–330 and 335–343) play an essential role in the formation of the dimer. G335D mutation induces helix unfolding and promotes α-to-β conversion. G335D mutation alters the conformational distribution of TDP-43311–360 dimers and causes population shift from helix-rich to β-sheet-rich conformations, which facilitates the fibrillization of the TDP-43311–360 peptide. Our MD and REST2 simulation results suggest that the 321–330 region is of paramount importance to α-to-β transition and could be the initiation site for TDP-43311–360 fibrillization. Our work reveals the mechanism underlying the enhanced aggregation propensity of the G335D TDP-43311–360 peptide, which provides atomistic insights into the G335D mutation-caused pathogenicity of TDP-43 protein.

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Section: Resultsmentioning

confidence: 99%

Dissecting the Effect of ALS Mutation G335D on the Early Aggregation of the TDP-43 Amyloidogenic Core Peptide: Helix-to-β-Sheet Transition and Conformational Shift

Chen

Tang

et al. 2023

J. Chem. Inf. Model.

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Diffusion Metamaterials: Basic Simulation Methods

Jin

2024

Diffusionics

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Recent theoretical advances have spurred the development of metamaterials endowed with exceptional thermal properties. Traditional approaches, however, falter when applied to irregular geometries. The application of coordinate transformation theory necessitates metamaterials that exhibit inhomogeneous and anisotropic properties, a demand that natural materials struggle to meet. Fortunately, cutting-edge simulation techniques are poised to bridge this gap, enabling the use of bulk materials. This chapter delves into the most prominent simulation strategies that harness intelligent algorithms for the creation of metamaterials, and evaluates their efficacy through finite element analysis. These algorithm-driven designs promise to significantly broaden the adaptability, functionality, and flexibility of metamaterials beyond the constraints of conventional configurations.

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Convective Heat Transfer in Porous Materials

Yang,

Huang

2024

Diffusionics

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Thermal convection stands out as an exceptionally efficient thermal transport mechanism, distinctly separate from conduction and radiation. Yet, the inherently elusive nature of fluid motion poses challenges in accurately controlling convective heat flow. While recent innovations have harnessed thermal convection to achieve effective thermal conductivity, fusing thermal convection in liquids and thermal conduction in solids together to form hybrid thermal metamaterials is still challenging. In this chapter, we introduce the latest progress in convective heat transfer. Leveraging the right porous materials as a medium allows for a harmonious balance and synergy between convection and conduction, establishing stable heat and fluid flows. This paves the way for the innovative advancements in transformation thermotics. These findings demonstrate the remarkable tunability of convective heat transport in complex multicomponent thermal metamaterials.

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Dissecting how ALS-associated D290V mutation enhances pathogenic aggregation of hnRNPA2286–291 peptides: Dynamics and conformational ensembles

Cited by 5 publications

References 82 publications

Dissecting the Effect of ALS Mutation G335D on the Early Aggregation of the TDP-43 Amyloidogenic Core Peptide: Helix-to-β-Sheet Transition and Conformational Shift

Dissecting the Effect of ALS Mutation G335D on the Early Aggregation of the TDP-43 Amyloidogenic Core Peptide: Helix-to-β-Sheet Transition and Conformational Shift

Diffusion Metamaterials: Basic Simulation Methods

Convective Heat Transfer in Porous Materials

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