Search Results (8)

Semiconducting conjugated polymers (CPs) are pivotal in advancing organic electronics, offering tunable properties for solar cells and field-effect transistors. Here, we carry out first-principle calculations to study individual cis-polyacetylene (cis-PA) oligomers and their ensembles. The ground electronic structures are obtained using density functional theory (DFT), and excited state dynamics are explored by computing nonadiabatic couplings (NACs) between electronic and nuclear degrees of freedom. We compute the nonradiative relaxation of charge carriers and photoluminescence (PL) using the Redfield theory. Our findings show that electrons relax faster than holes. The ensemble of oligomers shows faster relaxation compared to the single oligomer. The calculated PL spectra show features from both interband and intraband transitions. The ensemble shows broader line widths, redshift of transition energies, and lower intensities compared to the single oligomer. This comparative study suggests that the dispersion forces and orbital hybridizations between chains are the leading contributors to the variation in PL. It provides insights into the fundamental behaviors of CPs and the molecular-level understanding for the design of more efficient optoelectronic devices. Full article

Alzheimer’s disease (AD) is a neurological disorder associated with amyloid $\beta$-protein (A$\beta$) assembly into toxic oligomers. In addition to the two predominant alloforms, A${\beta }_{1-40}$ and A${\beta }_{1-42}$, other C-terminally truncated A$\beta$ peptides, including A${\beta }_{1-38}$ and A${\beta }_{1-43}$, are produced in the brain. Here, we use discrete molecular dynamics (DMD) and a four-bead protein model with amino acid-specific hydropathic interactions, DMD4B-HYDRA, to examine oligomer formation of A${\beta }_{1-38}$, A${\beta }_{1-40}$, A${\beta }_{1-42}$, and A${\beta }_{1-43}$. Self-assembly of 32 unstructured monomer peptides into oligomers is examined using 32 replica DMD trajectories for each of the four peptides. In a quasi-steady state, A${\beta }_{1-38}$ and A${\beta }_{1-40}$ adopt similar unimodal oligomer size distributions with a maximum at trimers, whereas A${\beta }_{1-42}$ and A${\beta }_{1-43}$ oligomer size distributions are multimodal with the dominant maximum at trimers or tetramers, and additional maxima at hexamers and unidecamers (for A${\beta }_{1-42}$) or octamers and pentadecamers (for A${\beta }_{1-43}$). The free energy landscapes reveal isoform- and oligomer-order specific structural and morphological features of oligomer ensembles. Our results show that oligomers of each of the four isoforms have unique features, with A${\beta }_{1-42}$ alone resulting in oligomers with disordered and solvent-exposed N-termini. Our findings help unravel the structure–function paradigm governing oligomers formed by various A$\beta$ isoforms. Full article

Antisense oligonucleotide (ASO)-mediated exon skipping has become a valuable tool for investigating gene function and developing gene therapy. Machine-learning-based computational methods, such as eSkip-Finder, have been developed to predict the efficacy of ASOs via exon skipping. However, these methods are computationally demanding, and the accuracy of predictions remains suboptimal. In this study, we propose a new approach to reduce the computational burden and improve the prediction performance by using feature selection within machine-learning algorithms and ensemble-learning techniques. We evaluated our approach using a dataset of experimentally validated exon-skipping events, dividing it into training and testing sets. Our results demonstrate that using a three-way-voting approach with random forest, gradient boosting, and XGBoost can significantly reduce the computation time to under ten seconds while improving prediction performance, as measured by R² for both 2′-O-methyl nucleotides (2OMe) and phosphorodiamidate morpholino oligomers (PMOs). Additionally, the feature importance ranking derived from our approach is in good agreement with previously published results. Our findings suggest that our approach has the potential to enhance the accuracy and efficiency of predicting ASO efficacy via exon skipping. It could also facilitate the development of novel therapeutic strategies. This study could contribute to the ongoing efforts to improve ASO design and optimize gene therapy approaches. Full article

The assembly of the amyloid-β peptide (Aβ) into toxic oligomers and fibrils is associated with Alzheimer’s disease and dementia. Therefore, disrupting amyloid assembly by direct targeting of the Aβ monomeric form with small molecules or antibodies is a promising therapeutic strategy. However, given the dynamic nature of Aβ, standard computational tools cannot be easily applied for high-throughput structure-based virtual screening in drug discovery projects. In the current study, we propose a computational pipeline—in the framework of the ensemble docking strategy—to identify catechins’ binding sites in monomeric Aβ₄₂. It is shown that both hydrophobic aromatic interactions and hydrogen bonding are crucial for the binding of catechins to Aβ₄₂. Additionally, it has been found that all the studied ligands, especially EGCG, can act as potent inhibitors against amyloid aggregation by blocking the central hydrophobic region of Aβ. Our findings are evaluated and confirmed with multi-microsecond MD simulations. Finally, it is suggested that our proposed pipeline, with low computational cost in comparison with MD simulations, is a suitable approach for the virtual screening of ligand libraries against Aβ. Full article

Tauopathies, including Alzheimer’s disease (AD), are a group of neurodegenerative disorders characterized by pathological aggregation of microtubule binding protein tau. The presence of tau neurofibrillary tangles, which are insoluble β-sheet fibrils, in the brain has been the histopathological hallmark of these diseases as their level correlates with the degree of cognitive impairment. However, recent studies suggest that tau oligomers, which are soluble proteins that are formed prior to insoluble fibrils, are the principal toxic species impairing neurons and inducing neurodegeneration. Targeting toxic tau oligomers is challenging, as they are mostly unstructured and adopting multiple conformations. The heterogeneity of tau oligomers is further illustrated by the different oligomeric species formed by various methods. The current models and technologies to study tau oligomerization represent important resources and avenues to push the forefront of elucidating the true toxic tau species. In this review, we will summarize the distinct tau oligomers generated using different strategies and discuss their conformational characteristics, neurotoxicity, relevance to pathological phenotypes, as well as their applications in drug discovery. This information will provide insights to understanding heterogeneous tau oligomers and their role as molecular targets for AD and related tauopathies. Full article

The pathogenesis of type 2 diabetes (T2D) is highly related to the abnormal self-assembly of the human islet amyloid polypeptide (hIAPP) into amyloid aggregates. To inhibit hIAPP aggregation is considered a promising therapeutic strategy for T2D treatment. Melatonin (Mel) was reported to effectively impede the accumulation of hIAPP aggregates and dissolve preformed fibrils. However, the underlying mechanism at the atomic level remains elusive. Here, we performed replica-exchange molecular dynamics (REMD) simulations to investigate the inhibitory effect of Mel on hIAPP oligomerization by using hIAPP_20–29 octamer as templates. The conformational ensemble shows that Mel molecules can significantly prevent the β-sheet and backbone hydrogen bond formation of hIAPP_20–29 octamer and remodel hIAPP oligomers and transform them into less compact conformations with more disordered contents. The interaction analysis shows that the binding behavior of Mel is dominated by hydrogen bonding with a peptide backbone and strengthened by aromatic stacking and CH–π interactions with peptide sidechains. The strong hIAPP–Mel interaction disrupts the hIAPP_20–29 association, which is supposed to inhibit amyloid aggregation and cytotoxicity. We also performed conventional MD simulations to investigate the influence and binding affinity of Mel on the preformed hIAPP_1–37 fibrillar octamer. Mel was found to preferentially bind to the amyloidogenic region hIAPP_20–29, whereas it has a slight influence on the structural stability of the preformed fibrils. Our findings illustrate a possible pathway by which Mel alleviates diabetes symptoms from the perspective of Mel inhibiting amyloid deposits. This work reveals the inhibitory mechanism of Mel against hIAPP_20–29 oligomerization, which provides useful clues for the development of efficient anti-amyloid agents. Full article

The proteostasis network allows organisms to support and regulate the life cycle of proteins. Especially regarding stress, molecular chaperones represent the main players within this network. Small heat shock proteins (sHsps) are a diverse family of ATP-independent molecular chaperones acting as the first line of defense in many stress situations. Thereby, the promiscuous interaction of sHsps with substrate proteins results in complexes from which the substrates can be refolded by ATP-dependent chaperones. Particularly in vertebrates, sHsps are linked to a broad variety of diseases and are needed to maintain the refractive index of the eye lens. A striking key characteristic of sHsps is their existence in ensembles of oligomers with varying numbers of subunits. The respective dynamics of these molecules allow the exchange of subunits and the formation of hetero-oligomers. Additionally, these dynamics are closely linked to the chaperone activity of sHsps. In current models a shift in the equilibrium of the sHsp ensemble allows regulation of the chaperone activity, whereby smaller oligomers are commonly the more active species. Different triggers reversibly change the oligomer equilibrium and regulate the activity of sHsps. However, a finite availability of high-resolution structures of sHsps still limits a detailed mechanistic understanding of their dynamics and the correlating recognition of substrate proteins. Here we summarize recent advances in understanding the structural and functional relationships of human sHsps with a focus on the eye-lens αA- and αB-crystallins. Full article

Amyloid-β and α-synuclein are intrinsically disordered proteins (IDPs), which are at the center of Alzheimer’s and Parkinson’s disease pathologies, respectively. These IDPs are extremely flexible and do not adopt stable structures. Furthermore, both amyloid-β and α-synuclein can form toxic oligomers, amyloid fibrils and other type of aggregates in Alzheimer’s and Parkinson’s diseases. Experimentalists face challenges in investigating the structures and thermodynamic properties of these IDPs in their monomeric and oligomeric forms due to the rapid conformational changes, fast aggregation processes and strong solvent effects. Classical molecular dynamics simulations complement experiments and provide structural information at the atomic level with dynamics without facing the same experimental limitations. Artificial missense mutations are employed experimentally and computationally for providing insights into the structure-function relationships of amyloid-β and α-synuclein in relation to the pathologies of Alzheimer’s and Parkinson’s diseases. Furthermore, there are several natural genetic variations that play a role in the pathogenesis of familial cases of Alzheimer’s and Parkinson’s diseases, which are related to specific genetic defects inherited in dominant or recessive patterns. The present review summarizes the current understanding of monomeric and oligomeric forms of amyloid-β and α-synuclein, as well as the impacts of artificial and pathological missense mutations on the structural ensembles of these IDPs using molecular dynamics simulations. We also emphasize the recent investigations on residual secondary structure formation in dynamic conformational ensembles of amyloid-β and α-synuclein, such as β-structure linked to the oligomerization and fibrillation mechanisms related to the pathologies of Alzheimer’s and Parkinson’s diseases. This information represents an important foundation for the successful and efficient drug design studies. Full article