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Aggregation of profilin-1 (PFN1) causes a fatal neurodegenerative disease, familial amyotrophic lateral sclerosis (fALS). Histidine (His) tautomerism has been linked to the formation of fibril aggregation causing neurodegenerative disease. Characterization of intermediate species that form during aggregation is crucial, however, this has proven very challenging for experimentalists due to their transient nature. Hence, molecular dynamics (MD) simulations have been performed on the His tautomeric isomers εε, εδ, δε, and δδ of PFN1 to explain the structural changes and to correlate them with its aggregation propensity. MD simulations show that His133 presumably plays a major role in the aggregation of PFN1 upon His tautomerism compared to His119. Further, the formation of a new 3 10 -helix is observed in εε and δε but 3 10 -helix is not observed in δδ and εδ isomers. In addition, our findings unveil that β-sheet dominating conformations are observed in His119(δ)-His133(δ) δδ isomer of PFN1 with significant antiparallel β-sheets between residues T15-G23, S29-A33, L63-L65, Q68-S76, F83-T89, T97-T105, and K107-K115, suggesting a novel aggregation mechanism possibly occur for the formation of PFN1 aggregates. Overall, these results propose that MD simulations of PFN1 His tautomers can provide a detailed microscopic understanding of the aggregation mechanisms which are hard to probe through experiments. [ABSTRACT FROM AUTHOR]

Mutations and histidine (His) tautomerism in profilin-1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS). The conformational changes in PFN1 caused by the collective effects of G117V mutation and His tautomeric isomers εε, εδ, δε, and δδ were clarified using molecular dynamics (MD) simulations. The predominant structural variations were seen in α-helices, β-sheets, turns, and coils and the His tautomer's unique degree of disruption was seen in these conformations. The content of α-helices was 23.2 % in the εε and δδ isomers, but the observed α-helices in the isomers εδ and δε were 20.3 % and 21.7 % respectively. The percentage of β-sheet was found to be higher (34.1) in the εε isomer than in the εδ, δε, and δδ isomers, and the values were 30.4, 29.7, and 31.9, respectively. Intermolecular water dynamics analysis discloses that His 133 can form an intramolecular H-bond interaction (Nα-H---Nδ), confirming the experimental observations in the simulations of εε, δε, and δδ isomers of G117V PFN1 mutant. It was concluded that these solvent molecules are crucial for aggregation and must be considered in future research on the PFN1 associated with ALS. Overall, the study offers a thorough microscopic understanding of the pathogenic mechanisms behind conformational changes that cause aggregation illnesses like ALS. [ABSTRACT FROM AUTHOR]

Aggregated amyloid β-peptide (Aβ) in small oligomeric forms inside the brain causes synaptic function disruption and the development of Alzheimer's disease (AD). Histidine is an important amino acid that may lead to structural changes. Aβ42 monomer chain includes 3 histidine residues that considering two ε and δ tautomers 8 isomers, including (εεε) and (εδδ) could be formed. Molecular dynamics simulation on homodimerization of (εεε) (the most common type of tautomers) and (εδδ) tautomers with different initial configurations using monomer chains from our previous work were performed to uncover the tautomeric behavior of histidine on Aβ42 aggregation in a physiological pH which is still largely unknown and impossible to observe experimentally. We found a higher propensity of forming β-sheet in (εδδ) homodimers and specifically in a greater amount from Aβ42 than from Aβ40. A smaller amount of β-sheet formation was observed for (εεε) homodimers compared with (εδδ). Additionally, interactions in (εδδ) homodimers may indicate the importance of the hydrophobic core and C-/N-terminals during oligomerization. Our findings indicate the important role of the tautomeric effect of histidine and (εδδ) homodimers at the early stage of Aβ aggregation. • (εδδ) tautomers show a high propensity to generate β-sheets during homodimerization. • (εδδ) homodimers may play an important role at the early stage of Aβ aggregation. • Histidine tautomerism can affect the structural properties of the amyloid peptides. [ABSTRACT FROM AUTHOR]

Aptamers are increasingly recognized as potent alternatives to antibodies for diagnostic and therapeutic applications. The application of deep learning, particularly attention-based models, for aptamer (DNA/RNA) sequences is an innovative field. The ongoing advancements in aptamer sequencing technologies coupled with machine learning algorithms have resulted in novel developments. Further research is required to investigate the full potential of deep learning models and address the challenges associated with the generation of sequences, like the large search space of possible sequences. In this study, we propose a workflow that integrates an attention mechanism within a framework of a generative variational autoencoder, to generate novel sequences by expanding latent memory. They show 100 % novelty compared with the dataset, and approximately 88 % of them show negative values for the minimum free energy, which may indicate the likelihood of an RNA sequence folding into a functional structure. Because the field of aptamer discovery is affected by data scarcity, advanced strategies that facilitate the generation of diverse and superior sequences are necessitated. The utilization of our workflow can result in novel aptamers. Thus, investigations such as the present study can address the abovementioned challenge. Our research is anticipated to facilitate further discoveries and advancements in aptamer fields. • We leverage attention-based variational autoencoders for the generation of novel aptamer sequences. • The application of deep learning, particularly attention-based models, for aptamers is an innovative and emerging field. • The field of aptamer (DNA/RNA) discovery is affected by data scarcity, so strategies for generation of diverse sequences are necessitated. [ABSTRACT FROM AUTHOR]

Aptamers are increasingly recognized as potent alternatives to antibodies for diagnostic and therapeutic applications. The application of deep learning, particularly attention-based models, for aptamer (DNA/RNA) sequences is an innovative field. The ongoing advancements in aptamer sequencing technologies coupled with machine learning algorithms have resulted in novel developments. Further research is required to investigate the full potential of deep learning models and address the challenges associated with the generation of sequences, like the large search space of possible sequences. In this study, we propose a workflow that integrates an attention mechanism within a framework of a generative variational autoencoder, to generate novel sequences by expanding latent memory. They show 100 % novelty compared with the dataset, and approximately 88 % of them show negative values for the minimum free energy, which may indicate the likelihood of an RNA sequence folding into a functional structure. Because the field of aptamer discovery is affected by data scarcity, advanced strategies that facilitate the generation of diverse and superior sequences are necessitated. The utilization of our workflow can result in novel aptamers. Thus, investigations such as the present study can address the abovementioned challenge. Our research is anticipated to facilitate further discoveries and advancements in aptamer fields. • We leverage attention-based variational autoencoders for the generation of novel aptamer sequences. • The application of deep learning, particularly attention-based models, for aptamers is an innovative and emerging field. • The field of aptamer (DNA/RNA) discovery is affected by data scarcity, so strategies for generation of diverse sequences are necessitated. [ABSTRACT FROM AUTHOR]

Controlling protein misfolding and accumulation in neurodegeneration is a challenge in chemical neuroscience. The application of appropriate electric fields (EFs) can be a potential noninvasive therapy to treat neuro disorders. The effect of EFs of varying intensities and directions on the conformational dynamics of β-Amyloid40 (Aβ40) under histidine tautomerism has been investigated for the first time. Our findings suggest that peptides tend to align their dipole moments with the orientation of EF. Irrespective of the EF direction, the dipole moment magnitude is affected by the EF strength. With the conformational changes, the EF strength equal to 0.5 V/nm destroyed the β-sheet content of the δδδ isomer as a potentially toxic agent. The content of the alpha-helical structure which can be transformed into the β-sheet is reduced. The strength of the EF showed a significant influence on the reduction of the number of intra-protein hydrogen bonds especially when EF is equal to 0.5 V/nm which could facilitate destabilization of the structure of the peptides. Current findings provide quantitative insights into the tautomerization-mediated Aβ40 dynamic and conformational changes induced by the external EFs in aqueous solutions, which may provide beneficial information for use as a therapeutic technique. • We explored the combined effect of an external EF and histidine tautomerism on the misfolding of monomeric Aβ40. • When EF = 0.5 V/nm was applied the β-sheet structure of the δδδ isomer was destroyed. • This work can be helpful for studying EF dependency structural changes in the presence of the tautomeric states. [ABSTRACT FROM AUTHOR]