An integrated machine learning approach delineates an entropic expansion mechanism for the binding of a small molecule to α-synuclein.

The mis-folding and aggregation of intrinsically disordered proteins (IDPs) such as α-synuclein (αS) underlie the pathogenesis of various neurodegenerative disorders. However, targeting αS with small molecules faces challenges due to the lack of defined ligand-binding pockets in its disordered structure. Here, we implement a deep artificial neural network-based machine learning approach, which is able to statistically distinguish the fuzzy ensemble of conformational substates of αS in neat water from those in aqueous fasudil (small molecule of interest) solution.

Regulation of microtubule dynamics and function in living cells cucurbit[7]uril host-guest assembly.

Living systems utilize sophisticated biochemical regulators and various signal transduction mechanisms to program bio-molecular assemblies and their associated functions. Creating synthetic assemblies that can replicate the functional and signal-responsive properties of these regulators, while also interfacing with biomolecules, holds significant interest within the realms of supramolecular chemistry and chemical biology. This pursuit not only aids in understanding the fundamental design principles of life but also introduces novel capabilities that contribute to the advancements in medical and therapeutic research.

Modulation of α-synuclein aggregation amid diverse environmental perturbation.

Intrinsically disordered protein α-synuclein (αS) is implicated in Parkinson's disease due to its aberrant aggregation propensity. In a bid to identify the traits of its aggregation, here we computationally simulate the multi-chain association process of αS in aqueous as well as under diverse environmental perturbations. In particular, the aggregation of αS in aqueous and varied environmental condition led to marked concentration differences within protein aggregates, resembling liquid-liquid phase separation (LLPS).

TDP-43 dysregulation of polyadenylation site selection is a defining feature of RNA misprocessing in ALS/FTD and related disorders.

Nuclear clearance and cytoplasmic aggregation of the RNA-binding protein TDP-43 are observed in many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and fronto- temporal dementia (FTD). Although TDP-43 dysregulation of splicing has emerged as a key event in these diseases, TDP-43 can also regulate polyadenylation; yet, this has not been adequately studied. Here, we applied the dynamic analysis of polyadenylation from RNA-seq (DaPars) tool to ALS/FTD transcriptome datasets, and report extensive alternative polyadenylation (APA) upon TDP-43 alteration in ALS/FTD cell models and postmortem ALS/FTD neuronal nuclei.

Emergence of Catalytic Triad by Short Peptide Based Nanofibrillar Assemblies.

Through millions of years of the evolutionary journey, contemporary enzymes observed in extant metabolic pathways have evolved to become specialized, in contrast to their ancestors, which displayed promiscuous activities with wider substrate specificities. However, there remain critical gaps in our understanding of how these early enzymes could show such catalytic versatility despite lacking the complex three-dimensional folds of the existing modern-day enzymes. Herein, we report the emergence of a promiscuous catalytic triad by short amyloid peptide based nanofibers that access paracrystalline folds of β-sheets to expose three residues (lysine, imidazole, and tyrosine) toward solvent.

Conformational Plasticity in α-Synuclein and How Crowded Environment Modulates It.

A 140-residue intrinsically disordered protein (IDP), α-synuclein (αS), is known to adopt conformations that are vastly plastic and susceptible to environmental cues and crowders. However, the inherently heterogeneous nature of αS has precluded a clear demarcation of its monomeric precursor between aggregation-prone and functionally relevant aggregation-resistant states and how a crowded environment could modulate their mutual dynamic equilibrium. Here, we identify an optimal set of distinct metastable states of αS in aqueous media by dissecting a 73 μs-long molecular dynamics ensemble via building a comprehensive Markov state model (MSM).

Short peptide-based cross-β amyloids exploit dual residues for phosphoesterase like activity.

Herein, we report that short peptides are capable of exploiting their anti-parallel registry to access cross-β stacks to expose more than one catalytic residue, exhibiting the traits of advanced binding pockets of enzymes. Binding pockets decorated with more than one catalytic residue facilitate substrate binding and process kinetically unfavourable chemical transformations. The solvent-exposed guanidinium and imidazole moieties on the cross-β microphases synergistically bind to polarise and hydrolyse diverse kinetically stable model substrates of nucleases and phosphatase.

Microcarrier-Based Culture of Human Pluripotent Stem-Cell-Derived Retinal Pigmented Epithelium.

Dry age-related macular degeneration (AMD) is estimated to impact nearly 300 million individuals globally by 2040. While no treatment options are currently available, multiple clinical trials investigating retinal pigmented epithelial cells derived from human pluripotent stem cells (hPSC-RPE) as a cellular replacement therapeutic are currently underway. It has been estimated that a production capacity of >109 RPE cells annually would be required to treat the afflicted population, but current manufacturing protocols are limited, being labor-intensive and time-consuming.

Dynamical Manifestations of Supercooling in Amyloid Hydration.

The effect of extreme temperature on amyloidogenic species remains sparsely explored. In a recent study (, , , (10)), we employed exhaustive molecular dynamics simulations to explore the cold thermal response of a putative small amyloid oligomer and to elicit the role of solvent modulation. Herein, we investigate the dynamical response of the hydration waters of the oligomer within the supercooled states.

Nanoscale Interplay of Membrane Composition and Amyloid Self-Assembly.

Cell membranes are complex assemblies of lipids and proteins exhibiting lipid compositional heterogeneity between the inner and outer leaflets of the bilayer. Aberrant protein aggregation, implicated in a number of neurodegenerative diseases including Alzheimer's, is known to result in both extracellular and intracellular deposits with divergent pathophysiological effects. Mounting evidence substantiates membrane-mediated amyloid effects and indicates membrane composition, particularly gangliosides, as a plausible factor influencing the fibrillation process.

The Cold Thermal Response of an Amyloid Oligomer Differs from Typical Globular Protein Cold Denaturation.

In contrast with the general behavior of folded proteins, the cold thermal response of amyloid assemblies is difficult to elicit with simple models. We exploit exhaustive simulations to evaluate the thermal response of a barrel-shaped model amyloid oligomer, with a distinct hydrophobic core akin to that of folded proteins. Cumulative thermal data over the range of 210-483 K indicate a sharp inflection and rise in structural stability as the temperature is decreased below the melting temperature of the water model.

Perturbations in inter-domain associations may trigger the onset of pathogenic transformations in PrP(C): insights from atomistic simulations.

Conversion of the predominantly α-helical cellular prion protein (PrP(C)) to the misfolded β-sheet enriched Scrapie form (PrP(Sc)) is a critical event in prion pathogenesis. However, the conformational triggers that lead to the isoform conversion (PrP(C) to PrP(Sc)) remain obscure, and conjectures about the role of unusually hydrophilic, short helix H1 of the C-terminal globular domain in the transition are varied. Helix H1 is anchored to helix H3 via a few stabilizing polar interactions.

In silico profiling and structural insights of missense mutations in RET protein kinase domain by molecular dynamics and docking approach.

A major challenge remaining in drug design efforts towards protein kinase is due to the development of drug resistance initiated by the missense mutations in the kinase catalytic domain. Gain or loss of function mutations in the REarranged during Transfection (RET) tyrosine kinase gene have been associated with the development of a wide range of human associated cancers and Hirschsprung's disease. However, to what extent these mutations might affect bio-molecular functions remains unclear.