Controlling the polymorphic assemblies of α-synuclein (αS) oligomers is crucial to reroute toxic protein aggregation implicated in Parkinson's disease (PD). One potential mediator is the interaction of αS tetramers with cell membranes, which may regulate the dynamic balance between aggregation-prone disordered monomers and aggregation-resistant helical tetramers. Here, we model diverse tetramer-cell interactions and compare the structure-function relations at the supramolecular-biological interface with available experimental data. The models predict preferential interaction of compact αS tetramers with highly charged membrane surfaces, which may further stabilize this aggregation-resistant conformer. On moderately charged membranes, extended structures are preferred. In addition to surface charge, curvature influences tetramer thermodynamic stability and aggregation, with potential for selective isolation of tetramers regio-specific interactions with strongly negatively charged micelles that screen further aggregation. Our modeling data set highlights diverse beneficial nano-bio interactions to redirect biomolecule assembly, supporting new therapeutic approaches for PD based on lipid-mediated conformational selection and inhibition.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11523075 | PMC |
| http://dx.doi.org/10.1021/acs.jcim.4c01459 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Attributes novel drug candidate: Constitutive GPCR signal bias mediated by purinergic receptors.
Pharmacol Ther
January 2025
School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China; School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.
G protein-coupled receptors (GPCRs) can transmit signals via G protein-dependent or independent pathways due to the conformational changes of receptors and ligands, which is called biased signaling. This concept posits that ligands can selectively activate a specific signaling pathway after receptor activation, facilitating downstream signaling along a preferred pathway. Biased agonism enables the development of ligands that prioritize therapeutic signaling pathways while mitigating on-target undesired effects.
View Article and Find Full Text PDFMapping conformational landscape in protein folding: Benchmarking dimensionality reduction and clustering techniques on the Trp-Cage mini-protein.
Biophys Chem
January 2025
Department of Chemical and Biological Sciences, S. N. Bose National Centre for Basic Sciences, Kolkata 700106, India. Electronic address:
Quantitative characterization of protein conformational landscapes is a computationally challenging task due to their high dimensionality and inherent complexity. In this study, we systematically benchmark several widely used dimensionality reduction and clustering methods to analyze the conformational states of the Trp-Cage mini-protein, a model system with well-documented folding dynamics. Dimensionality reduction techniques, including Principal Component Analysis (PCA), Time-lagged Independent Component Analysis (TICA), and Variational Autoencoders (VAE), were employed to project the high-dimensional free energy landscape onto 2D spaces for visualization.
View Article and Find Full Text PDFEffects of Additional Flexible and Rigid Structure on BDT-BDD Terpolymer and the Performance of Organic Solar Cells.
Polymers (Basel)
January 2025
School of Materials Science and Engineering, Ocean University of China, Qingdao 266100, China.
In organic solar cells, the aggregation and crystallization of polymers are significant for bulk heterojunction. Blending with acceptor materials, polymer donor materials can adjust their aggregation by the movement of the chain segments. In this paper, the unfused structures based on thiophene and carbazole are respectively designed and introduced into the donor-acceptor copolymer donor materials to investigate the influence of flexible and rigid structures on polymer-aggregation leading photoelectric performance.
View Article and Find Full Text PDF()-1-(3-(3-Hydroxy-4-Methoxyphenyl)-1-(3,4,5-Trimethoxyphenyl)allyl)-1-1,2,4-Triazole and Related Compounds: Their Synthesis and Biological Evaluation as Novel Antimitotic Agents Targeting Breast Cancer.
Pharmaceuticals (Basel)
January 2025
School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College Dublin, D02 PN40 Dublin, Ireland.
The synthesis of ()-1-(1,3-diphenylallyl)-1-1,2,4-triazoles and related compounds as anti-mitotic agents with activity in breast cancer was investigated. These compounds were designed as hybrids of the microtubule-targeting chalcones, indanones, and the aromatase inhibitor letrozole. : A panel of 29 compounds was synthesized and examined by a preliminary screening in estrogen receptor (ER) and progesterone receptor (PR)-positive MCF-7 breast cancer cells together with cell cycle analysis and tubulin polymerization inhibition.
View Article and Find Full Text PDFSynthesis of Anti-Inflammatory Drugs' Chalcone Derivatives and a Study of Their Conformational Properties Through a Combination of Nuclear Magnetic Resonance Spectroscopy and Molecular Modeling.
Pharmaceuticals (Basel)
January 2025
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimioupolis Zografou, 11571 Athens, Greece.
Background: In this study, two chalcone analogs were synthesized through in silico and experimental methods, and their potential to inhibit the lipoxygenase enzyme, which plays a role in the inflammation pathway, was assessed. Specifically, this study is a continuation of previous research in which chalcone derivatives were synthesized and characterized.
Objectives/methods: In the current work, we present the re-synthesis of two chalcones, with a focus on their docking studies, NMR analysis, and dynamic simulations.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!