Recent Force Field Strategies for Intrinsically Disordered Proteins

Journal of Chemical Information and Modeling, Journal Year: 2021, Volume and Issue: 61(3), P. 1037 - 1047

Published: Feb. 16, 2021

Intrinsically disordered proteins (IDPs) are widely distributed across eukaryotic cells, playing important roles in molecular recognition, assembly, post-translational modification, and other biological processes. IDPs also associated with many diseases such as cancers, cardiovascular diseases, neurodegenerative diseases. Due to their structural flexibility, conventional experimental methods cannot reliably capture heterogeneous structures. Molecular dynamics simulation becomes an complementary tool quantify IDP This review covers recent force field strategies proposed for more accurate simulations of IDPs. The include adjusting dihedral parameters, adding grid-based energy correction map (CMAP) refining protein–water interactions, others. Different fields were found perform well on specific observables but limited reproducing all available consistently tested We conclude the perspective areas improvements future

Language: Английский

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Energy Landscapes of Protein Aggregation and Conformation Switching in Intrinsically Disordered Proteins

Journal of Molecular Biology, Journal Year: 2021, Volume and Issue: 433(20), P. 167182 - 167182

Published: Aug. 3, 2021

Language: Английский

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Amyloid-β peptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(39)

Published: Sept. 20, 2021

Significance The aggregation of the amyloid- β peptide (A ) into neurotoxic oligomers is central to development Alzheimer’s disease. One possible source their toxicity results from interactions A with neuronal membrane, damaging membrane integrity and thus neurons. However, molecular details these are unclear. Here, we contrast dimerization in solution at membrane. Our clearly indicate that sugar moieties GM1 sequester by forming key hydrogen bonds peptide, which diverts configuration dimers away -sheet–rich structures. These findings underline importance disease progression provide a nanoscopic basis for its reported neuroprotective effect.

Language: Английский

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Disorder-to-order transition of the amyloid-β peptide upon lipid binding

Biophysical Chemistry, Journal Year: 2021, Volume and Issue: 280, P. 106700 - 106700

Published: Oct. 26, 2021

Language: Английский

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Delineating the activation mechanism and conformational landscape of a class B G protein-coupled receptor glucagon receptor

Computational and Structural Biotechnology Journal, Journal Year: 2022, Volume and Issue: 20, P. 628 - 639

Published: Jan. 1, 2022

Class B G protein-coupled receptors (GPCRs) are important targets in the treatment of metabolic syndrome and diabetes. Although multiple structures class GPCRs–G protein complexes have been elucidated, detailed activation mechanism remains unclear. Here, we combine Gaussian accelerated molecular dynamics simulations Markov state models (MSM) to investigate a canonical GPCR, human glucagon receptor–GCGR, including negative allosteric modulator-bound inactive state, agonist glucagon-bound active both glucagon- Gs-bound fully state. The free-energy landscapes GCGR show conformational ensemble consisting three activation-associated states: inactive, active, active. structural analysis indicates high upon binding with conformations ensemble. Significantly, H8 TM6 exhibits distinct features from states. additional demonstrate role recruitment Gs. Gs presents crucial function stabilizing site MSM highlights absolute requirement help reach Together, our results reveal view dynamics.

Language: Английский

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A Small Molecule Stabilizes the Disordered Native State of the Alzheimer’s Aβ Peptide

ACS Chemical Neuroscience, Journal Year: 2022, Volume and Issue: 13(12), P. 1738 - 1745

Published: June 1, 2022

The stabilization of native states proteins is a powerful drug discovery strategy. It still unclear, however, whether this approach can be applied to intrinsically disordered proteins. Here, we report small molecule that stabilizes the state Aβ42 peptide, an protein fragment associated with Alzheimer's disease. We show takes place by binding mechanism, in which both and peptide remain disordered. This mechanism involves enthalpically favorable local π-stacking interactions coupled entropically advantageous global effects. These results indicate molecules stabilize their through transient non-specific provide enthalpic gain while simultaneously increasing conformational entropy

Language: Английский

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A Hairpin Motif in the Amyloid-β Peptide Is Important for Formation of Disease-Related Oligomers

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(33), P. 18340 - 18354

Published: Aug. 9, 2023

The amyloid-β (Aβ) peptide is associated with the development of Alzheimer's disease and known to form highly neurotoxic prefibrillar oligomeric aggregates, which are difficult study due their transient, low-abundance, heterogeneous nature. To obtain high-resolution information about oligomer structure dynamics as well relative populations assembly states, we here employ a combination native ion mobility mass spectrometry molecular simulations. We find that formation Aβ oligomers dependent on presence specific β-hairpin motif in sequence. Oligomers initially grow spherically but start extended linear aggregates at states larger than those tetramer. population could be notably increased by introducing an intramolecular disulfide bond, prearranges hairpin conformation, thereby promoting structures preventing conversion into mature fibrils. Conversely, truncating one β-strand-forming segments decreased propensity thus population, removed entirely, aggregation peptide. propose observed state related antiparallel sheet state, then nucleates amyloid state. These studies provide mechanistic understanding earliest steps suggest inhibition folding conformation viable strategy for reducing amount toxic oligomers.

Language: Английский

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Energy landscapes of Aβ monomers are sculpted in accordance with Ostwald’s rule of stages

Science Advances, Journal Year: 2023, Volume and Issue: 9(12)

Published: March 22, 2023

The transition from a disordered to an assembly-competent monomeric state (N*) in amyloidogenic sequences is crucial event the aggregation cascade. Using well-calibrated model for intrinsically proteins (IDPs), we show that N* states, which bear considerable resemblance polymorphic fibril structures found experiments, not only appear as excitations free energy landscapes of Aβ40 and Aβ42, but also initiate For transitions different states are accord with Ostwald's rule stages, least stable forming ahead thermodynamically favored ones. Aβ42 monomer exhibit extents local frustration, have profound implications dictating subsequent self-assembly. kinetic networks, illustrate most dimerization routes proceed via states. We argue holds fused sarcoma polyglutamine proteins.

Language: Английский

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A brief history of amyloid aggregation simulations

Wiley Interdisciplinary Reviews Computational Molecular Science, Journal Year: 2024, Volume and Issue: 14(1)

Published: Jan. 1, 2024

Abstract Amyloid proteins are characterized by their tendency to aggregate into amyloid fibrils, which often associated with devastating diseases. Aggregation pathways typically involve unfolding or misfolding of monomeric and formation transient oligomers protofibrils before the final aggregation product is formed. The conformational dynamics polymorphic volatile nature these intermediates make characterization experimental techniques alone insufficient also require computational approaches. Over past 25 years, size simulated systems length simulations have increased significantly. These advances discussed here. review includes simulation approaches that model aggregating peptides at both all‐atom coarse‐grained levels, use molecular Monte Carlo sampling simulate changes, present results for various ranging from Lys‐Phe‐Phe‐Glu (KFFE) as smallest system an intermediate‐sized peptide α‐synuclein. presentation history concludes a discussion where future may lie. This article categorized under: Structure Mechanism > Computational Biochemistry Biophysics Molecular Statistical Mechanics Dynamics Monte‐Carlo Methods

Language: Английский

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How did we get there? AI applications to biological networks and sequences

Computers in Biology and Medicine, Journal Year: 2025, Volume and Issue: 190, P. 110064 - 110064

Published: April 5, 2025

The rapidly advancing field of artificial intelligence (AI) has transformed numerous scientific domains, including biology, where a vast and complex volume data is available for analysis. This paper provides comprehensive overview the current state AI-driven methodologies in genomics, proteomics, systems biology. We discuss how machine learning algorithms, particularly deep models, have enhanced accuracy efficiency embedding sequences, motif discovery, prediction gene expression protein structure. Additionally, we explore integration AI analysis biological networks, protein-protein interaction networks multi-layered networks. By leveraging large-scale data, techniques enabled unprecedented insights into processes disease mechanisms. work underlines potential applying to highlighting applications suggesting directions future research further this evolving field.

Language: Английский

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