Utilizing Molecular Dynamics Simulations, Machine Learning, Cryo-EM, and NMR Spectroscopy to Predict and Validate Protein Dynamics

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9725 - 9725

Published: Sept. 8, 2024

Protein dynamics play a crucial role in biological function, encompassing motions ranging from atomic vibrations to large-scale conformational changes. Recent advancements experimental techniques, computational methods, and artificial intelligence have revolutionized our understanding of protein dynamics. Nuclear magnetic resonance spectroscopy provides atomic-resolution insights, while molecular simulations offer detailed trajectories motions. Computational methods applied X-ray crystallography cryo-electron microscopy (cryo-EM) enabled the exploration dynamics, capturing ensembles that were previously unattainable. The integration machine learning, exemplified by AlphaFold2, has accelerated structure prediction analysis. These approaches revealed importance allosteric regulation, enzyme catalysis, intrinsically disordered proteins. shift towards ensemble representations structures application single-molecule techniques further enhanced ability capture dynamic nature Understanding is essential for elucidating mechanisms, designing drugs, developing novel biocatalysts, marking significant paradigm structural biology drug discovery.

Language: Английский

---

Functional Characterization of Residues Affecting the Catalytic Activity of Glucosyltransferase from Streptococcus mutans

The Journal of Physical Chemistry B, Journal Year: 2025, Volume and Issue: unknown

Published: May 19, 2025

Dental caries is a multifactorial, biofilm-mediated disease primarily caused by Streptococcus mutans, key etiological agent. This bacterium secretes extracellular enzymes known as glucosyltransferases (Gtfs), also termed glucansucrases, which play pivotal role in the synthesis of exopolysaccharides through metabolism dietary sucrose. These provide binding sites for attachment and colonization other microorganisms, contributing to initiation progression dental caries. study investigates catalytic mechanisms from S. mutans using molecular dynamics simulations, with focus on conformational interactions amino acid residues that modulate enzymatic activity. Wild-type mutant models glucosyltransferase, bound maltose, sucrose (substrates), acarbose (an inhibitor), were generated analyze patterns these molecules. The systems' stability was assessed root-mean-square deviation, fluctuation, radius gyration, principal component analysis, free energy landscape, dynamic cross-correlation matrix analysis. MMGBSA method employed evaluate relative energies systems. Our findings revealed mutations increased sucrose-bound system while decreasing acarbose-bound system, consistent fluctuation observed across different ligands. changes glucosyltransferase behavior could influence its efficiency.

Language: Английский

---

Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 17, 2024

Abstract In classical amyloidoses, amyloid fibres form through the nucleation and accretion of protein monomers, with protofibrils fibrils exhibiting a cross-β motif parallel or antiparallel β-sheets oriented perpendicular to fibre direction. These can intertwine mature fibres. Similar phenomena occur in blood from individuals circulating inflammatory molecules (also those originating viruses bacteria). presence inflammagens, pathological clotting occur, that results an anomalous termed fibrinaloid microclots. Previous proteomic analyses these microclots have shown non-fibrin(ogen) proteins, suggesting more complex mechanism than simple entrapment. We provide evidence against entrapment model, noting clot pores are too large centrifugation would removed weakly bound proteins. Instead, we explore whether co-aggregation into may involve axial (multiple proteins within same fibril), lateral (single-protein contributing fibre), both types integration. Our analysis data different diseases shows no significant overlap normal plasma proteome correlation between abundance Notably, abundant like α-2-macroglobulin, fibronectin, transthyretin absent microclots, while less such as adiponectin, periostin, von Willebrand Factor well represented. Using bioinformatic tools including AmyloGram AnuPP, found entrapped exhibit high amyloidogenic tendencies, their integration elements structures. This likely contributes microclots’ resistance proteolysis. findings underscore role cross-seeding microclot formation highlight need for further investigation structural properties implications thrombotic diseases. insights foundation developing novel diagnostic therapeutic strategies targeting disorders.

Language: Английский

---

Proteomic Evidence for Amyloidogenic Cross-Seeding in Fibrinaloid Microclots

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(19), P. 10809 - 10809

Published: Oct. 8, 2024

In classical amyloidoses, amyloid fibres form through the nucleation and accretion of protein monomers, with protofibrils fibrils exhibiting a cross-β motif parallel or antiparallel β-sheets oriented perpendicular to fibre direction. These can intertwine mature fibres. Similar phenomena occur in blood from individuals circulating inflammatory molecules (and also some originating viruses bacteria). Such pathological clotting result an anomalous termed fibrinaloid microclots. Previous proteomic analyses these microclots have shown presence non-fibrin(ogen) proteins, suggesting more complex mechanism than simple entrapment. We thus provide evidence against such entrapment model, noting that clot pores are too large centrifugation would removed weakly bound proteins. Instead, we explore whether co-aggregation into may involve axial (multiple proteins within same fibril), lateral (single-protein contributing fibre), both types integration. Our analysis data different diseases shows no significant quantitative overlap normal plasma proteome correlation between abundance their Notably, abundant like α-2-macroglobulin, fibronectin, transthyretin absent microclots, while less as adiponectin, periostin, von Willebrand factor well represented. Using bioinformatic tools, including AmyloGram AnuPP, found entrapped exhibit high amyloidogenic tendencies, integration elements structures. This likely contributes microclots’ resistance proteolysis. findings underscore role cross-seeding microclot formation highlight need for further investigation structural properties implications thrombotic diseases. insights foundation developing novel diagnostic therapeutic strategies targeting disorders.

Language: Английский

---

Hsp60 and artificial intelligence

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 275 - 281

Published: Nov. 1, 2024

Language: Английский

---