Protein Ensemble Generation Through Variational Autoencoder Latent Space Sampling

Journal of Chemical Theory and Computation, Journal Year: 2024, Volume and Issue: 20(7), P. 2689 - 2695

Published: March 28, 2024

Mapping the ensemble of protein conformations that contribute to function and can be targeted by small molecule drugs remains an outstanding challenge. Here, we explore use variational autoencoders for reducing challenge dimensionality in structure generation problem. We convert high-dimensional structural data into a continuous, low-dimensional representation, carry out search this space guided quality metric, then RoseTTAFold sampled information generate 3D structures. approach ensembles cancer relevant K-Ras, train VAE on subset available K-Ras crystal structures MD simulation snapshots, assess extent sampling close withheld from training. find our latent procedure rapidly generates with high is able sample within 1 Å held-out structures, consistency higher than or AlphaFold2 prediction. The sufficiently recapitulate cryptic pockets allow docking.

Language: Английский

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Targeted inhibition of WIP1 and histone H3K27 demethylase activity synergistically suppresses neuroblastoma growth

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 19, 2025

Abstract High-risk neuroblastoma frequently exhibits segmental gain of chromosome 17q, including the locus PPM1D , which encodes phosphatase WIP1, a regulator p53 activity, DNA repair, and apoptosis. High expression is correlated to poor prognosis, genetic or pharmacologic inhibition WIP1 suppresses growth. Here, we show that combining drugs target H3K27 demethylation induces synergistic cytotoxicity in neuroblastoma. We screened 527 different compounds together with inhibitors identified strong cytotoxic synergism between inhibitor SL-176 GSK-J4, specific demethylase JMJD3. Viability assays cell lines treatment tumor spheroids confirmed effect GSK-J4. Immunoblot experiments demonstrated marked on downstream targets apoptosis markers, while qPCR showed upregulation PUMA p21. RNA sequencing revealed vast number differentially expressed genes, suggesting pervasive this drug combination transcription, enrichment pathways involved damage response. Finally, was reduce growth zebrafish xenograft experiments. In conclusion, epigenetic modifier GSK-J4 cells by potentiating effects.

Language: Английский

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Toward physics‐based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants

Protein Science, Journal Year: 2024, Volume and Issue: 33(3)

Published: Feb. 15, 2024

The goal of precision medicine is to utilize our knowledge the molecular causes disease better diagnose and treat patients. However, there a substantial mismatch between small number food drug administration (FDA)-approved drugs annotated coding variants compared needs medicine. This review introduces concept physics-based medicine, scalable framework that promises improve understanding sequence-function relationships accelerate discovery. We show accounting for ensemble structures protein adopts in solution with computer simulations overcomes many limitations imposed by assuming single structure. highlight studies dynamics recent methods analysis structural ensembles. These demonstrate differences conformational distributions predict functional within families variants. Thanks new computational tools are providing unprecedented access ensembles, this insight may enable accurate predictions variant pathogenicity entire libraries further explicitly like alchemical free energy calculations or docking Markov state models, can uncover novel lead compounds. To conclude, we cryptic pockets, cavities absent experimental structures, provide an avenue target proteins currently considered undruggable. Taken together, provides roadmap field science

Language: Английский

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AlphaFold and Protein Folding: Not Dead Yet! The Frontier Is Conformational Ensembles

Annual Review of Biomedical Data Science, Journal Year: 2024, Volume and Issue: 7(1), P. 51 - 57

Published: April 11, 2024

Like the black knight in classic Monty Python movie, grand scientific challenges such as protein folding are hard to finish off. Notably, AlphaFold is revolutionizing structural biology by bringing highly accurate structure prediction masses and opening up innumerable new avenues of research. Despite this enormous success, calling prediction, much less related problems, “solved” dangerous, doing so could stymie further progress. Imagine what world would be like if we had declared flight solved after first commercial airlines opened stopped investing research development. Likewise, there still important limitations that benefit from addressing. Moreover, limited our understanding diversity different structures a single can adopt (called conformational ensemble) dynamics which explores space. What clear ensembles critical function, aspect will advance ability design proteins drugs.

Language: Английский

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A journey from molecule to physiology and in silico tools for drug discovery targeting the transient receptor potential vanilloid type 1 (TRPV1) channel

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 24, 2024

The heat and capsaicin receptor TRPV1 channel is widely expressed in nerve terminals of dorsal root ganglia (DRGs) trigeminal innervating the body face, respectively, as well other tissues organs including central nervous system. a versatile that detects harmful heat, pain, various internal external ligands. Hence, it operates polymodal sensory channel. Many pathological conditions neuroinflammation, cancer, psychiatric disorders, are linked to abnormal functioning peripheral tissues. Intense biomedical research underway discover compounds can modulate provide pain relief. molecular mechanisms underlying temperature sensing remain largely unknown, although they closely transduction. Prolonged exposure generates analgesia, hence numerous analogs have been developed efficient analgesics for emergence silico tools offered significant techniques modeling machine learning algorithms indentify druggable sites repositioning current drugs aimed at TRPV1. Here we recapitulate physiological pathophysiological functions channel, structural models obtained through cryo-EM, pharmacological tested on TRPV1, drug discovery repositioning.

Language: Английский

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Dissecting oxidative folding of conotoxins using 3D structures of cysteine mutants predicted by AlphaFold 3: A case study of α-conotoxin RgIA, χ-conotoxin CMrVIA and ω-conotoxin MVIIA-Gly

Toxicon, Journal Year: 2025, Volume and Issue: unknown, P. 108402 - 108402

Published: May 1, 2025

Language: Английский

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A Reversible Spherical Geometric Conversion of Protein Backbone Structure Coordinate Matrix to Three Independent Vectors of ρ, θ and φ

Published: April 8, 2024

Due to the vast conformational space proteins can adopt, accurate and efficient prediction of protein structure remains still a challenging task, coupled with intricacies interatomic interactions limitations current computational models in effectively navigating this complex molecular landscape. Additionally, lack comprehensive experimental data for all structures further exacerbates difficulty reliable machine learning-based three-dimensional conformations proteios building block life. Geometrically, Cartesian coordinate system (CCS, X, Y Z) spherical (SCS, ρ, θ φ) are two interconvertible systems, like sides one coin. Since beginning Protein Data Bank (PDB) 1971, CCS has been default approach specify atomic positions Z PDB. In manuscript, therefore, I present novel method reversible geometric conversion backbone matrices three independent vectors: φ. This facilitates lossless extraction essential structural features from data, enabling development advanced algorithms future. short, inter-atomic SCS offers yet means representing geometry, leveraging coordinates capture spatial relationships compact intuitive manner, provide robust framework feature ongoing efforts advancing field prediction, holy grail biology.

Language: Английский

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Exploring Conformational Landscapes and Cryptic Binding Pockets in Distinct Functional States of the SARS-CoV-2 Omicron BA.1 and BA.2 Trimers: Mutation-Induced Modulation of Protein Dynamics and Network-Guided Prediction of Variant-Specific Allosteric Binding Sites

Viruses, Journal Year: 2023, Volume and Issue: 15(10), P. 2009 - 2009

Published: Sept. 27, 2023

A significant body of experimental structures SARS-CoV-2 spike trimers for the BA.1 and BA.2 variants revealed a considerable plasticity protein emergence druggable binding pockets. Understanding interplay conformational dynamics changes induced by Omicron identification cryptic dynamic pockets in S is paramount importance as exploring broad-spectrum antiviral agents to combat emerging imperative. In current study, we explore landscapes characterize universe multiple open closed functional states variants. By using combination atomistic simulations, network analysis, an allostery-guided screening ensembles conformations, identified all experimentally known allosteric sites discovered variant-specific differences distribution trimers. This study provided structural characterization predicted captured sites, revealing critical role modulating cross-talk between sites. We found that mutational variant can induce remodeling stabilization pocket N-terminal domain, while this drastically altered may no longer be available ligand variant. Our results site receptor-binding domain remains stable ranks most favorable but could become fragmented less probable conformations. also uncovered several formed at inter-domain inter-protomer interface, including regions S2 subunit stem helix region, which are consistent with residues transitions antibody recognition. The particularly understanding features proteins, well effects Omicron-variant-specific modulation preferential exploration present new previously underappreciated opportunity therapeutic interventions through conformation-selective targeting involved changes.

Language: Английский

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Protein Ensemble Generation through Variational Autoencoder Latent Space Sampling

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 1, 2023

Abstract Mapping the ensemble of protein conformations that contribute to function and can be targeted by small molecule drugs remains an outstanding challenge. Here we explore use soft-introspective variational autoencoders for reducing challenge dimensionality in structure generation problem. We convert high-dimensional structural data into a continuous, low-dimensional representation, carry out search this space guided quality metric, then RoseTTAFold generate 3D structures. approach ensembles cancer relevant K-Ras, training VAE on subset available K-Ras crystal structures MD simulation snapshots, assessing extent sampling close withheld from training. find our latent procedure rapidly generates with high is able sample within 1 angstrom held structures, consistency higher than or AlphaFold2 prediction. The sampled sufficiently recapitulate cryptic pockets held-out allow docking.

Language: Английский

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AlphaFold for a medicinal chemist: tool or toy?

Russian Chemical Reviews, Journal Year: 2024, Volume and Issue: 93(3), P. RCR5107 - RCR5107

Published: Jan. 16, 2024

The development of novel small drug molecules is a complex and important cross-disciplinary task. In the early stages development, chemoinformatics bioinformatics methods are routinely used to reduce cost finding lead compound. Among tools medicinal chemistry, docking molecular dynamics occupy special place. These predict possible mechanism binding potential ligand protein target. However, in order perform study, it necessary know spatial structure under investigation. Although databases crystallographic structures available, three-dimensional representations many have not been reported. There therefore need model such conformations. Several computer algorithms published solve this problem. AlphaFold considered by scientific community be most effective approach predicting proteins. scope its application especially for virtual screening, remains unclear. This review describes provides representative examples use design rational selection ligands. Special attention given publications presenting results experimental validation approach. On basis performed analysis, main problems field ways them formulated.<br> bibliography includes 154 references.

Language: Английский

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