A high-throughput and rapid computational method for screening of RNA post-transcriptional modifications that can be recognized by target proteins

Gonzalez-Rivera, Juan C.; Wilson, Mark R.; Bhikha, P. Reena; Wang, Daiqi; Contreras, Lydia M.; Orr, Asuka A.

doi:10.1016/j.ymeth.2018.01.015

Cited by 8 publications

(7 citation statements)

References 122 publications

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“…As powerful end-point binding free energy calculation tools, MM/PBSA and MM/GBSA have also been widely used in many other fields besides small-molecule drug design. For example, a very useful application of MM/PB(GB)SA is to predict the interactions between macromolecules, such as protein–protein, ,,,− protein–peptide, ,,− and protein–nucleic acid interactions. ,,− At present, calculations of the absolute binding free energies for these problems remain very challenging for alchemical methods.…”

Section: Applications In Macromolecular Interactionsmentioning

confidence: 99%

“…Partly because the existing scoring functions for protein–RNA interactions (PRIs) are unreliable, accurately predicting the 3D structures and binding affinities for PRIs is still quite difficult. To solve this problem, the MM/PB(GB)SA approaches have also been employed in studying the PRIs. ,, For instance, Orr et al presented a computational tool to accurately characterize the interactions between proteins and RNA with post-transcriptional modifications, in which they used MM/GBSA to predict whether an RNA modification is favorable for binding with the target protein, and the predictions showed a very high correlation with the experimental data ( r 2 > 0.9). Moreover, we systemically investigated the performance of MM/PBSA and MM/GBSA to predict the binding affinities and identify the near-native binding structures for 148 protein–RNA systems with different solvent models and solute dielectric constants .…”

Section: Applications In Macromolecular Interactionsmentioning

confidence: 99%

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End-Point Binding Free Energy Calculation with MM/PBSA and MM/GBSA: Strategies and Applications in Drug Design

et al. 2019

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Molecular mechanics Poisson−Boltzmann surface area (MM/PBSA) and molecular mechanics generalized Born surface area (MM/GBSA) are arguably very popular methods for binding free energy prediction since they are more accurate than most scoring functions of molecular docking and less computationally demanding than alchemical free energy methods. MM/PBSA and MM/GBSA have been widely used in biomolecular studies such as protein folding, protein−ligand binding, protein−protein interaction, etc. In this review, methods to adjust the polar solvation energy and to improve the performance of MM/PBSA and MM/GBSA calculations are reviewed and discussed. The latest applications of MM/GBSA and MM/PBSA in drug design are also presented. This review intends to provide readers with guidance for practically applying MM/PBSA and MM/GBSA in drug design and related research fields. CONTENTS 1. Introduction 9478 2. Methodology 9480 3. Assessing the Performance of MM/PBSA and MM/GBSA 9484 4. The Polar Solvation Energy and Entropy Terms in MM/PB(GB)SA Calculations 9485 4.1. The Polar Solvation Energy Term in MM/ PBSA 9485 4.2. The Polar Energy Solvation Term in MM/ GBSA 9486 4.3. Theory, Implementation, and Limitations of the Variable Dielectric Model in MM/GBSA 9487 4.4. Comparison between PB and GB 9488 4.5. Efficient Entropy Calculation Methods To Estimate the Entropy Change upon Ligand Binding 9488 5.

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Section: Applications In Macromolecular Interactionsmentioning

confidence: 99%

Section: Applications In Macromolecular Interactionsmentioning

confidence: 99%

End-Point Binding Free Energy Calculation with MM/PBSA and MM/GBSA: Strategies and Applications in Drug Design

et al. 2019

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“…To refine the initial structure and to allow the COUP-TFII binding pocket to potentially expand, and thus facilitate the initial, independent placement of the two compounds, we introduced a short 10 ns constrained explicit-solvent molecular dynamics (MD) simulation in which binding pocket residues (207–223, 245–300, 370–396) and the modeled loop residues (194–206, 269–285) were unconstrained and the remaining residues were lightly constrained with 1.0 kcal/mol on heavy backbone atoms and 0.5 kcal/mol on heavy side chain atoms. The MD simulation was performed in a 109 Å cubic water box with the N- and C-terminal ends of the modeled protein acetylated and amidated to eliminate artificially placed positive and negative charges at the backbone termini analogously to References [41,42,43,44,45,46,47].…”

Section: Methodsmentioning

confidence: 99%

Activation of COUP-TFI by a Novel Diindolylmethane Derivative

Yoon

Chen

Orr

et al. 2019

Cells

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Chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) is an orphan receptor and member of the nuclear receptor superfamily. Among a series of methylene substituted diindolylmethanes (C-DIMs) containing substituted phenyl and heteroaromatic groups, we identified 1,1-bis(3′-indolyl)-1-(4-pyridyl)-methane (DIM-C-Pyr-4) as an activator of COUP-TFI. Structure activity studies with structurally diverse heteroaromatic C-DIMs showed that the pyridyl substituted compound was active and the 4-pyridyl substituent was more potent than the 2- or 3-pyridyl analogs in transactivation assays in breast cancer cells. The DIM-C-Pyr-4 activated chimeric GAL4-COUP-TFI constructs containing full length, C- or N-terminal deletions, and transactivation was inhibited by phosphatidylinositol-3-kinase and protein kinase A inhibitors. However, DIM-C-Pyr-4 also induced transactivation and interactions of COUP-TFI and steroid receptor coactivators-1 and -2 in mammalian two-hybrid assays, and ligand-induced interactions of the C-terminal region of COUP-TFI were not affected by kinase inhibitors. We also showed that DIM-C-Pyr-4 activated COUP-TFI-dependent early growth response 1 (Egr-1) expression and this response primarily involved COUP-TFI interactions with Sp3 and to a lesser extent Sp1 bound to the proximal region of the Egr-1 promoter. Modeling studies showed interactions of DIM-C-Pyr-4 within the ligand binding domain of COUP-TFI. This report is the first to identify a COUP-TFI agonist and demonstrate activation of COUP-TFI-dependent Egr-1 expression.

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“…Simulations have been widely employed to study protein-RNA interactions [122] , [123] ; advances in the development of force fields of RNA modifications [124] , [125] , and in the ability to parametrize chemical groups [126] , [127] have laid the foundation for the computational study of the interface between proteins and the epitranscriptome using MD simulations. One such application of these advancements can be found in a high-throughput computational platform for screening protein targets for modified RNA recognition [128] . This protocol employed trees of chemical modifications to the four canonical nucleosides, with the complexity of the chemical modifications increasing along the branch points.…”

Section: Computational Advancements Accelerating the Study Of Epitran...mentioning

confidence: 99%

Characterization of epitranscriptome reader proteins experimentally and in silico: Current knowledge and future perspectives beyond the YTH domain

Miller,

Demny,

Tamamis

et al. 2023

Computational and Structural Biotechnology Journal

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A high-throughput and rapid computational method for screening of RNA post-transcriptional modifications that can be recognized by target proteins

Cited by 8 publications

References 122 publications

End-Point Binding Free Energy Calculation with MM/PBSA and MM/GBSA: Strategies and Applications in Drug Design

End-Point Binding Free Energy Calculation with MM/PBSA and MM/GBSA: Strategies and Applications in Drug Design

Activation of COUP-TFI by a Novel Diindolylmethane Derivative

Characterization of epitranscriptome reader proteins experimentally and in silico: Current knowledge and future perspectives beyond the YTH domain

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