CrystEngComm, Journal Year: 2023, Volume and Issue: 25(47), P. 6549 - 6555
Published: Jan. 1, 2023
Harmonious quaternary interactions consisting of G*–Ag and CH + –NO 3 − base pairs are disclosed in a mixed hydrogel system.
Language: Английский
Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(22)
Published: March 26, 2024
Ribonucleic acids (RNAs) play a vital role in living organisms. Many of their cellular functions depend critically on chemical modification. Methods to modify RNA controlled manner-both vitro and vivo-are thus essential evaluate understand biology at the molecular mechanistic levels. The diversity modifications, combined with size uniformity (made up only 4 nucleotides) makes its site-specific modification challenging task that needs be addressed by complementary approaches. One such approach is solid-phase synthesis. We discuss recent developments this field, starting new protection concepts ongoing effort overcome current limitations. continue selected modifications have posed significant challenges for incorporation into RNA. These include deazapurine bases required atomic mutagenesis elucidate aspects catalytic RNAs, containing xanthosine, N
Language: Английский
Citations
9
Nature Chemical Biology, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 8, 2025
Abstract Ribozymes that catalyze site-specific RNA modification have recently gained increasing interest for their ability to mimic methyltransferase enzymes and application install molecular tags. Recently, we reported SAMURI as a alkyltransferase ribozyme using S -adenosylmethionine (SAM) or stabilized analog transfer methyl propargyl group N 3 of an adenosine. Here, report the crystal structures in postcatalytic state. The reveal three-helix junction with catalytic core folded into four stacked layers, harboring cofactor modified nucleotide. Detailed structure–activity analyses explain scope structural basis site selectivity. A comparison SAM riboswitches sheds light on how synthetic overcomes strategies natural avoid self-methylation. Our results suggest its analogs may serve substrates various RNA-catalyzed reactions, which corresponding ribozymes remain be identified.
Language: Английский
Citations
1
Trends in Biochemical Sciences, Journal Year: 2025, Volume and Issue: unknown
Published: March 1, 2025
Language: Английский
Citations
1
Nature Chemistry, Journal Year: 2023, Volume and Issue: 15(11), P. 1523 - 1531
Published: Sept. 4, 2023
Post-transcriptional RNA modification methods are in high demand for site-specific labelling and analysis of functions. In vitro-selected ribozymes attractive tools research have the potential to overcome some limitations chemoenzymatic approaches with repurposed methyltransferases. Here we report an alkyltransferase ribozyme that uses a synthetic, stabilized S-adenosylmethionine (SAM) analogue catalyses transfer propargyl group specific adenosine target RNA. Almost quantitative conversion was achieved within 1 h under wide range reaction conditions vitro, including physiological magnesium ion concentrations. A genetically encoded version SAM analogue-utilizing (SAMURI) expressed HEK293T cells, intracellular propargylation confirmed by fluorescent labelling. SAMURI is general tool installation smallest tag azide-alkyne click chemistry, which can be further functionalized fluorophores, affinity tags or other functional probes.
Language: Английский
Citations
22
Molecules, Journal Year: 2023, Volume and Issue: 28(14), P. 5532 - 5532
Published: July 20, 2023
Ribonucleic acid (RNA) molecules play vital roles in numerous important biological functions such as catalysis and gene regulation. The of RNAs are strongly coupled to their structures or proper structure changes, RNA prediction has been paid much attention the last two decades. Some computational models have developed predict three-dimensional (3D) silico, these generally composed predicting 3D ensemble, evaluating near-native from refining identified RNAs. In this review, we will make a comprehensive overview recent advances modeling, including ensemble prediction, evaluation, refinement. Finally, emphasize some insights perspectives modeling structures.
Language: Английский
Citations
19
Fundamental Research, Journal Year: 2023, Volume and Issue: 3(5), P. 727 - 737
Published: June 12, 2023
RNA molecules serve a wide range of functions that are closely linked to their structures. The basic structural units consist single- and double-stranded regions. In order carry out advanced such as catalysis ligand binding, certain types RNAs can adopt higher-order analysis structures has progressed alongside advancements in biology techniques, but it comes with its own set challenges corresponding solutions. this review, we will discuss recent advances structure including probing methods, X-ray crystallography, nuclear magnetic resonance, cryo-electron microscopy, small-angle scattering. Often, combination multiple techniques is employed for the integrated We also survey important have been recently determined using various techniques.
Language: Английский
Citations
18
The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(26), P. 6257 - 6271
Published: June 21, 2024
We present software infrastructure for the design and testing of new quantum mechanical/molecular mechanical machine-learning potential (QM/MM-ΔMLP) force fields a wide range applications. The integrates Amber's molecular dynamics simulation capabilities with fast, approximate models in xtb package corrections DeePMD-kit. implements recently developed density-functional tight-binding QM multipolar electrostatics density-dependent dispersion (GFN2-xTB), interface Amber enables their use periodic boundary QM/MM simulations linear-scaling particle-mesh Ewald electrostatics. accuracy semiempirical is enhanced by including correction potentials (ΔMLPs) enabled through an DeePMD-kit software. goal this paper to validate implementation free energy simulations. utility demonstrated proof-of-concept example elements presented here are open source freely available. Their provides powerful enabling technology QM/MM-ΔMLP studying problems, biomolecular reactivity protein-ligand binding.
Language: Английский
Citations
8
Journal of Chemical Theory and Computation, Journal Year: 2024, Volume and Issue: 20(5), P. 2058 - 2073
Published: Feb. 17, 2024
We present a surface-accelerated string method (SASM) to efficiently optimize low-dimensional reaction pathways from the sampling performed with expensive quantum mechanical/molecular mechanical (QM/MM) Hamiltonians. The SASM accelerates convergence of path using aggregate obtained current and previous iterations, whereas approaches like in collective variables (SMCV) or modified (MSMCV) update only iteration. Furthermore, decouples number images used perform synthetic represent path. is optimized on best estimate free energy surface all available sampling, proposed set new simulations not restricted being located along Instead, umbrella potential placement chosen extend range improve quality estimates near In this manner, shown exploration for minimum pathway regions where relatively flat. it improves profile when discretized too few images. compare SASM, SMCV, MSMCV 3 QM/MM applications: ribozyme methyltransferase 2 coordinates, 2′-O-transphosphorylation Hammerhead tautomeric B-DNA 5 coordinates. show that converges paths roughly times less than SMCV methods. All three algorithms have been implemented FE-ToolKit package made freely available.
Language: Английский
Citations
6
Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 51(9), P. 4508 - 4518
Published: April 18, 2023
Abstract A methyltransferase ribozyme (MTR1) was selected in vitro to catalyze alkyl transfer from exogenous O6-methylguanine (O6mG) a target adenine N1, and recently, high-resolution crystal structures have become available. We use combination of classical molecular dynamics, ab initio quantum mechanical/molecular mechanical (QM/MM) alchemical free energy (AFE) simulations elucidate the atomic-level solution mechanism MTR1. Simulations identify an active reactant state involving protonation C10 that hydrogen bonds with O6mG:N1. The deduced involves stepwise two transition states corresponding proton C10:N3 O6mG:N1 rate-controlling methyl (19.4 kcal·mol−1 barrier). AFE predict pKa for be 6.3, close experimental apparent 6.2, further implicating it as critical general acid. intrinsic rate derived QM/MM simulations, together calculations, enables us activity–pH profile agrees well experiment. insights gained provide support putative RNA world establish new design principles RNA-based biochemical tools.
Language: Английский
Citations
12
Cell Proliferation, Journal Year: 2024, Volume and Issue: 57(9)
Published: June 28, 2024
High-throughput sequencing has sparked increased research interest in RNA modifications, particularly tRNA methylation, and its connection to various diseases. However, the precise mechanisms underpinning development of these diseases remain largely elusive. This review sheds light on roles several methylations (m1A, m3C, m5C, m1G, m2G, m7G, m5U, Nm) diverse biological functions, including metabolic processing, stability, protein interactions, mitochondrial activities. It further outlines linked aberrant related enzymes, potential underlying mechanisms. Moreover, disruptions regulation abnormalities tRNA-derived small RNAs (tsRNAs) contribute disease pathogenesis, highlighting their as biomarkers for diagnosis. The also delves into exploration drugs targeting methylation emphasizing therapeutic prospects modulating processes. Continued is imperative a comprehensive comprehension integration molecular diagnosis treatment.
Language: Английский
Citations
4