The optimal particle-mesh interpolation basis

Wang, Han; Fang, Jun; Gao, Xingyu

doi:10.1063/1.4994857

Cited by 5 publications

(4 citation statements)

References 26 publications

(44 reference statements)

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“…Equilibration was achieved using PMEMD to heat the systems to 310 K followed by independent MD simulations performed with a periodic boundary condition at a constant pressure of 1 atm with isotropic molecule-based scaling at a time step of 2.0 fs. All simulations used a dielectric constant of 1.0, Particle Mesh Ewald summation 56 to calculate long-range electrostatic interactions and bond-length constraints applied to all bonds to H atoms. Trajectories were saved at 20 ps intervals and visualized using VMD 57 .…”

Section: Methodsmentioning

confidence: 99%

Mechanism of biomolecular recognition of trimethyllysine by the fluorinated aromatic cage of KDM5A PHD3 finger

et al. 2020

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The understanding of biomolecular recognition of posttranslationally modified histone proteins is centrally important to the histone code hypothesis. Despite extensive binding and structural studies on the readout of histones, the molecular language by which posttranslational modifications on histone proteins are read remains poorly understood. Here we report physical-organic chemistry studies on the recognition of the positively charged trimethyllysine by the electron-rich aromatic cage containing PHD3 finger of KDM5A. The aromatic character of two tryptophan residues that solely constitute the aromatic cage of KDM5A was fine-tuned by the incorporation of fluorine substituents. Our thermodynamic analyses reveal that the wild-type and fluorinated KDM5A PHD3 fingers associate equally well with trimethyllysine. This work demonstrates that the biomolecular recognition of trimethyllysine by fluorinated aromatic cages is associated with weaker cation-π interactions that are compensated by the energetically more favourable trimethyllysine-mediated release of high-energy water molecules that occupy the aromatic cage.

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Section: Methodsmentioning

confidence: 99%

Mechanism of biomolecular recognition of trimethyllysine by the fluorinated aromatic cage of KDM5A PHD3 finger

et al. 2020

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“…Equilibration was achieved using PMEMD to heat the systems to 310 K followed by independent MD simulations performed with a periodic boundary condition at a constant pressure of 1 atm with isotropic molecule-based scaling at a time step of 2.0 fs. All simulations used a dielectric constant of 1.0, Particle Mesh Ewald summation 65 to calculate long-range electrostatic interactions and bond-length constraints applied to all bonds to H atoms. Trajectories were saved at 20 ps intervals and visualised using VMD 66 .…”

Section: Methodsmentioning

confidence: 99%

Reading and erasing of the phosphonium analogue of trimethyllysine by epigenetic proteins

et al. 2022

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Nε-Methylation of lysine residues in histones plays an essential role in the regulation of eukaryotic transcription. The ‘highest’ methylation mark, Nε-trimethyllysine, is specifically recognised by Nε-trimethyllysine binding ‘reader’ domains, and undergoes demethylation, as catalysed by 2-oxoglutarate dependent JmjC oxygenases. We report studies on the recognition of the closest positively charged Nε-trimethyllysine analogue, i.e. its trimethylphosphonium derivative (KPme3), by Nε-trimethyllysine histone binding proteins and Nε-trimethyllysine demethylases. Calorimetric and computational studies with histone binding proteins reveal that H3KP4me3 binds more tightly than the natural H3K4me3 substrate, though the relative differences in binding affinity vary. Studies with JmjC demethylases show that some, but not all, of them can accept the phosphonium analogue of their natural substrates and that the methylation state selectivity can be changed by substitution of nitrogen for phosphorus. The combined results reveal that very subtle changes, e.g. substitution of nitrogen for phosphorus, can substantially affect interactions between ligand and reader domains / demethylases, knowledge that we hope will inspire the development of highly selective small molecules modulating their activity.

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“…Trajectories were visualized using visual molecular dynamics (VMD 1.9.2., Champaign, IL, USA) [41]. Endstate free energies and electrostatic energies were calculated using MM-GBSA calculations [42].…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Comparison of Molecular Recognition of Trimethyllysine and Trimethylthialysine by Epigenetic Reader Proteins

et al. 2020

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Gaining a fundamental insight into the biomolecular recognition of posttranslationally modified histones by epigenetic reader proteins is of crucial importance to understanding the regulation of the activity of human genes. Here, we seek to establish whether trimethylthialysine, a simple trimethyllysine analogue generated through cysteine alkylation, is a good trimethyllysine mimic for studies on molecular recognition by reader proteins. Histone peptides bearing trimethylthialysine and trimethyllysine were examined for binding with five human reader proteins employing a combination of thermodynamic analyses, molecular dynamics simulations and quantum chemical analyses. Collectively, our experimental and computational findings reveal that trimethylthialysine and trimethyllysine exhibit very similar binding characteristics for the association with human reader proteins, thereby justifying the use of trimethylthialysine for studies aimed at dissecting the origin of biomolecular recognition in epigenetic processes that play important roles in human health and disease.The highest mark, trimethyllysine, is recognized by the aromatic cage-containing readers, including tandem tudor domains (TTD), chromodomains (CD) and the plant homeodomain (PHD) zinc finger proteins ( Figure 1B) [6]. To gain a better understanding of the exact role of lysine methylation in epigenetics, it is important to develop novel chemical tools for studying the molecular mechanisms that govern the molecular recognition of methylated lysines by reader proteins. An installation of chemically modified methylated lysine analogues into histone proteins [7] and histone peptides [8][9][10][11] has been a valuable method to study how changes in structure affect the association with reader proteins. In addition, a variety of methods have been developed to incorporate unnatural amino acids in both histone proteins and peptides, notably by auxotrophic expression systems [12] or employing the amber stop codon (TAG) [13]. Major drawbacks of both methods include severe limitations of amino acid variants that can be incorporated into histones. Furthermore, when using auxotrophic strains, the protein expression yield is decreased dramatically, and the process of developing an amber codon pair is time consuming and laborious [14,15].

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The optimal particle-mesh interpolation basis

Cited by 5 publications

References 26 publications

Mechanism of biomolecular recognition of trimethyllysine by the fluorinated aromatic cage of KDM5A PHD3 finger

Mechanism of biomolecular recognition of trimethyllysine by the fluorinated aromatic cage of KDM5A PHD3 finger

Reading and erasing of the phosphonium analogue of trimethyllysine by epigenetic proteins

Comparison of Molecular Recognition of Trimethyllysine and Trimethylthialysine by Epigenetic Reader Proteins

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