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A large-scale quantum chemical calculation program, Dcdftbmd, was integrated with a Python-based advanced atomistic simulation program, i-PI. The implementation of a client–server model enabled hierarchical parallelization with respect to replicas and force evaluations. The established framework demonstrated that quantum path integral molecular dynamics simulations can be executed with high efficiency for systems consisting of a few tens of replicas and containing thousands of atoms. The application of the framework to bulk water systems, with and without an excess proton, demonstrated that nuclear quantum effects are significant for intra- and inter-molecular structural properties, including oxygen–hydrogen bond distance and radial distribution function around the hydrated excess proton.

In eukaryotes, three RNA polymerases (RNAPs) play essential roles in the synthesis of various types of RNA: namely, RNAPI for rRNA; RNAPII for mRNA and most snRNAs; and RNAPIII for tRNA and other small RNAs. All three RNAPs possess a short flexible tail derived from their common subunit RPB6. However, the function of this shared N-terminal tail (NTT) is not clear. Here we show that NTT interacts with the PH domain (PH-D) of the p62 subunit of the general transcription/repair factor TFIIH, and present the structures of RPB6 unbound and bound to PH-D by nuclear magnetic resonance (NMR). Using available cryo-EM structures, we modelled the activated elongation complex of RNAPII bound to TFIIH. We also provide evidence that the recruitment of TFIIH to transcription sites through the p62–RPB6 interaction is a common mechanism for transcription-coupled nucleotide excision repair (TC-NER) of RNAPI- and RNAPII-transcribed genes. Moreover, point mutations in the RPB6 NTT cause a significant reduction in transcription of RNAPI-, RNAPII- and RNAPIII-transcribed genes. These and other results show that the p62–RPB6 interaction plays multiple roles in transcription, TC-NER, and cell proliferation, suggesting that TFIIH is engaged in all RNAP systems.

Bacteriorhodopsin (BR) transports a proton from intracellular to extracellular (EC) sites through five proton transfers. The second proton transfer is the release of an excess proton stored in BR into the EC medium, and an atomistic understanding of this whole process has remained unexplored due to its ubiquitous environment. Here, fully quantum mechanical (QM) molecular dynamics (MD) and metadynamics (MTD) simulations for this process were performed at the divide-and-conquer density-functional tight-binding level using realistic models (∼50000 and ∼20000 atoms) based on the time-resolved photointermediate structures from an X-ray free electron laser. Regarding the proton storage process, the QM-MD/MTD simulations confirmed the Glu-shared mechanism, in which an excess proton is stored between Glu194 and Glu204, and clarified that the activation occurs by localizing the proton at Glu204 in the photocycle. Furthermore, the QM-MD/MTD simulations elucidated a release pathway from Glu204 through Ser193 to the EC water molecules and clarified that the proton release starts at ∼250 μs. In the ubiquitous proton diffusion in the EC medium, the transient proton receptors predicted experimentally were assigned to carboxylates in Glu9 and Glu74. Large-scale QM-MD/MTD simulations beyond the conventional sizes, which provided the above findings and confirmations, were possible by adopting our Dcdftbmd program.

Polycomb repressive complex 1 (PRC1) and PRC2 are responsible for epigenetic gene regulation. PRC1 ubiquitinates histone H2A (H2Aub), which subsequently promotes PRC2 to introduce the H3 lysine 27 tri-methyl (H3K27me3) repressive chromatin mark. Although this mechanism provides a link between the two key transcriptional repressors, PRC1 and PRC2, it is unknown how histone-tail dynamics contribute to this process. Here, we have examined the effect of H2A ubiquitination and linker-DNA on H3-tail dynamics and H3K27 methylation by PRC2. In naïve nucleosomes, the H3-tail dynamically contacts linker DNA in addition to core DNA, and the linker-DNA is as important for H3K27 methylation as H2A ubiquitination. H2A ubiquitination alters contacts between the H3-tail and DNA to improve the methyltransferase activity of the PRC2-AEBP2-JARID2 complex. Collectively, our data support a model in which H2A ubiquitination by PRC1 synergizes with linker-DNA to hold H3 histone tails poised for their methylation by PRC2-AEBP2-JARID2.

Background/aim The significance of epidermal growth factor receptor (EGFR) mutation in untreated patients with non-small cell lung cancer (NSCLC) remains uncertain. We aimed to determine the significance of EGFR mutation in patients who received best supportive care (BSC) alone, and compare the outcomes of only EGFR- tyrosine kinase inhibitors (TKI)-treated vs. BSC patients. Patients and methods Between April 1991-August 2018, 1,197 patients diagnosed with unresectable NSCLC at our institutions were enrolled in the study. Results Among 226 patients who underwent EGFR mutation analysis and received BSC alone, 35 and 191 did and did not harbor the mutation, and the median survival times (MST) did not differ significantly between these groups. A comparison of only EGFR-TKI-treated and BSC patients with EGFR mutation revealed that the former had a three times longer MST than the latter. Conclusion Our results may help explain the benefit of EGFR-TKI for patients who would be directed towards BSC.

Ceria (CeO2) is a promising metal-oxide support that is used in three-way catalysis (TWC). The activity of ceria-supported TWC depends on the location and concentration of oxygen vacancies. Oxygen ...

Here, extensions to quantum chemical nanoreactor molecular dynamics simulations for discovering complex reactive events are presented. The species-selective algorithm, where the nanoreactor effectively works for the selected desired reactants, was introduced to the original scheme. Moreover, for efficient simulations of large model systems with the modified approach, the divide-and-conquer linear-scaling density functional tight-binding method was exploited. Two illustrative applications of the polymerization of propylene and cyclopropane mixtures and the aggregation of sodium chloride from aqueous solutions indicate that species-selective quantum chemical nanoreactor molecular dynamics is a promising method to accelerate the sampling of multicomponent chemical processes proceeding under relatively mild conditions.

TFIIH is a crucial transcription and DNA repair factor consisting of the seven-subunit core. The core subunit p62 contains a pleckstrin homology domain (PH-D), which is essential for locating TFIIH at transcription initiation and DNA damage sites, and two BSD (BTF2-like transcription factors, synapse-associated proteins and DOS2-like proteins) domains. A recent cryo-electron microscopy (cryo-EM) structure of human TFIIH visualized most parts of core, except for the PH-D. Here, by nuclear magnetic resonance spectroscopy we have established the solution structure of human p62 PH-D connected to the BSD1 domain by a highly flexible linker, suggesting the flexibility of PH-D in TFIIH. Based on this dynamic character, the PH-D was modeled in the cryo-EM structure to obtain the whole human TFIIH core structure, which indicates that the PH-D moves around the surface of core with a specific but limited spatial distribution; these dynamic structures were refined by molecular dynamics (MD) simulations. Furthermore, we built models, also refined by MD simulations, of TFIIH in complex with five p62-binding partners, including transcription factors TFIIEα, p53 and DP1, and nucleotide excision repair factors XPC and UVSSA. The models explain why the PH-D is crucially targeted by these factors, which use their intrinsically disordered acidic regions for TFIIH recruitment.

The standard treatment for locally advanced non‐small cell lung cancer (NSCLC) is chemoradiotherapy (CRT) followed by anti‐programmed cell death‐ligand 1 (anti‐PD‐L1) treatment. BIM deletion polymorphism induces the suppression of apoptosis resulting from epidermal growth factor (EGFR)‐tyrosine kinase inhibitors in EGFR‐mutated NSCLC patients. We aimed to examine the effects of BIM polymorphism on CRT and anti‐PD‐L1/PD‐1 treatment in NSCLC patients. In this retrospective study of 1312 patients with unresectable NSCLC treated at Higashi‐Hiroshima Medical Center and Hiroshima University Hospital between April 1994 and October 2019, we enrolled those who underwent CRT or chemotherapy using carboplatin + paclitaxel or cisplatin + vinorelbine, or anti‐PD‐L1/PD‐1 treatment. Of 1312 patients, 88, 80, and 74 underwent CRT, chemotherapy, and anti‐PD‐L1/PD‐1 treatment, respectively, and 17.0%, 15.2% and 17.6% of these patients showed BIM polymorphism. Among patients receiving CRT, the progression‐free survival was significantly shorter in those with BIM deletion than in those without. In the multivariate analyses, BIM polymorphism was an independent factor of poor anti‐tumor effects. These results were not observed in the chemotherapy and anti‐PD‐L1/PD‐1 treatment groups. In in vitro experiments, BIM expression suppression using small interfering RNA in NSCLC cell lines showed a significantly suppressed anti‐tumor effect and apoptosis after irradiation but not chemotherapy. In conclusion, we showed that BIM polymorphism was a poor‐predictive factor for anti‐tumor effects in NSCLC patients who underwent CRT, specifically radiotherapy. In the implementation of CRT in patients with BIM polymorphism, we should consider subsequent treatment, keeping in mind that CRT may be insufficient., We showed that progression‐free survival and overall survival durations were significantly shorter in the CRT‐treated NSCLC patients with BIM polymorphism than in those without. Our findings indicate that BIM polymorphism is associated with the efficacy of radiotherapy but not chemotherapy in patients with CRT.

Bacteriorhodopsin (BR) is a model protein for light-driven proton pumps, where the vectorial active proton transport results in light-energy conversion. To clarify the microscopic mechanism of primary proton transfer from retinal Schiff base (SB) to Asp85 in BR, herein, we performed quantum-mechanical metadynamics simulations with the isolated BR model (∼3750 atoms). The simulations showed a novel proton transfer mechanism, viz. the hydroxide ion mechanism, in which the deprotonation of specific internal water (Wat452) yields the protonation of Asp85 via Thr89, after which the resulting hydroxide ion accepts the remaining proton from retinal SB. Systematic investigations adopting four sequential snapshots obtained by the time-resolved serial femtosecond crystallography revealed that proton transfer took 2-5.25 μs on the photocycle. The presence of Wat401, which is the main difference between snapshots at 2 and 5.25 μs, is found to be essential in assisting the primary proton transfer. Furthermore, the hydroxide ion mechanism was confirmed by the minimum energy path for the primary proton transfer in BR obtained by the nudged elastic band calculations with the embedded BR model (10,119 atoms), in which BR was embedded within lipid membranes in between water solvents.

Massively parallel divide-and-conquer density functional tight-binding (DC-DFTB) molecular dynamics and metadynamics simulations are efficient approaches for describing various chemical reactions and dynamic processes of large complex systems via quantum mechanics. In this study, DC-DFTB simulations were combined with multi-replica techniques. Specifically, multiple walkers metadynamics, replica exchange molecular dynamics, and parallel tempering metadynamics methods were implemented hierarchically into the in-house Dcdftbmd program. Test simulations in an aqueous phase of the internal rotation of formamide and conformational changes of dialanine showed that the newly developed extensions increase the sampling efficiency and the exploration capabilities in DC-DFTB configuration space.

In this study, divide-and-conquer (DC) based density-functional tight-binding (DFTB) and time-dependent density-functional tight-binding (TD-DFTB) methods were developed using long-range correction (LC), which resolved the underestimation of energy gaps between the highest occupied molecular orbital and lowest unoccupied molecular orbital. We implemented the LC term by the entrywise product for the effective utilization of the math kernel library. Test calculations of formaldehyde in explicit water molecules demonstrate the efficiency of the developed method. Furthermore, the DC-TD-LCDFTB method was applied to 2,2'-bipyridine-3,3'-diol (BP(OH)

Water confined within one-dimensional (1D) hydrophobic nanochannels has attracted significant interest due to its unusual structure and dynamic properties. As a representative system, water-filled carbon nanotubes (CNTs) are generally studied, but direct observation of the crystal structure and proton transport is difficult for CNTs due to their poor crystallinity and high electron conduction. Here, we report the direct observation of a unique water-cluster structure and high proton conduction realized in a metal-organic nanotube, [Pt(dach)(bpy)Br]4(SO4)4·32H2O (dach: (1R, 2R)-(–)-1, 2-diaminocyclohexane; bpy: 4, 4’-bipyridine). In the crystalline state, a hydrogen-bonded ice nanotube composed of water tetramers and octamers is found within the hydrophobic nanochannel. Single-crystal impedance measurements along the channel direction reveal a high proton conduction of 10−2 Scm−1. Moreover, fast proton diffusion and continuous liquid-to-solid transition are confirmed using solid-state 1H-NMR measurements. Our study provides valuable insight into the structural and dynamical properties of confined water within 1D hydrophobic nanochannels., ナノサイズの空間に閉じ込められた水が示す不思議な性質を実証 --高速で水素イオンを運ぶ水の状態を解明--. 京都大学プレスリリース. 2020-02-18.

The structural unit of eukaryotic chromatin is a nucleosome, comprising two histone H2A/H2B heterodimers and one histone (H3/H4)

Dcdftbmd developed in our group was an efficient quantum chemical calculation code based on the divide-and-conquer density functional tight-binding (DC-DFTB) method. The bottleneck for its applicat...

The structural unit of eukaryotic chromatin is a nucleosome, comprising two histone H2A-H2B heterodimers and one histone (H3-H4) 2 tetramer, wrapped around by ∼146 bp of DNA. The N-terminal flexible histone tails stick out from the histone core and have extensive posttranslational modifications, causing epigenetic changes of chromatin. Although crystal and cryogenic electron microscopy structures of nucleosomes are available, the flexible tail structures remain elusive. Using NMR, we have examined the dynamics of histone H3 tails in nucleosomes containing unmodified and tetra-acetylated H4 tails. In unmodified nucleosome, the H3 tail adopts a dynamic equilibrium structure between DNA-contact and reduced-contact states. In acetylated H4 nucleosome, however, the H3 tail equilibrium shifts to a mainly DNA-contact state with a minor reduced-contact state. The acetylated H4 tail is dynamically released from its own DNA-contact state to a reduced-contact state, while the H3 tail DNA-contact state becomes major. Notably, H3 K14 in the acetylated H4 nucleosome is much more accessible to acetyltransferase Gcn5 relative to unmodified nucleosome, possibly due to the formation of a favorable H3 tail conformation for Gcn5. In summary, each histone tail adopts a characteristic dynamic state but regulates one other, probably creating a histone tail network even on a nucleosome.

Facilitates chromatin transcription (FACT) is a histone chaperone, which accomplishes both nucleosome assembly and disassembly. Our combined cryo-electron microscopy (EM) and native mass spectrometry (MS) studies revealed novel key steps of nucleosome reorganization conducted by a Mid domain and its adjacent acidic AID segment of human FACT. We determined three cryo-EM structures of respective octasomes complexed with the Mid-AID and AID regions, and a hexasome alone. We discovered extensive contacts between a FACT region and histones H2A, H2B, and H3, suggesting that FACT is competent to direct functional replacement of a nucleosomal DNA end by its phosphorylated AID segment (pAID). Mutational assays revealed that the aromatic and phosphorylated residues within pAID are essential for octasome binding. The EM structure of the hexasome, generated by the addition of Mid-pAID or pAID, indicated that the dissociation of H2A-H2B dimer causes significant alteration from the canonical path of the nucleosomal DNA.

Dcdftbmd is a Fortran 90/95 program that enables efficient quantum mechanical molecular dynamics (MD) simulations using divide-and-conquer density functional tight-binding (DC-DFTB) method. Based on the remarkable performance of previous massively parallel DC-DFTB energy and gradient calculations for huge systems, the code has been specialized to MD simulations. Recent implementations and modifications including DFTB extensions, improved computational speed in the DC-DFTB computational steps, algorithms for efficient initial guess charge prediction, and free energy calculations via metadynamics technique have enhanced the capability to obtain atomistic insights in novel applications to nanomaterials and biomolecules. The energy, structure, and other molecular properties are also accessible through the single-point calculation, geometry optimization, and vibrational frequency analysis. The available functionalities are outlined together with efficiency tests and simulation examples. © 2019 Wiley Periodicals, Inc.

8528 Background: The standard treatment for locally advanced non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT) followed by treatment of durvalumab, one of immune checkpoint inhibitors (ICI). Interstitial lung disease (ILD) is a clinically life-threatening toxicity of CRT or durvalumab. The patient-characteristics or dose-volume histogram parameters of radiotherapy have been reported to be the risk factors for radiation-induced pneumonitis. However, the risk factors for ILD during durvalumab therapy has not been established. Interstitial lung abnormalities (ILA) are generated by aging or smoking, and manifest as minor interstitial shadow on lung computed tomography (CT). We previously reported that ILA were risk factors for ICI-induced ILD in patients with advanced NSCLC, as well as non-lung cancer. Therefore, we investigated whether ILA could be risk factors for ILD during the durvalumab therapy. Methods: We retrospectively enrolled NSCLC patients who received durvalumab after CRT at 10 institutions from July 2018 to June 2021. Patient-information, patient-characteristics, dose-volume histogram parameters, chest CT findings, and laboratory data, were obtained. CT findings were examined using CT obtained after CRT and prior to durvalumab therapy. Results: A total of 153 patients were enrolled, and the prevalence of ILA was 37.8% (56 patients) before durvalumab treatment. Among the enrolled patients, 94 (63.5%) developed ILD during durvalumab therapy. The proportion of patients with grade 1, grade 2, or grade 3 ILD was observed to be 29.7% (44 patients), 25.7% (38 patients), and 8% (12 patients), respectively. Univariate logistic regression analysis revealed that higher age, higher dose volume histogram parameters (V5, V20, mean lung dose), and the presence of ILA were significant risk factors for grade 2 or more ILD. Multivariate logistic regression analysis showed that ILA, especially ground grass attenuation in ILA, was an independent risk factor for grade 2 or more ILD (odds ratio: 7.02, 95% CI: 2.95-16.69, p < 0.0001). Conclusions: Pre-existing ILA are risk factors for ILD during durvalumab treatment after CRT. This observation is consistent with previously reported findings in patients with advanced lung cancer and non-lung cancer. Therefore, we should pay more attention to the development of grade 2 or more ILD during durvalumab treatment in patients with ILA.

The density-functional tight-binding (DFTB) method is one of the useful quantum chemical methods, which provides a good balance between accuracy and computational efficiency. In this account, we reviewed the basis of the DFTB method, the linear-scaling divide-and-conquer (DC) technique, as well as the parameterization process. We also provide some refinement, modifications, and extension of the existing parameters that can be applicable for lithium-ion battery systems. The diffusion constants of common electrolyte molecules and LiTFSA salt in solution have been estimated using DC-DFTB molecular dynamics simulation with our new parameters. The resulting diffusion constants have good agreement to the experimental diffusion constants.

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) receptors play a central role in neurotransmission and neuronal function. A positron emission tomography (PET) tracer for AMPA receptors, [Derivatives of K-2 labeled withSome of the synthesized

The significance of epidermal growth factor receptor (EGFR) mutation in untreated patients with non-small cell lung cancer (NSCLC) remains uncertain. We aimed to determine the significance of EGFR mutation in patients who received best supportive care (BSC) alone, and compare the outcomes of only EGFR- tyrosine kinase inhibitors (TKI)-treated vs. BSC patients.Between April 1991-August 2018, 1,197 patients diagnosed with unresectable NSCLC at our institutions were enrolled in the study.Among 226 patients who underwent EGFR mutation analysis and received BSC alone, 35 and 191 did and did not harbor the mutation, and the median survival times (MST) did not differ significantly between these groups. A comparison of only EGFR-TKI-treated and BSC patients with EGFR mutation revealed that the former had a three times longer MST than the latter.Our results may help explain the benefit of EGFR-TKI for patients who would be directed towards BSC.

Density-functional tight-binding (DFTB) parameters are presented for the simulation of the bulk phases of zirconium. Electronic parameters were obtained using a band structure fitting strategy, while two-center repulsive potentials were created by particle swarm optimization. As objective functions for the repulsive potential fitting, we employed the Birch-Murnaghan equations of state for hexagonal close-packed (HCP), body-centered cubic (BCC) and ω phases of Zr from density-functional theory (DFT). When fractional atomic coordinates are not allowed to change in the generation of the equation-of-state curves, long-range repulsive DFTB potentials are able to almost perfectly reproduce equilibrium structures, relative DFT energies of the bulk phases, and bulk moduli. However, the same potentials lead to artifacts in the DFTB potential energy surfaces when atom positions in the unit cell are allowed to fully relax during the change of unit cell parameters. Conventional short-range repulsive DFTB potentials, while inferior in their ability to reproduce DFT bulk energetics, are able to correctly reproduce the qualitative shape of the DFT potential energy surfaces, including the location of global minima, and can therefore be considered more transferable.

The nucleosome comprises two histone dimers of H2A-H2B and one histone tetramer of (H3-H4), wrapped around by ~145bp of DNA. Detailed core structures of nucleosomes have been established by X-ray and cryo-EM, however, histone tails have not been visualized. Here, we have examined the dynamic structures of the H2A and H2B tails in 145-bp and 193-bp nucleosomes using NMR, and have compared them with those of the H2A and H2B tail peptides unbound and bound to DNA. Whereas the H2A C-tail adopts a single but different conformation in both nucleosomes, the N-tails of H2A and H2B adopt two distinct conformations in each nucleosome. To clarify these conformations, we conducted molecular dynamics (MD) simulations, which suggest that the H2A N-tail can locate stably in either the major or minor grooves of nucleosomal DNA. While the H2B N-tail, which sticks out between two DNA gyres in the nucleosome, was considered to adopt two different orientations, one toward the entry/exit side and one on the opposite side. Then, the H2A N-tail minor groove conformation was obtained in the H2B opposite side and the H2B N-tail interacts with DNA similarly in both sides, though more varied conformations are obtained in the entry/exit side. Collectively, the NMR findings and MD simulations suggest that the minor groove conformer of the H2A N-tail is likely to contact DNA more strongly than the major groove conformer, and the H2A N-tail reduces contact with DNA in the major groove when the H2B N-tail is located in the entry/exit side.

A preceding experiment suggested that a compound, which inhibits binding of the REST/NRSF segment to the cleft of a receptor protein mSin3B, can be a potential drug candidate to ameliorate many neuropathies. We have recently developed an enhanced conformational sampling method, genetic-algorithm-guided multi-dimensional virtual-system-coupled canonical molecular dynamics, and in the present study, applied it to three systems consisting of mSin3B and one of three compounds, sertraline, YN3, and acitretin. Other preceding experiments showed that only sertraline inhibits the binding of REST/NRSF to mSin3B. The current simulation study produced the spatial distribution of the compounds around mSin3B, and showed that sertraline and YN3 bound to the cleft of mSin3B with a high propensity, although acitretin did not. Further analyses of the simulation data indicated that only the sertraline–mSin3B complex produced a hydrophobic core similar to that observed in the molecular interface of the REST/NRSF–mSin3B complex: An aromatic ring of sertraline sunk deeply in the mSin3B’s cleft forming a hydrophobic core contacting to hydrophobic amino-acid residues located at the bottom of the cleft. The present study proposes a step to design a compound that inhibits competitively the binding of a ligand to its receptor.