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DNA molecular dynamics

Christopher H Douse, Stuart Bloor, Yangci Liu, Maria Shamin, Iva A Tchasovnikarova, Richard T Timms, Paul J Lehner, Yorgo Modis
Missense mutations in MORC2 cause neuropathies including spinal muscular atrophy and Charcot-Marie-Tooth disease. We recently identified MORC2 as an effector of epigenetic silencing by the human silencing hub (HUSH). Here we report the biochemical and cellular activities of MORC2 variants, alongside crystal structures of wild-type and neuropathic forms of a human MORC2 fragment comprising the GHKL-type ATPase module and CW-type zinc finger. This fragment dimerizes upon binding ATP and contains a hinged, functionally critical coiled-coil insertion absent in other GHKL ATPases...
February 13, 2018: Nature Communications
Arnaud De Muyt, Alexandra Pyatnitskaya, Jessica Andréani, Lepakshi Ranjha, Claire Ramus, Raphaëlle Laureau, Ambra Fernandez-Vega, Daniel Holoch, Elodie Girard, Jérome Govin, Raphaël Margueron, Yohann Couté, Petr Cejka, Raphaël Guérois, Valérie Borde
Meiotic crossover formation requires the stabilization of early recombination intermediates by a set of proteins and occurs within the environment of the chromosome axis, a structure important for the regulation of meiotic recombination events. The molecular mechanisms underlying and connecting crossover recombination and axis localization are elusive. Here, we identified the ZZS (Zip2-Zip4-Spo16) complex, required for crossover formation, which carries two distinct activities: one provided by Zip4, which acts as hub through physical interactions with components of the chromosome axis and the crossover machinery, and the other carried by Zip2 and Spo16, which preferentially bind branched DNA molecules in vitro...
February 9, 2018: Genes & Development
María M Cameranesi, Jorgelina Morán-Barrio, Adriana S Limansky, Guillermo D Repizo, Alejandro M Viale
Members of the genus Acinetobacter possess distinct plasmid types which provide effective platforms for the acquisition, evolution, and dissemination of antimicrobial resistance structures. Many plasmid-borne resistance structures are bordered by short DNA sequences providing potential recognition sites for the host XerC and XerD site-specific tyrosine recombinases (XerC/D-like sites). However, whether these sites are active in recombination and how they assist the mobilization of associated resistance structures is still poorly understood...
2018: Frontiers in Microbiology
Bharati Pandey, Abhinav Grover, Pradeep Sharma
BACKGROUND: The WRKY transcription factors are a class of DNA-binding proteins involved in diverse plant processes play critical roles in response to abiotic and biotic stresses. Genome-wide divergence analysis of WRKY gene family in Hordeum vulgare provided a framework for molecular evolution and functional roles. So far, the crystal structure of WRKY from barley has not been resolved; moreover, knowledge of the three-dimensional structure of WRKY domain is pre-requisites for exploring the protein-DNA recognition mechanisms...
February 12, 2018: BMC Genomics
Achim Sandmann, Heinrich Sticht
Protein binding can induce DNA kinks, which are for example important to enhance the specificity of the interaction and to facilitate the assembly of multi protein complexes. The respective proteins frequently exhibit amino acid sidechains that intercalate between the DNA base steps at the site of the kink. However, on a molecular level there is only little information available about the role of individual sidechains for kink formation. To unravel structural principles of protein-induced DNA kinking we have performed molecular dynamics (MD) simulations of five complexes that varied in their architecture, function, and identity of intercalated residues...
2018: PloS One
Wei-Fei Chen, Stephane Rety, Hai-Lei Guo, Yang-Xue Dai, Wen-Qiang Wu, Na-Nv Liu, Daniel Auguin, Qian-Wen Liu, Xi-Miao Hou, Shuo-Xing Dou, Xu-Guang Xi
Helicase DHX36 plays essential roles in cell development and differentiation at least partially by resolving G-quadruplex (G4) structures. Here we report crystal structures of the Drosophila homolog of DHX36 (DmDHX36) in complex with RNA and a series of DNAs. By combining structural, small-angle X-ray scattering, molecular dynamics simulation, and single-molecule fluorescence studies, we revealed that positively charged amino acids in RecA2 and OB-like domains constitute an elaborate structural pocket at the nucleic acid entrance, in which negatively charged G4 DNA is tightly bound and partially destabilized...
January 29, 2018: Structure
Ilda D'Annessa, Anna Gandaglia, Elena Brivio, Gilda Stefanelli, Angelisa Frasca, Nicoletta Landsberger, Daniele Di Marino
Mutations in the X-linked MECP2 gene represent the main origin of Rett syndrome, causing a profound intellectual disability in females. MeCP2 is an epigenetic transcriptional regulator containing two main functional domains: a methyl-CpG binding domain (MBD) and a transcription repression domain (TRD). Over 600 pathogenic mutations were reported to affect the whole protein; almost half of missense mutations affect the MBD. Understanding the impact of these mutations on the MBD structure and interaction with DNA will foster the comprehension of their pathogenicity and possibly genotype/phenotype correlation studies...
February 8, 2018: Biochimica et Biophysica Acta
Reza Kazemi Oskuee, Maryam Dabbaghi, Leila Gholami, Sajedeh Taheri-Bojd, Mahdi Balali-Mood, Seyyed Hadi Mousavi, Bizhan Malaekeh-Nikouei
AIMS: Gene therapy is a promising strategy for the treatment of various diseases. Polyethylenimine (PEI) has received considerable attention for gene delivery applications due to their appropriate properties. However, their toxicity has raised concerns which cause to be used with cautious. This study aimed to prepare different complexes of PEI/DNA and evaluate their parameters affecting in vitro cytotoxicity. Also, apoptosis rate was measured to determine the mechanism of cell toxicity...
February 8, 2018: Life Sciences
Umesh Kalathiya, Monikaben Padariya, Maciej Baginski
The telomere repeat binding-factor 1 and 2 (TRF1 and TRF2) proteins of the shelterin complex bind to duplex telomeric DNA as homodimers, and the homodimerization is mediated by their TRFH (TRF-homology) domains. We performed molecular dynamic (MD) simulations of the dimer forms of TRF1TRFH and TRF2TRFH in the presence/absence of the TIN2TBM (TIN2, TRF-interacting nuclear protein 2, TBM, TRF-binding motif) peptide. The MD results suggest that TIN2TBM is necessary to ensure the stability of TRF1TRFH homodimer but not the TRF2TRFH homodimer...
February 8, 2018: Archives of Biochemistry and Biophysics
Clara Montagut, Guillem Argilés, Fortunato Ciardiello, Thomas T Poulsen, Rodrigo Dienstmann, Michael Kragh, Scott Kopetz, Trine Lindsted, Cliff Ding, Joana Vidal, Jenifer Clausell-Tormos, Giulia Siravegna, Francisco J Sánchez-Martín, Klaus Koefoed, Mikkel W Pedersen, Michael M Grandal, Mikhail Dvorkin, Lucjan Wyrwicz, Ana Rovira, Antonio Cubillo, Ramon Salazar, Françoise Desseigne, Cristina Nadal, Joan Albanell, Vittorina Zagonel, Salvatore Siena, Guglielmo Fumi, Giuseppe Rospo, Paul Nadler, Ivan D Horak, Alberto Bardelli, Josep Tabernero
Importance: Acquired resistance to anti-EGFR therapy (epidermal growth factor receptor) is frequently due to RAS and EGFR extracellular domain (ECD) mutations in metastatic colorectal cancer (mCRC). Some anti-EGFR-refractory patients retain tumor EGFR dependency potentially targetable by agents such as Sym004, which is a mixture of 2 nonoverlapping monoclonal antibodies targeting EGFR. Objective: To determine if continuous blockade of EGFR by Sym004 has survival benefit...
February 8, 2018: JAMA Oncology
Petros Kolovos, Rutger W W Brouwer, Christel E M Kockx, Michael Lesnussa, Nick Kepper, Jessica Zuin, A M Ali Imam, Harmen J G van de Werken, Kerstin S Wendt, Tobias A Knoch, Wilfred F J van IJcken, Frank Grosveld
Chromosome conformation capture (3C) and its derivatives (e.g., 4C, 5C and Hi-C) are used to analyze the 3D organization of genomes. We recently developed targeted chromatin capture (T2C), an inexpensive method for studying the 3D organization of genomes, interactomes and structural changes associated with gene regulation, the cell cycle, and cell survival and development. Here, we present the protocol for T2C based on capture, describing all experimental steps and bio-informatic tools in full detail. T2C offers high resolution, a large dynamic interaction frequency range and a high signal-to-noise ratio...
March 2018: Nature Protocols
Yue Yang, Xiu-Ping Zhao, Hua-Chun Zou, Min-Jie Chu, Ping Zhong, Xiao-Shan Li, Xiao-Yan Li, Yu-Hui Yu, Ke-Xin Zhu, Yu-Jia Chen, Fei Xia, Bo-Wen Zhu, Luan-Qi Ruan, Yi-Ning Bao, Xun Zhuang
The prevalence and incidence of human immunodeficiency virus type 1 (HIV-1) among men who have sex with men (MSM) are on the rise throughout China. With a large population of MSM, Jiangsu Province is facing an escalating HIV-1 epidemic.The aim of this study was to explore the phylogenetic and temporal dynamics of HIV-1 CRF01_AE and CRF07_BC among antiretroviral therapy (ART)-naïve MSM recently infected with HIV-1 in Jiangsu Province.We recruited MSM in Jiangsu Province (Suzhou, Wuxi, Nantong, Taizhou and Yancheng) 2012 to 2015...
February 2018: Medicine (Baltimore)
Mariano Provencio, María Torrente, Virginia Calvo, David Pérez-Callejo, Lourdes Gutiérrez, Fernando Franco, Clara Pérez-Barrios, Miguel Barquín, Ana Royuela, Francisco García-García, Coralia Bueno, Aranzazu Garcia-Grande, Carlos Camps, Bartomeu Massuti, Eduardo Sotomayor, Atocha Romero
Background: Circulating tumor DNA (ctDNA) levels correlate well with tumor bulk. In this paper we aim to estimate the prognostic value of the dynamic quantification of ctDNA levels. Materials and Methods: A total of 251 serial plasma samples from 41 non-small-cell lung cancer patients who carried an activating EGFR mutation were analysed by digital PCR. For survival analysis, ctDNA levels were computed as a time-dependent covariate. Results: Dynamic ctDNA measurements had prognostic significance (hazard ratio for overall survival and progression free survival according to p...
January 2, 2018: Oncotarget
Kristin N Parent, Jason R Schrad, Gino Cingolani
The majority of viruses on Earth form capsids built by multiple copies of one or more types of a coat protein arranged with 532 symmetry, generating an icosahedral shell. This highly repetitive structure is ideal to closely pack identical protein subunits and to enclose the nucleic acid genomes. However, the icosahedral capsid is not merely a passive cage but undergoes dynamic events to promote packaging, maturation and the transfer of the viral genome into the host. These essential processes are often mediated by proteinaceous complexes that interrupt the shell's icosahedral symmetry, providing a gateway through the capsid...
February 7, 2018: Viruses
R Lettieri, M D'Abramo, L Stella, A La Bella, F Leonelli, L Giansanti, M Venanzi, E Gatto
Thymidine phosphorylase (TP) is an enzyme that is up-regulated in a wide variety of solid tumors, including breast and colorectal cancers. It is involved in tumor growth and metastasis, for this reason it is one of the key enzyme to be inhibited, in an attempt to prevent tumor proliferation. However, it also plays an active role in cancer treatment, through its contribution in the conversion of the anti-cancer drug 5-fluorouracil (5-FU) to an irreversible inhibitor of thymidylate synthase (TS), responsible of the inhibition of the DNA synthesis...
January 16, 2018: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
S Amirhossein Tabatabaei-Dakhili, Rodrigo Aguayo-Ortiz, Laura Domínguez, Carlos A Velázquez-Martínez
The FOXM1 protein is a relevant transcription factor involved in cancer cell proliferation. The direct or indirect inhibition of this protein's transcriptional activity by small molecule drugs correlates well with a potentially significant anti-cancer profile, making this macro molecule a promising drug target. There are a few drug molecules reported to interact with (and inhibit) the FOXM1 DNA binding domain (FOXM1-BD), causing downregulation of protein expression and cancer cell proliferation inhibition. Among these drug molecules are the proteasome inhibitor thiostrepton, the former antidiabetic drug troglitazone, and the new FDI-6 molecule...
January 27, 2018: Journal of Molecular Graphics & Modelling
Ida Autiero, Menotti Ruvo, Roberto Improta, Luigi Vitagliano
BACKGROUND: Aptamers are RNA/DNA biomolecules representing an emerging class of protein interactors and regulators. Despite the growing interest in these molecules, current understanding of chemical-physical basis of their target recognition is limited. Recently, the characterization of the aptamer targeting the protein-S8 has suggested that flexibility plays important functional roles. We investigated the structural versatility of the S8-aptamer by molecular dynamics simulations. METHODS: Five different simulations have been conducted by varying starting structures and temperatures...
January 31, 2018: Biochimica et Biophysica Acta
P Sneha, D Thirumal Kumar, Jose Lijo, M Megha, R Siva, C George Priya Doss
Protein-protein interactions (PPIs) play vital roles in various cellular pathways. Most of the proteins perform their responsibilities by interacting with an enormous number of proteins. Understanding these interactions of the proteins and their interacting partners has shed light toward the field of drug discovery. Also, PPIs enable us to understand the functions of a protein by understanding their interacting partners. Consequently, in the current study, PPI network of the proteins causing MODY (Maturity Onset Diabetes of the Young) was drawn, and their correlation in causing a disease condition was marked...
2018: Advances in Protein Chemistry and Structural Biology
Adrián González, Andrew R Wildes, Marta Marty-Roda, Santiago Cuesta-López, Estelle Mossou, Andrew Studer, Bruno Demé, Gaél Moiroux, Jean-Luc Garden, Nikos Theodorakopoulos, Michel Peyrard
The influence of molecular confinement on the melting transition of oriented Na-DNA fibers submerged in poly(ethylene glycol) (PEG) solutions has been studied. The PEG solution exerts an osmotic pressure on the fibers which, in turn, is related to the DNA intermolecular distance. Calorimetry measurements show that the melting temperature increases and the width of the transition decreases with decreasing intermolecular distance. Neutron scattering was used to monitor the integrated intensity and width of a Bragg peak from the B-form of DNA as a function of temperature...
February 7, 2018: Journal of Physical Chemistry. B
Semiha Kevser Bali, Antoine Marion, Ilke Ugur, Ayse Kumru Dikmenli, Saron Catak, Viktorya Aviyente
Topotecan (TPT) is a non-toxic anti-cancer drug characterized by a pH dependent lactone/carboxyl equilibrium. TPT acts on the covalently bonded DNA/Topoisomerase I (DNA/TopoI) complex by intercalating between two DNA bases at the active site. This turns TopoI into a DNA-damaging agent and inhibits supercoil relaxation. Although only the lactone form of the drug is active and effectively inhibits TopoI, both forms have been co-crystalized at the same location within the DNA/TopoI complex. To gain further insights into the pH dependent activity of TPT, the differences between two TPT:DNA/TopoI complexes presenting either the lactone (acidic pH) or the carboxyl (basic pH) form of TPT were studied by means of molecular dynamic simulations, QM/MM calculations, and topological analysis...
February 7, 2018: Biochemistry
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