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DNA molecular dynamics

Jejoong Yoo, Chen-Yu Li, Scott Michael Slone, Christopher Maffeo, Aleksei Aksimentiev
The DNA origami method exploits the self-assembly property of nucleic acids to build diverse nanoscale systems. The all-atom molecular dynamics (MD) method has emerged as a powerful computational tool for atomic-resolution characterization of the in situ structure and physical properties of DNA origami objects. This chapter provides step-by-step instructions for building atomic-scale models of DNA origami systems, using the MD method to simulate the models, and performing basic analyses of the resulting MD trajectories...
2018: Methods in Molecular Biology
José L Neira, María Belén López, Paz Sevilla, Bruno Rizzuti, Ana Cámara-Artigas, Miguel Vidal, Juan L Iovanna
NUPR1 is a protumoral multifunctional intrinsically disordered protein (IDP), which is activated during the acute phases of pancreatitis. It interacts with other IDPs such as prothymosin α, as well as with folded proteins such as the C-terminal region of RING1-B (C-RING1B) of the Polycomb complex; in all those interactions, residues around Ala33 and Thr68 (the "hot-spot" region) of NUPR1 intervene. Its paralogue, NUPR1L, is also expressed in response to DNA-damage, it is p53-regulated, and its expression down-regulates that of the NUPR1 gene...
June 20, 2018: Biochemical Journal
Elisa Gobbini, Corinne Cassani, Jacopo Vertemara, Weibin Wang, Fabiana Mambretti, Erika Casari, Patrick Sung, Renata Tisi, Giuseppe Zampella, Maria Pia Longhese
Homologous recombination is triggered by nucleolytic degradation (resection) of DNA double-strand breaks (DSBs). DSB resection requires the Mre11-Rad50-Xrs2 (MRX) complex, which promotes the activity of Exo1 nuclease through a poorly understood mechanism. Here, we describe the Mre11-R10T mutant variant that accelerates DSB resection compared to wild-type Mre11 by potentiating Exo1-mediated processing. This increased Exo1 resection activity leads to a decreased association of the Ku complex to DSBs and an enhanced DSB resection in G1, indicating that Exo1 has a direct function in preventing Ku association with DSBs...
June 19, 2018: EMBO Journal
Yongjian Wang, Palma Rico-Lastres, Ainhoa Lezamiz, Marc Mora, Carles Solsona, Guillaume Stirnemann, Sergi Garcia-Manyes
Understanding the molecular mechanisms governing protein-nucleic acid interactions is fundamental to many nuclear processes. However, how nucleic acid binding affects the conformation and dynamics of the substrate protein remains poorly understood. Here we use a combination of single molecule force spectroscopy AFM and biochemical assays to show that the binding of TG-rich ssDNA triggers a mechanical switch in the RRM1 domain of TDP-43, toggling between an entropic spring devoid of mechanical stability and a shock absorber bound-form that resists unfolding forces of 40 pN...
June 20, 2018: Journal of Physical Chemistry Letters
Preetleen Kathuria, Purshotam Sharma, Richard A Manderville, Stacey D Wetmore
Exposure to ochratoxin A (OTA) is associated with chronic renal diseases and carcinogenesis. The deleterious effects of OTA have been linked to its covalent binding at C8 position of guanine (G) to form DNA adduct (OT-G), which causes various mutations. To contribute towards understanding the complex mutagenic profile of OTA, the present work uses a robust computational approach to characterize post-replication DNA structures containing OT-G mismatched with canonical nucleobases. Our MD simulations provide insight into the effects of the opposing base, adduct ionization state and flanking base on duplex structural features for the competing (major groove (B-type), wedge (W) and stacked (S)) conformers...
June 20, 2018: Chemical Research in Toxicology
Ryan W Kung, Purshotam Sharma, Stacey D Wetmore
The present work investigates the effects of the size and shape of the nitrogen containing aromatic (NCA) skeleton on the structure of DNA damaged through adduct formation at C8 of 2'-deoxyguanosine (dG), a common DNA lesion associated with chemical carcinogenesis. Specifically, density functional theory (DFT) calculations (B3LYP-D3) and molecular dynamics (MD) simulations (AMBER) are performed on seven model adducts with systematic expansion of the NCA moiety. DFT calculations reveal that the NCA moiety shape affects the structure at the nucleobase-carcinogen linkage...
June 20, 2018: Journal of Chemical Information and Modeling
David M Engelhard, Andreas Meyer, Andreas Berndhäuser, Olav Schiemann, Guido H Clever
Artificial metal-base tetrads composed of square-planar CuII(pyridine)4 complexes were covalently attached to both the 3' and 5' ends of tetramolecular DNA G-quadruplexes [Ld(G3-5)LdT]4 (L = pyridine ligand) of different lengths. Owing to the planar four-point attachment of the metal complexes, the magnetic orbitals (dx2-y2) of the d9-configured CuII cations are placed in a coplanar fashion, separated by the stacked guanine tetrads. Pulsed EPR-derived CuII-CuII distances and angles were found to be in agreement with those obtained from molecular dynamics simulations...
June 18, 2018: Chemical Communications: Chem Comm
M Cabanero, M S Tsao
The advent of targeted therapy in non-small-cell lung cancer (nsclc) has made the routine molecular diagnosis of EGFR mutations crucial for optimal patient management. Obtaining tumour tissue for biomarker testing, especially in the setting of re-biopsy, can present many challenges. A potential alternative source of tumour dna is circulating cell-free tumour-derived dna (ctdna). Although ctdna is present in low quantities in plasma, the convenience of sample acquisition and the increasing reliability of detection methods make this approach a promising one...
June 2018: Current Oncology
Nattawee Poomsuk, Tirayut Vilaivan, Khatcharin Siriwong
Peptide nucleic acid (PNA) is a powerful biomolecule with a wide variety of important applications. In this work, the molecular structures and binding affinity of PNA with a D-prolyl-2-aminocyclopentane carboxylic acid backbone (acpcPNA) that binds to both DNA and RNA were studied using molecular dynamics simulations. The simulated structures of acpcPNA-DNA and acpcPNA-RNA duplexes more closely resembled the typical structures of B-DNA and A-RNA than the corresponding duplexes of aegPNA. The calculated binding free energies are in good agreement with the experimental results that the acpcPNA-DNA duplex is more stable than the acpcPNA-RNA duplex regardless of the base sequences...
June 12, 2018: Journal of Molecular Graphics & Modelling
Rajesh Kumar Pathak, Ayushi Gupta, Rohit Shukla, Mamta Baunthiyal
Xanthine oxidoreductase plays an important role in formation of uric acid and its regulation during purine catabolism. Uncontrolled expression of this enzyme is responsible for overproduction and deposition of uric acid in blood that is potentially injurious because it can breakdown DNA and protein molecules, triggering many diseases. Human Xanthine oxidoreductase (HsXOR) is considered to be a pharmacological target for the treatment of hyperuricemia. Many of the HsXOR-inhibitor drugs such as Febuxostat and Allopurinol are known to have significant adverse effects...
May 28, 2018: Computational Biology and Chemistry
Wei Lai, Lei Ren, Qian Tang, Xiangmeng Qu, Jiang Li, Lihua Wang, Li Li, Chunhai Fan, Hao Pei
Programmable regulation of chemical reaction networks (CRNs) represents a major challenge toward the development of complex molecular devices performing sophisticated motions and functions. Nevertheless, regulation of artificial CRNs is generally energy- and time-intensive as compared to natural regulation. Inspired by allosteric regulation in biological CRNs, we herein develop an intramolecular conformational motion strategy (InCMS) for programmable regulation of DNA CRNs. We design a DNA switch as the regulatory element to program the distance between toehold and branch migration domain...
June 15, 2018: ACS Nano
Sarfaraj Niazi, Madhusudan Purohit, Archana Sonawani, Javed H Niazi
Single-stranded (ss) oligonucleotide aptamers are emerging as the promising substitutes for monoclonal antibodies because of their low production cost and good batch-to-batch consistency. Aptamers vividly bind to a variety of cellular targets and alter their functions with a remarkable degree of specificities. In this study, the positive clones of human epidermal growth factor receptor 2 (HER2) specific binding ssDNA aptamers which were previously identified by in vitro Systematic Evolution of Ligands by EXponential enrichment (SELEX) process, hitherto lacking the putative binding site information and residues crucial for aptamer recognition are studied...
June 6, 2018: Journal of Molecular Graphics & Modelling
Fabrizio Cleri, Fabio Landuzzi, Ralf Blossey
Double strand breaks (DSB) in the DNA backbone are the most lethal type of defect induced in the cell nucleus by chemical and radiation treatments of cancer. However, little is known about the outcomes of damage in nucleosomal DNA, and on its effects on damage repair. We performed microsecond-long molecular dynamics computer simulations of nucleosomes including a DSB at various sites, to characterize the early stages of the evolution of this DNA lesion. The damaged structures are studied by the essential dynamics of DNA and histones, and compared to the intact nucleosome, thus exposing key features of the interactions...
June 14, 2018: PLoS Computational Biology
Nicholas J Emery, Sagardip Majumder, Allen P Liu
Point-of-care molecular diagnostic tests show great promise for providing accurate, timely results in low-infrastructure healthcare settings and at home. The design space for these tests is limited by a variety of possible background reactions, which often originate from relatively weak promiscuous activities of the enzymes used for nucleic acid amplification. When this background signal is amplified alongside the signal of the intended biomarker, the dynamic range of the test can be severely compromised. Therefore, a detailed knowledge of potential side reactions arising from enzyme promiscuity can improve rational design of point-of-care molecular diagnostic tests...
June 2018: Synthetic and Systems Biotechnology
Ruth Stoney, David L Robertson, Goran Nenadic, Jean-Marc Schwartz
Molecular interaction networks are routinely used to map the organization of cellular function. Edges represent interactions between genes, proteins, or metabolites. However, in living cells, molecular interactions are dynamic, necessitating context-dependent models. Contextual information can be integrated into molecular interaction networks through the inclusion of additional molecular data, but there are concerns about completeness and relevance of this data. We developed an approach for representing the organization of human cellular processes using pathways as the nodes in a network...
2018: NPJ Systems Biology and Applications
Melis Goktas, Chuanfu Luo, Ruby May A Sullan, Ana E Bergues-Pupo, Reinhard Lipowsky, Ana Vila Verde, Kerstin G Blank
Coiled coils are important nanomechanical building blocks in biological and biomimetic materials. A mechanistic molecular understanding of their structural response to mechanical load is essential for elucidating their role in tissues and for utilizing and tuning these building blocks in materials applications. Using a combination of single-molecule force spectroscopy (SMFS) and steered molecular dynamics (SMD) simulations, we have investigated the mechanics of synthetic heterodimeric coiled coils of different length (3-4 heptads) when loaded in shear geometry...
May 28, 2018: Chemical Science
Matthias Benoit, Lauriane Simon, Sophie Desset, Céline Duc, Sylviane Cotterell, Axel Poulet, Samuel Le Goff, Christophe Tatout, Aline V Probst
Developmental phase transitions are often characterized by changes in the chromatin landscape and heterochromatin reorganization. In Arabidopsis, clustering of repetitive heterochromatic loci into so-called chromocenters is an important determinant of chromosome organization in nuclear space. Here, we investigated the molecular mechanisms involved in chromocenter formation during the switch from a heterotrophic to a photosynthetically competent state during early seedling development. We characterized the spatial organization and chromatin features at centromeric and pericentromeric repeats and identified mutant contexts with impaired chromocenter formation...
June 13, 2018: New Phytologist
Lihua Bie, Likai Du, Qiaoxia Yuan, Jun Gao
CpG methylation can regulate gene expression by altering the specific binding of protein and DNA. In order to understand how a single 5mC regulates protein-DNA interactions, we have compared the structures and dynamics of CEBP/βprotein-DNA complexes before and after methylation, and the results indicate that even a single 5mC can regulate protein-DNA recognition by steric-hindrance effect of methyl group and changing the hydrogen bond interactions. The interactions between the methyl group, mCpG motif, and the conserved residue arginine make the protein read out the variation of local environment, which further enhances the specific recognition and affects the base pair stacking...
June 11, 2018: Journal of Molecular Modeling
Ryuma Sato, Hirotaka Kitoh-Nishioka, Koji Ando, Takahisa Yamato
The photoinduced electron transfer (ET) reaction of cyclobutane pyrimidine dimer (CPD) photolyase plays an essential role in its DNA repair reaction, and the molecular mechanism of the ET reaction has attracted a large number of experimental and theoretical studies. We investigated the quantum mechanical nature of their ET reactions, characterized by multiple ET pathways of the CPD photolyase derived from A. nidulans. Using the generalized Mulliken-Hush (GMH) method and the bridge green function (GF) methods, we estimated the electronic coupling matrix element, TDA , to be 36±30 cm-1 from the donor (FADH- ) to the acceptor (CPD)...
June 11, 2018: Journal of Physical Chemistry. B
Andrea Stoccoro, Fabio Coppedè
Advances in molecular biology technologies have allowed uncovering the role of epigenetic regulation in several complex diseases, such as cancer and neurodegenerative disorders. Although the role of epigenetic mechanisms in Alzheimer's disease is still little understood, recent findings clearly show that such mechanisms are dysregulated during disease progression, already in its early stages. However, it is not clear if the observed epigenetic changes represent a cause or a consequence of the disease. Promising results are emerging from studies performed in peripheral blood DNA that could provide early biomarkers of the pathology...
June 11, 2018: Neurodegenerative Disease Management
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