Nanomechanical DNA resonators for sensing and structural analysis of DNA-ligand complexes

The effect of direct or indirect binding of intercalant molecules on DNA structure is of fundamental importance in understanding the biological functioning of DNA. Here we report on self-suspended DNA nanobundles as ultrasensitive nanomechanical resonators for structural studies of DNA-ligand complexes. Such vibrating nanostructures represent the smallest mechanical resonator entirely composed of DNA. A correlative analysis between the mechanical and structural properties is exploited to study the intrinsic changes of double strand DNA, when interacting with different intercalant molecules (YOYO-1 and GelRed) and a chemotherapeutic drug (Cisplatin), at different concentrations. Possible implications of our findings are related to the study of interaction mechanism of a wide category of molecules with DNA, and to further applications in medicine, such as optimal titration of chemotherapeutic drugs and environmental studies for the detection of heavy metals in human serum.Intercalating molecules can significantly change the conformation of DNA. Here, the authors fabricated resonators fully composed of DNA forming bundles between microfabricated pillars to study the vibration property of the DNA bundles with/without intercalant molecules.

[1]  R. Haugland,et al.  Fluorescent Imaging of Nucleic Acids and Proteins in Gels , 1999 .

[2]  R. Hughes Patient Safety and Quality: An Evidence-Based Handbook for Nurses , 2008 .

[3]  F. Benfenati,et al.  Imaging and structural studies of DNA-protein complexes and membrane ion channels. , 2017, Nanoscale.

[4]  Y. Dzenis,et al.  Continuous DNA Nanofibers with Extraordinary Mechanical Properties and High Molecular Orientation , 2018, Macromolecular Materials and Engineering.

[5]  L. Lerman,et al.  Structural considerations in the interaction of DNA and acridines. , 1961, Journal of molecular biology.

[6]  B. Martinac,et al.  Nanomechanical properties of MscL α helices: A steered molecular dynamics study , 2017, Channels.

[7]  J. Justin Gooding,et al.  The electrochemical detection of cadmium using surface-immobilized DNA , 2007 .

[8]  J. Chaste,et al.  A nanomechanical mass sensor with yoctogram resolution. , 2012, Nature nanotechnology.

[9]  M. Roukes,et al.  Single-protein nanomechanical mass spectrometry in real time , 2012, Nature nanotechnology.

[10]  O. Sokolova,et al.  Effects of radiation damage in studies of protein-DNA complexes by cryo-EM. , 2017, Micron.

[11]  K. Weiss Vibration Problems in Engineering , 1965, Nature.

[12]  J. Anastassopoulou Metal–DNA interactions , 2003 .

[13]  J. Lepecq,et al.  A fluorescent complex between ethidium bromide and nucleic acids. Physical-chemical characterization. , 1967, Journal of molecular biology.

[14]  K. Taylor,et al.  λ DNA—membrane complex isolated in the CsCl density gradient , 1978, FEBS letters.

[15]  M. Nadeem,et al.  Heavy-metal-induced reactive oxygen species: phytotoxicity and physicochemical changes in plants. , 2014, Reviews of environmental contamination and toxicology.

[16]  Henrik H. J. Persson,et al.  DNA nanomechanics allows direct digital detection of complementary DNA and microRNA targets , 2009, Nature.

[17]  P. Gangavarapu,et al.  Dynamic range tuning of graphene nanoresonators , 2015 .

[18]  Sabrina Pricl,et al.  Biomechanical defects and rescue of cardiomyocytes expressing pathologic nuclear lamins , 2018, Cardiovascular research.

[19]  D. Karnofsky Mechanism of action of anticancer drugs at a cellular level , 1968, CA: a cancer journal for clinicians.

[20]  P. Comba Structure and function , 2010 .

[21]  Do-Nyun Kim,et al.  Structural Basis for Elastic Mechanical Properties of the DNA Double Helix , 2016, PloS one.

[22]  Remo Proietti Zaccaria,et al.  Direct imaging of DNA fibers: the visage of double helix. , 2012, Nano letters.

[23]  F. Crick,et al.  Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid , 1953, Nature.

[24]  A. Giordano,et al.  Erratum to: Liquid Biopsy in Cancer Patients: The Hand Lens for Tumor Evolution , 2017 .

[25]  S. Bianco,et al.  Evolution of nanomechanical properties and crystallinity of individual titanium dioxide nanotube resonators , 2018, Nanotechnology.

[26]  A. Eastman The formation, isolation and characterization of DNA adducts produced by anticancer platinum complexes. , 1987, Pharmacology & therapeutics.

[27]  J. Šponer,et al.  Reference simulations of noncanonical nucleic acids with different χ variants of the AMBER force field: quadruplex DNA, quadruplex RNA and Z-DNA. , 2012, Journal of chemical theory and computation.

[28]  M. Roukes,et al.  Zeptogram-scale nanomechanical mass sensing. , 2005, Nano letters.

[29]  Marco Amabili,et al.  Young's modulus of 2D materials extracted from their nonlinear dynamic response , 2017, 1704.05433.

[30]  N. Dokholyan,et al.  Molecular dynamic simulations of cisplatin- and oxaliplatin-d(GG) intrastand cross-links reveal differences in their conformational dynamics. , 2007, Journal of molecular biology.

[31]  Blessy B. Mathew,et al.  Toxicity, mechanism and health effects of some heavy metals , 2014, Interdisciplinary toxicology.

[32]  Simona Cocco,et al.  The micromechanics of DNA , 2003 .

[33]  H. Güntherodt,et al.  Dynamic force spectroscopy of single DNA molecules. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Scott S. Verbridge,et al.  High quality factor resonance at room temperature with nanostrings under high tensile stress , 2006 .

[35]  S. Smith,et al.  Direct mechanical measurements of the elasticity of single DNA molecules by using magnetic beads. , 1992, Science.

[36]  Andrea Toma,et al.  Breaking the diffusion limit with super-hydrophobic delivery of molecules to plasmonic nanofocusing SERS structures , 2011 .

[37]  Chem. , 2020, Catalysis from A to Z.

[38]  M. Arlorio,et al.  Microcantilever resonator arrays for immunodetection of β-lactoglobulin milk allergen , 2018 .

[39]  K. J. Miller,et al.  Interaction of molecules with nucleic acids. II. Two pairs of families of intercalation sites, unwinding angles, and the neighbor‐exclusion principle , 1979, Biopolymers.

[40]  E. Peterman,et al.  Quantifying how DNA stretches, melts and changes twist under tension , 2011 .

[41]  Hiroyuki Fujita,et al.  Real-time mechanical characterization of DNA degradation under therapeutic X-rays and its theoretical modeling , 2016, Microsystems & Nanoengineering.

[42]  T. Strick,et al.  Twisting and stretching single DNA molecules. , 2000, Progress in biophysics and molecular biology.

[43]  S. Smith,et al.  Single-molecule studies of DNA mechanics. , 2000, Current opinion in structural biology.

[44]  A. Giordano,et al.  Liquid Biopsy in Cancer Patients: The Hand Lens to Investigate Tumor Evolution , 2017 .

[45]  N. Cozzarelli,et al.  DNA overwinds when stretched , 2006, Nature.

[46]  Dong Wang,et al.  Cellular processing of platinum anticancer drugs , 2005, Nature Reviews Drug Discovery.

[47]  Silvan Schmid,et al.  Fundamentals of Nanomechanical Resonators , 2016 .

[48]  E. Strychalski,et al.  Electrospun DNA nanofibers , 2007 .

[49]  R. Fraser The structure of deoxyribose nucleic acid. , 2004, Journal of structural biology.

[50]  P G Steeneken,et al.  Nonlinear dynamic characterization of two-dimensional materials , 2017, Nature Communications.

[51]  A. Pühler,et al.  Advanced Molecular Genetics , 1984, Springer Berlin Heidelberg.

[52]  Ricardo Garcia,et al.  Nanomechanical mass sensing and stiffness spectrometry based on two-dimensional vibrations of resonant nanowires. , 2010, Nature nanotechnology.

[53]  T. Ebbesen,et al.  Exceptionally high Young's modulus observed for individual carbon nanotubes , 1996, Nature.

[54]  Experimental evidence of Fano resonances in nanomechanical resonators , 2017, Scientific Reports.

[55]  P. Deininger,et al.  Heavy Metal Exposure Influences Double Strand Break DNA Repair Outcomes , 2016, PloS one.

[56]  R. Franklin,et al.  Molecular Configuration in Sodium Thymonucleate , 1953, Nature.

[57]  M. S. Rocha Extracting physical chemistry from mechanics: a new approach to investigate DNA interactions with drugs and proteins in single molecule experiments. , 2015, Integrative biology : quantitative biosciences from nano to macro.

[58]  Sergei Lopatin,et al.  The structure of DNA by direct imaging , 2015, Science Advances.

[59]  A. Fontcuberta i Morral,et al.  Vectorial scanning force microscopy using a nanowire sensor. , 2016, Nature nanotechnology.

[60]  C. Bustamante,et al.  Ten years of tension: single-molecule DNA mechanics , 2003, Nature.