Uncertainty quantification of a DNA origami mechanism using a coarse-grained model and kinematic variance analysis.

Significant advances have been made towards the design, fabrication, and actuation of dynamic DNA nanorobots including the development of DNA origami mechanisms. These DNA origami mechanisms integrate relatively stiff links made of bundles of double-stranded DNA and relatively flexible joints made of single-stranded DNA to mimic the design of macroscopic machines and robots. Despite reproducing the complex configurations of macroscopic machines, these DNA origami mechanisms exhibit significant deviations from their intended motion behavior since nanoscale mechanisms are subject to significant thermal fluctuations that lead to variations in the geometry of the underlying DNA origami components. Understanding these fluctuations is critical to assess and improve the performance of DNA origami mechanisms and to enable precise nanoscale robotic functions. Here, we report a hybrid computational framework combining coarse-grained modeling with kinematic variance analysis to predict uncertainties in the motion pathway of a multi-component DNA origami mechanism. Coarse-grained modeling was used to evaluate the variation in geometry of individual components due to thermal fluctuations. This variation was incorporated in kinematic analyses to predict the motion pathway uncertainty of the entire mechanism, which agreed well with experimental characterization of motion. We further demonstrated the ability to predict the probability density of DNA origami mechanism conformations based on analysis of mechanical properties of individual joints. This integration of computational analysis, modeling tools, and experimental methods establish the foundation to predict and manage motion uncertainties of general DNA origami mechanisms to guide the design of DNA-based nanoscale machines and robots.

[1]  T. G. Martin,et al.  Cryo-EM structure of a 3D DNA-origami object , 2012, Proceedings of the National Academy of Sciences.

[2]  M. Bathe,et al.  Quantitative prediction of 3D solution shape and flexibility of nucleic acid nanostructures , 2011, Nucleic acids research.

[3]  W. Chiu,et al.  Designer nanoscale DNA assemblies programmed from the top down , 2016, Science.

[4]  Jejoong Yoo,et al.  De novo reconstruction of DNA origami structures through atomistic molecular dynamics simulation , 2016, Nucleic acids research.

[5]  Toma E Tomov,et al.  DNA bipedal motor walking dynamics: an experimental and theoretical study of the dependency on step size , 2017, Nucleic acids research.

[6]  Conrad C. Huang,et al.  UCSF Chimera—A visualization system for exploratory research and analysis , 2004, J. Comput. Chem..

[7]  P. Rothemund Folding DNA to create nanoscale shapes and patterns , 2006, Nature.

[8]  Kenneth J. Waldron,et al.  Kinematics, dynamics, and design of machinery , 1998 .

[9]  Hai-Jun Su,et al.  Three-dimensional structural dynamics of DNA origami Bennett linkages using individual-particle electron tomography , 2018, Nature Communications.

[10]  Alexey Savelyev,et al.  Chemically accurate coarse graining of double-stranded DNA , 2010, Proceedings of the National Academy of Sciences.

[11]  Friedrich C Simmel,et al.  Long-range movement of large mechanically interlocked DNA nanostructures , 2016, Nature Communications.

[12]  Flavio Romano,et al.  Characterizing the Motion of Jointed DNA Nanostructures Using a Coarse-Grained Model. , 2017, ACS nano.

[13]  N. Seeman Nucleic acid junctions and lattices. , 1982, Journal of theoretical biology.

[14]  Shawn M. Douglas,et al.  Multilayer DNA origami packed on a square lattice. , 2009, Journal of the American Chemical Society.

[15]  J. Doye,et al.  Characterizing DNA Star-Tile-Based Nanostructures Using a Coarse-Grained Model. , 2016, ACS nano.

[16]  Carlos E. Castro,et al.  Conformational Dynamics of Mechanically Compliant DNA Nanostructures from Coarse-Grained Molecular Dynamics Simulations. , 2017, ACS nano.

[17]  Flavio Romano,et al.  Introducing improved structural properties and salt dependence into a coarse-grained model of DNA. , 2015, The Journal of chemical physics.

[18]  Hai-Jun Su,et al.  Paper Origami-Inspired Design and Actuation of DNA Nanomachines with Complex Motions. , 2018, Small.

[19]  T. G. Martin,et al.  Facile and Scalable Preparation of Pure and Dense DNA Origami Solutions , 2014, Angewandte Chemie.

[20]  Jejoong Yoo,et al.  Molecular mechanics of DNA bricks: in situ structure, mechanical properties and ionic conductivity , 2016 .

[21]  J. Doye,et al.  Sequence-dependent thermodynamics of a coarse-grained DNA model. , 2012, The Journal of chemical physics.

[22]  Hao Yan,et al.  Lattice-free prediction of three-dimensional structure of programmed DNA assemblies , 2014, Nature Communications.

[23]  William P. Bricker,et al.  Structure and conformational dynamics of scaffolded DNA origami nanoparticles , 2017, Nucleic acids research.

[24]  I. Z. Reguly,et al.  A comparison between parallelization approaches in molecular dynamics simulations on GPUs , 2014, J. Comput. Chem..

[25]  Mark S.P. Sansom,et al.  Carbon nanotube/detergent interactions via coarse-grained molecular dynamics. , 2007, Nano letters.

[26]  S. Whitelam,et al.  Avoiding unphysical kinetic traps in Monte Carlo simulations of strongly attractive particles. , 2005, The Journal of chemical physics.

[27]  O. Tabata,et al.  Coarse-Grained Molecular Dynamics Model of Double-Stranded DNA for DNA Nanostructure Design. , 2017, The journal of physical chemistry. B.

[28]  Hai-Jun Su,et al.  Mechanical design of DNA nanostructures. , 2015, Nanoscale.

[29]  Mingdong Dong,et al.  DNA origami design of dolphin-shaped structures with flexible tails. , 2008, ACS nano.

[30]  Hai-Jun Su,et al.  Direct design of an energy landscape with bistable DNA origami mechanisms. , 2015, Nano letters.

[31]  K. Bathe,et al.  Computing Nonequilibrium Conformational Dynamics of Structured Nucleic Acid Assemblies. , 2016, Journal of chemical theory and computation.

[32]  Shawn M. Douglas,et al.  Self-assembly of DNA into nanoscale three-dimensional shapes , 2009, Nature.

[33]  J. SantaLucia,et al.  A unified view of polymer, dumbbell, and oligonucleotide DNA nearest-neighbor thermodynamics. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Robert L. Norton,et al.  Design of machinery : an introduction to the synthesis and analysis of mechanisms and machines , 1999 .

[35]  Wesley R Browne,et al.  Making molecular machines work , 2006, Nature nanotechnology.

[36]  Jonathan P. K. Doye,et al.  Direct Simulation of the Self-Assembly of a Small DNA Origami. , 2016, ACS nano.

[37]  J. Doye,et al.  Structural, mechanical, and thermodynamic properties of a coarse-grained DNA model. , 2010, The Journal of chemical physics.

[38]  Adam H. Marblestone,et al.  Rapid prototyping of 3D DNA-origami shapes with caDNAno , 2009, Nucleic acids research.

[39]  M. Zacharias,et al.  Single-molecule dissection of stacking forces in DNA , 2016, Science.

[40]  Jenny V Le,et al.  Probing Nucleosome Stability with a DNA Origami Nanocaliper. , 2016, ACS nano.

[41]  Wei Li,et al.  A cargo-sorting DNA robot , 2017, Science.

[42]  Hai-Jun Su,et al.  Programmable motion of DNA origami mechanisms , 2015, Proceedings of the National Academy of Sciences.

[43]  Hendrik Dietz,et al.  Nanoscale rotary apparatus formed from tight-fitting 3D DNA components , 2016, Science Advances.

[44]  Jejoong Yoo,et al.  Large-Conductance Transmembrane Porin Made from DNA Origami , 2016, ACS nano.

[45]  Kazuhiro Oiwa,et al.  Creating biomolecular motors based on dynein and actin-binding proteins. , 2017, Nature nanotechnology.

[46]  Mark Bathe,et al.  A primer to scaffolded DNA origami , 2011, Nature Methods.

[47]  Xilun Ding,et al.  Analysis of angular-error uncertainty in planar multiple-loop structures with joint clearances , 2015 .

[48]  Carlos E. Castro,et al.  Directing folding pathways for multi-component DNA origami nanostructures with complex topology , 2016 .

[49]  H. Dietz,et al.  Dynamic DNA devices and assemblies formed by shape-complementary, non–base pairing 3D components , 2015, Science.

[50]  Alberto Credi,et al.  Light-powered autonomous and directional molecular motion of a dissipative self-assembling system. , 2015, Nature nanotechnology.

[51]  Lorenzo Rovigatti,et al.  Coarse-graining DNA for simulations of DNA nanotechnology. , 2013, Physical chemistry chemical physics : PCCP.

[52]  Pekka Orponen,et al.  DNA rendering of polyhedral meshes at the nanoscale , 2015, Nature.

[53]  D. Thirumalai,et al.  Statistical Mechanics of Semiflexible Chains: A Meanfield Variational Approach , 1997 .