Dresden University of Technology T. Hinze Computing with Molecules at Dresden University of Technology Thomas Hinze Dresden University of Technology Computer Science Department Theoretical Computer Science email: hinze@tcs.inf.tu-dresden.de www.molecular-computing.de 1/17 Computing with Molecules at TUD
✁ ✁ ✂ ✁ � ✂ � ✁ � ✂ ✂ Dresden University of Technology T. Hinze Outline Who we are part of Biosaxony Network in Dresden research group of 10 persons approx. 80 companies foundations group leader: Dr. Monika Sturm external partners What we do Max Planck Institute of Molecular Cell Biology www.biosaxony.com BioInnovation Centre and Genetics aims and visions projects and results scientific collaborations Genetics Nanotechnology teaching activities Bioinformatics Artificial Intelligence Theoretical Computer Science 2/17 Computing with Molecules at TUD
� ✂ � � � � � � � � ✁ Dresden University of Technology T. Hinze Research Group Computing with Molecules Aims and Visions modelling and simulation of molecular biological processes investigation, description, and optimization of models for computation biomolecule based algorithmic design bridging gap between theoretical models and lab implementations Projects and Results wetware solution of the knapsack problem simulation system for phenomena undergoing side effects (Sisyphus) simple artificial chemistry experimental system (Saces) draft of universal programmable DNA based computer (TT6) library of data parallel algorithms based on Chomsky grammars genetic computing via microbial circuits in vivo 3/17 Computing with Molecules at TUD
☎ ✁ ✄ ☎ ☎ ☎ ✄ � ✎ ✏ ☛ ✑ ✒ ✁ ✄ ✞ ☎ ☎ ✁ ✝ ✡ ✄ ☎ ✞ � ✄ ☎ � ☎ ✁ ✂ ☎ ✌ ☎ ✄ ✁ ✝ ✄ ✞ ✟ ✠ ✂ Dresden University of Technology T. Hinze Knapsack Problem NP-complete , exponential need of resources, combinatorics Problem Definition There are natural numbers and reference number ✄✆☎ Is there a subset with ? ✏✔✓ ☞✍✌ Explanation : weights of objects . Is there a possibility to pack a selection of these objects into the knapsack and to meet the overall weight exactly? ? Example a = 5 2 5 1 object 1 a = 7 7 9 9 2 7 object 2 a = 2 solution 3 b = 9 2 object 3 "yes" . 4/17 Computing with Molecules at TUD
✂ � ✞ ✁ � ✂ � � ✓ � ✄ ✏ ✁ ✁ ✁ ✁ ✝ ✁ ✄ ☎ ☎ ☎ ✄ ✂ ✁ ✂ � ✁ ✂ � Dresden University of Technology T. Hinze Wetware Solution of the Knapsack Problem Brute Force Approach encode into DNA double strands by length ( ) generate all solution candidates by a controlled split-and-combine strategy separate the final DNA pool by length detect DNA at Starter length and answer yes problem instance of size implemented in vitro exponential need of resources moves from time to space limited scalability of the algorithm because of side effects and amount of DNA Starter 5 Starter a3 Starter a1 10 a1 a2 a3 separation Starter a2 by length 15 Starter Starter a1 a3 20 Starter a1 Starter a2 a3 DNA operations Starter DNA operations Starter a2 DNA operations Starter a1 a2 25 Starter Starter a1 Starter a1 a2 Starter a1 a2 a3 30 35 5/17 Computing with Molecules at TUD
✂ ✠ ✟ ☛ ✏ ✍ � ✁ ✂ ✄ ✂ ☛ ✝ ✟ � ✎ ✄ ✎ ✠ ✏ ✠ ✝ ✂ ✑ ✑ ✁ ✂ � ✁ � ✁ ✂ ✁ ✟ ✌ ✄ � � ✠ ✡ ✠ ✂ ✏ ✌ � Dresden University of Technology T. Hinze Modelling DNA Molecules Primary Structure A nucleotides without hydrogen bonds T C nucleotides with hydrogen bonds G G covalent bonds hydrogen bonds A T word over A T ✂✞✝ ✂☎✄ ✂☎✆ C G G C Secondary Structure T A P H C T 5’ T T A G A G G A C C T 3’ set of nucleotides 3’ A T C T C C T G G A T A 5’ A G H P T �☞☛ ✂✞✌ P H P H A T A G G T C C G T A T C T A T T A G A C T G C A A G T A C G T T G C A T G G A C C T P A T A ✂☎✆ G G T C relation of covalent bonds C G T A T relation of hydrogen bonds C T H A P T T inductive definition of and A G A C T G C mathematical model to describe A A G T A C term (graph) rewriting rules G T T G C A self assembly towards T G G A C C linear and nonlinear polymers H T allows formalization of DNA operations on a moderate abstraction level 6/17 Computing with Molecules at TUD
� � � � � Dresden University of Technology T. Hinze DNA Operations (I) Generating DNA Strands A C G G A A C synthesis (oligonucleotides) 5’−ACGGAAC−3’ isolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .from organisms Merging and Aliquoting union/split . . . . . . . . . . . . . . . . . . Modifying Hydrogen Bonds A C G G A A C A C G G A A C annealing (hybridization) T T G C C T T T T G C C T T . . A C G G A A C A C G G A A C melting (denaturation) T T G C C T T T T G C C T T . . . . 7/17 Computing with Molecules at TUD
� � � � � � � � Dresden University of Technology T. Hinze DNA Operations (II) Enzymatic Reactions T C G T A T T C G T A T P ligation (concatenation) A G C A T A A G C A T A . . . . . . . . . . P A G C G C A A G C G C A digestion (cleavage) P 5’ G C G C 3’ C G C G 3’ 5’ T C G C G T T C G C G T . . . . . . . . . . . . . . . HinP1 I P A G C G C A A G C G C A labeling (strand end modification) P T C G C G T T C G C G T + 5’−phosphate P polymerisation (blunting) A G C G C A A G C G . . . . . . . . . . G C T C G C PCR (polymerase chain reaction) . . . . . . . . . . duplicate strands Separating and Analyzing of DNA Pools B T B T A C C T A G A T A T affinity purification (sep. by biotin) G G A T C A T A C T + 5’−biotin A T A C T gel electrophoresis (sep. by length) . . .sort and detect strands sequencing (read out strand) A C G G A A C 5’−ACGGAAC−3’ . . . . . 8/17 Computing with Molecules at TUD
Dresden University of Technology T. Hinze Side Effects of DNA Operations operations performed with affinity purification gel electrophoresis synthesis annealing melting union ligation digestion labeling polymerisation PCR state of the art laboratory techniques point mutation (% mutation rate) classification of side effects mutations (differences in DNA sequence) deletion (% deletion rate, max. length of deletion) insertion loss of linear DNA strands by forming hairpins, artifacts (diff. from lin. DNA structure) bulges, loops, junctions, and compositions of them (% loss rate of tube contents) incomplete reaction (% unprocessed strands) failures in reaction procedure (differences from perfect specification of reaction) unspecificity (% error rate, maximum difference) supercoils strand instabilities caused by temperature or pH impurities by rests of reagences undetectable low DNA concentration (min. # copies) loss of DNA strands (% loss rate of tube contents) : supported in simulation tool in brackets: statistical parameters : significant side effect caused by the operation 9/17 Computing with Molecules at TUD
Dresden University of Technology T. Hinze A PCR Example (I) 1000 copies template1 1000 copies template2 8000 copies primer1 8000 copies primer2 Synthesis Synthesis Synthesis Synthesis Union 7910 Union correct synthesized strands 7909 (7910 copies of primer2, Union 7909 copies of primer1, 942 copies of template1, 942 941 copies of template2) 941 7 incorrect synthesized strands carrying 6 point mutations and deletions (totally 90 strands of primer2, 91 strands of primer1, 5 58 strands of template1, 59 strands of template2) 5 10/17 Computing with Molecules at TUD
Dresden University of Technology T. Hinze A PCR Example (II) Melting max. length: 100bp 1st PCR cycle min. bonding rate: 50% Annealing correct amplified double stranded 5965 template (5965 copies) 2739 Polymerisation primer rests 2713 Melting unwanted strands (including amplified 6 strands with deletions resulting in too 2nd PCR cycle max. length: 100bp short double stranded PCR fragments) min. bonding rate: 50% 1 2 3 4 5 Annealing 2 2 Polymerisation 1 Melting 1 3rd PCR cycle max. length: 100bp min. bonding rate: 50% 100 Annealing 50 lane 1: PCR negative control Polymerisation lanes 2, 3, 4: PCR product (simulation screenshot) lane 5: 50bp marker 11/17 Computing with Molecules at TUD
✂ ✁ ☎ ✁ ✄ � ☎ ✝ � ✞ ✌ ✌ ✂ ✄ ✁ ✆ ✝ � � � � ✁ ✂ � ✁ ✂ ✆ Dresden University of Technology T. Hinze Simple Artificial Chemistry Experimental System Idea behaviour of ideal gases can compute Principle set of particles molecules with parameters ( ) b ✂ ✂✁ ✂✞✌ randomly placed/speeded due to Maxwell-Boltzmann distribution set of reactions and global parameters y ( or can be empty) activation algorithm: Brownian movement (random walk) with elastic/inelastic collisions, retains momentum and energy analysis: animation, log, report, histogram x suitable for solution of NP-complete problems info and software download: http://saces.yce.ch z 12/17 Computing with Molecules at TUD
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