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1.
PLoS Comput Biol ; 16(7): e1007884, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32614821

RESUMO

Motivated by growing evidence for pathway heterogeneity and alternative functions of molecular machines, we demonstrate a computational approach for investigating two questions: (1) Are there multiple mechanisms (state-space pathways) by which a machine can perform a given function, such as cotransport across a membrane? (2) How can additional functionality, such as proofreading/error-correction, be built into machine function using standard biochemical processes? Answers to these questions will aid both the understanding of molecular-scale cell biology and the design of synthetic machines. Focusing on transport in this initial study, we sample a variety of mechanisms by employing Metropolis Markov chain Monte Carlo. Trial moves adjust transition rates among an automatically generated set of conformational and binding states while maintaining fidelity to thermodynamic principles and a user-supplied fitness/functionality goal. Each accepted move generates a new model. The simulations yield both single and mixed reaction pathways for cotransport in a simple environment with a single substrate along with a driving ion. In a "competitive" environment including an additional decoy substrate, several qualitatively distinct reaction pathways are found which are capable of extremely high discrimination coupled to a leak of the driving ion, akin to proofreading. The array of functional models would be difficult to find by intuition alone in the complex state-spaces of interest.


Assuntos
Transporte Biológico/fisiologia , Simulação por Computador , Computadores Moleculares , Biologia de Sistemas/métodos , Algoritmos , Cadeias de Markov , Proteínas de Membrana Transportadoras/química , Proteínas de Membrana Transportadoras/metabolismo , Método de Monte Carlo , Termodinâmica
3.
Nat Commun ; 11(1): 121, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913309

RESUMO

DNA strand displacement reactions (SDRs) provide a set of intelligent toolboxes for developing molecular computation. Whereas SDR-based logic gate circuits have achieved a high level of complexity, the scale-up for practical achievable computational tasks remains a hurdle. Switching circuits that were originally proposed by Shannon in 1938 and nowadays widely used in telecommunication represent an alternative and efficient means to realize fast-speed and high-bandwidth communication. Here we develop SDR-based DNA switching circuits (DSCs) for implementing digital computing. Using a routing strategy on a programmable DNA switch canvas, we show that arbitrary Boolean functions can be represented by DSCs and implemented with molecular switches with high computing speed. We further demonstrate the implementation of full-adder and square-rooting functions using DSCs, which only uses down to 1/4 DNA strands as compared with a dual-rail logic expression-based design. We expect that DSCs provide a design paradigm for digital computation with biomolecules.


Assuntos
Computadores , DNA/química , Eletricidade , Algoritmos , Simulação por Computador , Computadores Moleculares , DNA/genética
4.
Nat Commun ; 10(1): 5469, 2019 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784537

RESUMO

Biomolecular cryptography exploiting specific biomolecular interactions for data encryption represents a unique approach for information security. However, constructing protocols based on biomolecular reactions to guarantee confidentiality, integrity and availability (CIA) of information remains a challenge. Here we develop DNA origami cryptography (DOC) that exploits folding of a M13 viral scaffold into nanometer-scale self-assembled braille-like patterns for secure communication, which can create a key with a size of over 700 bits. The intrinsic nanoscale addressability of DNA origami additionally allows for protein binding-based steganography, which further protects message confidentiality in DOC. The integrity of a transmitted message can be ensured by establishing specific linkages between several DNA origamis carrying parts of the message. The versatility of DOC is further demonstrated by transmitting various data formats including text, musical notes and images, supporting its great potential for meeting the rapidly increasing CIA demands of next-generation cryptography.


Assuntos
Bacteriófago M13/genética , Segurança Computacional , Computadores Moleculares , DNA/genética , Comunicação , Confidencialidade , Humanos
5.
Nat Commun ; 10(1): 5250, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748511

RESUMO

Synthetic biology uses living cells as the substrate for performing human-defined computations. Many current implementations of cellular computing are based on the "genetic circuit" metaphor, an approximation of the operation of silicon-based computers. Although this conceptual mapping has been relatively successful, we argue that it fundamentally limits the types of computation that may be engineered inside the cell, and fails to exploit the rich and diverse functionality available in natural living systems. We propose the notion of "cellular supremacy" to focus attention on domains in which biocomputing might offer superior performance over traditional computers. We consider potential pathways toward cellular supremacy, and suggest application areas in which it may be found.


Assuntos
Computadores Moleculares , Computadores , Biologia Sintética , Células
6.
Nat Commun ; 10(1): 5390, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31772166

RESUMO

Powerful information processing and ubiquitous computing are crucial for all machines and living organisms. The Watson-Crick base-pairing principle endows DNA with excellent recognition and assembly abilities, which facilitates the design of DNA computers for achieving intelligent systems. However, current DNA computational systems are always constrained by poor integration efficiency, complicated device structures or limited computational functions. Here, we show a DNA arithmetic logic unit (ALU) consisting of elemental DNA logic gates using polymerase-mediated strand displacement. The use of an enzyme resulted in highly efficient logic gates suitable for multiple and cascaded computation. Based on our basic single-rail DNA configuration, additional combined logic gates (e.g., a full adder and a 4:1 multiplexer) have been constructed. Finally, we integrate the gates and assemble the crucial ALU. Our strategy provides a facile strategy for assembling a large-scale complex DNA computer system, highlighting the great potential for programming the molecular behaviors of complicated biosystems.


Assuntos
Computadores Moleculares , DNA de Cadeia Simples/química , DNA de Cadeia Simples/genética , Desenho de Equipamento , Lógica , Reação em Cadeia da Polimerase em Tempo Real
7.
Analyst ; 144(24): 7278-7282, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31696169

RESUMO

Benefiting from the simple DNAzyme and a duplex-specific nuclease, a series of microRNA-stimulated DNAzyme logic gates were rationally assembled for the highly accurate detection of multiple low-abundant microRNA biomarkers that correspond to the specific aberrant microRNA expression patterns of cancer tissues, thus showing a great potential in early diagnosis.


Assuntos
Biomarcadores Tumorais/análise , Computadores Moleculares , DNA Catalítico/química , MicroRNAs/análise , Neoplasias/diagnóstico , Alcanossulfonatos/química , Compostos Azo/química , Endodesoxirribonucleases/química , Fluoresceínas/química , Corantes Fluorescentes/química , Humanos , Limite de Detecção , Técnicas de Amplificação de Ácido Nucleico/métodos , Espectrometria de Fluorescência/métodos
8.
Nanoscale ; 11(45): 21856-21866, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31696192

RESUMO

In this paper, we propose a strategy involving coupling DNA structural nanoswitches with toehold mediated strand displacement for constructing novel DNA-based digital comparator (DC) logic systems, which are a basic part of traditional electronic computers and can compare whether two or more input numbers are equal. However, when the number of DC inputs is increased to a certain level, the speed and quality of the computing circuit can be affected because of the limitations of conventional electronic computers when it comes to handling large-scale quantities of data. To solve this problem, in this work, we introduce a multi-input to multi-output DNA switch-based platform that can enable complex DC logical comparison. These multifunctional DNA-based switches, each including two hairpin-shaped molecular beacons and a G4/NMM complex, were used as platforms for the step-by-step realization of 2-3 DC, 3-3 DC, and 4-3 DC logic operations. Also, experiments were designed to further verify the excellent selectivity, achieving single-base mismatch operations with the digital comparator. Based on our design, comparators (">", "<" and "=") can be realized. Our prototype can inspire new designs and have intelligent digital comparator and in-field applications.


Assuntos
Computadores Moleculares , DNA/química
9.
Molecules ; 24(22)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31731630

RESUMO

Recently, DNA molecules have been widely used to construct advanced logic devices due to their unique properties, such as a simple structure and predictable behavior. In fact, there are still many challenges in the process of building logic circuits. Among them, the scalability of the logic circuit and the elimination of the crosstalk of the cascade circuit have become the focus of research. Inspired by biological allosteric regulation, we developed a controllable molecular logic circuit strategy based on the activity of DNAzyme. The E6 DNAzyme sequence was temporarily blocked by hairpin DNA and activated under appropriate input trigger conditions. Using a substrate with ribonucleobase (rA) modification as the detection strand, a series of binary basic logic gates (YES, AND, and INHIBIT) were implemented on the computational component platform. At the same time, we demonstrate a parallel demultiplexer and two multi-level cascade circuits (YES-YES and YES-Three input AND (YES-TAND)). In addition, the leakage of the cascade process was reduced by exploring factors such as concentration and DNA structure. The proposed DNAzyme activity regulation strategy provides great potential for the expansion of logic circuits in the future.


Assuntos
Computadores Moleculares , DNA Catalítico/química , Conformação de Ácido Nucleico , Regulação Alostérica
10.
IET Nanobiotechnol ; 13(7): 665-673, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31573534

RESUMO

Early detection of cancer is very critical because it can reduce the treatment risk and cost. MicroRNAs (miRNAs) have been introduced in recent years as an efficient class of biomarkers for cancer early detection. Now, real-time polymerase chain reaction has been used to profile the miRNA expression, which is costly, time consuming and low accuracy. Most recently, DNA logic gates are used to detect the miRNA expression level that is more accurate and faster than previous methods. The DNA-based logic gates face with serious challenges such as the large complexity and low scalability. In this study, the authors proposed a methodology to design multi-threshold and multi-input DNA-based logic gates in response to specific miRNA inputs in live mammalian cells. The proposed design style can simultaneously recognise multiple miRNAs with different rising and falling thresholds. The design style has been evaluated on the lung cancer biomarkers and the experimental results show the efficiency of the proposed method in terms of accuracy, efficiency and speed.


Assuntos
Biomarcadores Tumorais/genética , Computadores Moleculares , DNA de Neoplasias/análise , Perfilação da Expressão Gênica/métodos , MicroRNAs/genética , Neoplasias/genética , DNA de Neoplasias/genética , Detecção Precoce de Câncer/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Lógica , Reprodutibilidade dos Testes , Projetos de Pesquisa , Sensibilidade e Especificidade , Transcriptoma
11.
IET Nanobiotechnol ; 13(7): 674-681, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31573535

RESUMO

Here, according to the type-based modulation technique, the authors develop a novel modulation scheme by utilising ion collision and reaction to mitigate inter-symbol interference (ISI) in diffusive molecular communication (MC) systems. Two types of ions are employed as messenger molecules that cause a chemical reaction in the medium. According to the residual molecules and chemical reaction, the proposed modulation scheme adaptively adjusts the number of emitted molecules, thereby guaranteeing that the number of molecules that arrived at the receiver remains at a stable level. The authors evaluate the performance of the proposed scheme by comparing it with the conventional binary molecule shift keying (BMoSK), BMoSK with power adjustment (BMoSK-PA), and ideal BMoSK (without ISI) modulation techniques via diffusion. Numerical results show that the bit error probability and channel capacity of the proposed modulation scheme are much closer to the ideal BMoSK modulation scheme compared to the conventional BMoSK and the BMoSK-PA modulation schemes.


Assuntos
Comunicação , Computadores Moleculares , Processamento Eletrônico de Dados/métodos , Ativação do Canal Iônico/fisiologia , Íons/metabolismo , Processamento de Sinais Assistido por Computador , Catálise , Simulação por Computador , Difusão , Humanos , Transporte de Íons , Íons/farmacocinética , Modelos Teóricos , Nanotecnologia/métodos
12.
J Mass Spectrom ; 54(11): 915-932, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31476247

RESUMO

Sesquiterpene lactones (SL) have been reported with various biological effects. Among the described SL skeletons, hirsutinolide and glaucolide have not been extensively studied by mass spectrometry (MS), especially how to distinguish them in organic matrices. Thus, this paper reports (1) a strategy of their differentiation based on MS behavior during the ionization and (2) a proposal of the fragmentation pattern for both SL-subtypes. ESI(+)-HRMS data of four isolated SL (hirsutinolides 1 and 3; glaucolides 2 and 4) were recorded by direct and UPLC water-sample combined injections. These analyses revealed that hirsutinolides and glaucolides formed [M+Na]+ ion during the operation of the direct MS injection, and ([M+Na]+ and [M+H-H2 O]+ ) and [M+H]+ ions were respectively observed for hirsutinolides and glaucolides during the operation of combined UPLC water and sample MS injection. Computational simulations showed that the complex hirsutinolide (1)-Na+ formed with a lower preparation energy compared with the complex glaucolide (2)-Na+ . However, despite their different behavior during the ionization process, ESI(+)-HRMS/MS analyses of 1-4 gave similar fragmentation patterns at m/z 277, 259, 241, and 231 that can be used as diagnostic ions for both skeletons. Moreover, the differentiation strategy based on the nature of the complex SL-adducts and their MS/MS fragmentation pattern were successfully applied for the chemical characterization of the extract from Vernonanthura tweedieana using UPLC-ESI-HRMS/MS. Among the characterized metabolites, SL with hirsutinolide and glaucolide skeletons showed the aforementioned diagnostic fragments and an ionization behavior that was similar to those observed during the water-sample combined injection.


Assuntos
Misturas Complexas/química , Lactonas/química , Sesquiterpenos/química , Asteraceae/química , Cátions/química , Cromatografia Líquida de Alta Pressão , Computadores Moleculares , Extratos Vegetais/química , Análise de Componente Principal , Sódio/química , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Água
13.
Nat Nanotechnol ; 14(11): 1075-1081, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31548688

RESUMO

DNA is a reliable biomolecule with which to build molecular computation systems. In particular, DNA logic circuits (diffusion-based) have shown good performance regarding scalability and correctness of computation. However, previous architectures of DNA logic circuits have two limitations. First, the speed of computation is slow, often requiring hours to compute a simple function. Second, the circuits are of high complexity regarding the number of DNA strands. Here, we introduce an architecture of DNA logic circuits based on single-stranded logic gates using strand-displacing DNA polymerase. The logic gates consist of only single DNA strands, which largely reduces leakage reactions and signal restoration steps such that the circuits are improved in regard to both speed of computation and the number of DNA strands needed. Large-scale logic circuits can be constructed from the gates by simple cascading strategies. In particular, we have demonstrated a fast and compact logic circuit that computes the square-root function of four-bit input numbers.


Assuntos
Computadores Moleculares , DNA de Cadeia Simples/química , Algoritmos , DNA Polimerase Dirigida por DNA/química , Conformação de Ácido Nucleico
14.
Comput Biol Chem ; 83: 107122, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31563020

RESUMO

The Monty Hall problem is a decision problem with an answer that is surprisingly counter-intuitive yet provably correct. Here we simulate and prove this decision in a high-throughput DNA sequencing machine, using a simple encoding. All possible scenarios are represented by DNA oligonucleotides, and gameplay decisions are implemented by sequencing these oligonucleotides from specific positions, with a single run simulating more than 12,000,000 independent games. This work highlights high-throughput DNA sequencing as a new tool that could extend existing capabilities and enable new encoding schemes for problems in DNA computing.


Assuntos
Computadores Moleculares , Sequenciamento de Nucleotídeos em Larga Escala , Resolução de Problemas , Humanos , Análise de Sequência de DNA
15.
IEEE Trans Nanobioscience ; 18(4): 651-660, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31425042

RESUMO

We study a drift-induced diffusive mobile molecular communication system where source, destination and cooperative nanomachines follow the one-dimensional Brownian motion. For information exchange from source nanomachine to receiver nanomachine, both direct and decode-forward (DF) relay-assisted cooperative paths are considered. The closed-form expressions for the probabilities of detection and false alarm are derived at the cooperative and destination nanomachines considering the multiple-source interference (MSI) and the inter-symbol-interference (ISI). The closed-form expressions for end-to-end average probability of error, and maximum achievable rate are also obtained. Moreover, to achieve minimum expected probability of error the optimum number of molecules to be transmitted from transmitter and optimal detection threshold in receiver nanomachine are found. The analytical expressions are validated through particle-based and Monte-Carlo simulation methods.


Assuntos
Computadores Moleculares , Nanotecnologia , Simulação por Computador , Método de Monte Carlo
16.
Nanoscale ; 11(35): 16241-16244, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31454010

RESUMO

In this work, a novel and general comparator was constructed based on cascaded strand displacement reactions and DNA hybridization and its potential in intelligently weighing the quantitative predominance of two targets was explored in a complex biological matrix, which not only enriches the information processing mode of DNA computation but also provides an instructive way to deal with quantitative analyzing tasks in further DNA-based logic sensors.


Assuntos
Computadores Moleculares , DNA/química
17.
Mol Cell ; 75(4): 769-780.e4, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31442423

RESUMO

The ability to process and store information in living cells is essential for developing next-generation therapeutics and studying biology in situ. However, existing strategies have limited recording capacity and are challenging to scale. To overcome these limitations, we developed DOMINO, a robust and scalable platform for encoding logic and memory in bacterial and eukaryotic cells. Using an efficient single-nucleotide-resolution Read-Write head for DNA manipulation, DOMINO converts the living cells' DNA into an addressable, readable, and writable medium for computation and storage. DOMINO operators enable analog and digital molecular recording for long-term monitoring of signaling dynamics and cellular events. Furthermore, multiple operators can be layered and interconnected to encode order-independent, sequential, and temporal logic, allowing recording and control over the combination, order, and timing of molecular events in cells. We envision that DOMINO will lay the foundation for building robust and sophisticated computation-and-memory gene circuits for numerous biotechnological and biomedical applications.


Assuntos
Computadores Moleculares , DNA , DNA/química , DNA/metabolismo , Células HEK293 , Humanos
18.
Biosystems ; 184: 103997, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31369836

RESUMO

DNA computing, as one of potential means to solve complicated computational problems, is a new field of interdisciplinary research, including computational mathematics, parallel algorithms, bioinformatics. Capacitated vehicle routing problem is one of famous NP-hard problems, which includes determining the path of a group same vehicles serving a set of clients, while minimizing the total transportation cost. Based on the bio-heuristic computing model and DNA molecular manipulations, parallel biocomputing algorithms for solving capacitated vehicle routing problem are proposed in this paper. We appropriately use different biological chains to mean vertices, edges, weights, and adopt appropriate biological operations to search the solutions of the problem with O(n2) time complexity. We enrich the application scope of biocomputing, reduce computational complexity, and verify practicability of DNA parallel algorithms through simulations.


Assuntos
Algoritmos , Biologia Computacional/métodos , Heurística Computacional , Computadores Moleculares , Modelos Teóricos , Resolução de Problemas , Acidentes de Trânsito/prevenção & controle , Cidades , Simulação por Computador , Humanos , Veículos Automotores , Transportes/métodos
19.
Adv Mater ; 31(39): e1902888, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31402516

RESUMO

Distinct spatial patterning of naturally produced materials is observed in many cellular structures and even among communities of microorganisms. Reoccurrence of spatially organized materials in all branches of life is clear proof that organization is beneficial for survival. Indeed, organisms can trick the evolutionary process by using organized materials in ways that can help the organism to avoid unexpected conditions. To expand the toolbox for synthesizing patterned living materials, Boolean type "AND" and "OR" control of curli fibers expression is demonstrated using recombinases. Logic gates are designed to activate the production of curli fibers. The gates can be used to record the presence of input molecules and give output as CsgA expression. Two different curli fibers (CsgA and CsgA-His-tag) production are then selectively activated to explore distribution of monomers upon coexpression. To keep track of the composition of fibers, CsgA-His-tag proteins are labeled with nickel-nitrilotriacetic acid (Ni-NTA-) conjugated gold nanoparticles. It is observed that an organized living material can be obtained upon inducing the coexpression of different CsgA fibers. It is foreseen that living materials with user-defined curli composition hold great potential for the development of living materials for many biomedical applications.


Assuntos
Amiloide/química , Computadores Moleculares , Lógica , Nanofibras/química , Nanotecnologia/métodos , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Engenharia Genética , Recombinases/genética
20.
Hum Vaccin Immunother ; 15(9): 2013-2029, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31448974

RESUMO

Swine H1 influenza viruses were stable within pigs for nearly 70 years until in 1998 when a classical swine virus reassorted with avian and human influenza viruses to generate the novel triple reassortant H1N1 strain that eventually led to the 2009 influenza pandemic. Previously, our group demonstrated broad protection against a panel of human H1N1 viruses using HA antigens derived by the COBRA methodology. In this report, the effectiveness of COBRA HA antigens (SW1, SW2, SW3 and SW4), which were designed using only HA sequences from swine H1N1 and H1N2 isolates, were tested in BALB/c mice. The effectiveness of these vaccines were compared to HA sequences designed using both human and swine H1 HA sequences or human only sequences. SW2 and SW4 elicited antibodies that detected the pandemic-like virus, A/California/07/2009 (CA/09), had antibodies with HAI activity against almost all the classical swine influenza viruses isolated from 1973-2015 and all of the Eurasian viruses in our panel. However, sera collected from mice vaccinated with SW2 or SW4 had HAI activity against ~25% of the human seasonal-like influenza viruses isolated from 2009-2015. In contrast, the P1 COBRA HA vaccine (derived from both swine and human HA sequences) elicited antibodies that had HAI activity against both swine and human H1 viruses and protected against CA/09 challenge, but not a human seasonal-like swine H1N2 virus challenge. However, the SW1 vaccine protected against this challenge as well as the homologous vaccine. These results support the idea that a pan-swine-human H1 influenza virus vaccine is possible.


Assuntos
Anticorpos Antivirais/sangue , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Infecções por Orthomyxoviridae/prevenção & controle , Animais , Antígenos Virais/genética , Antígenos Virais/imunologia , Computadores Moleculares , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza/administração & dosagem , Influenza Humana/virologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/virologia , Suínos , Vacinas de Partículas Semelhantes a Vírus/imunologia
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