scholarly journals Toeholder: a software for automated design and in silico validation of toehold riboswitches

2021 ◽  
Author(s):  
Angel Fernando Cisneros Caballero ◽  
Francois D. Rouleau ◽  
Carla Bautista ◽  
Pascale Lemieux ◽  
Nathan Dumont-Leblond
Keyword(s):  
In Silico ◽  
Dynamic Range ◽  
Regulatory Elements ◽  
Automated Design ◽  
Design And Optimization ◽  
Potential Applications ◽  
Dynamics Simulations ◽  
Effective Use ◽  
Biological Circuits ◽  
High Throughput Experiments

Synthetic biology aims to engineer biological circuits, which often involve gene expression. A particularly promising group of regulatory elements are riboswitches because of their versatility with respect to their targets, but early synthetic designs were not as attractive because of a reduced dynamic range with respect to protein regulators. Only recently, the creation of toehold switches helped overcome this obstacle by also providing an unprecedented degree of orthogonality. However, a lack of automated design and optimization tools prevents the widespread and effective use of toehold switches in high-throughput experiments. To address this, we developed Toeholder, a comprehensive open-source software for toehold design and in silico benchmarking. Toeholder takes into consideration sequence constraints as well as data derived from molecular dynamics simulations of a toehold switch. We describe the software and its in silico validation results, as well as its potential applications and impacts on the management and design of toehold switches.

scholarly journals Toehold Switch-Based Genetic Modulator for Tuning of Riboswitch Sensor

2020 ◽  
Author(s):  
Yunhee Hwang ◽  
Seong Gyeong Kim ◽  
Sungho Jang ◽  
Jongmin Kim ◽  
Gyoo Yeol Jung
Keyword(s):  
Dose Response ◽  
Dynamic Range ◽  
De Novo ◽  
Stoichiometric Ratio ◽  
Design And Optimization ◽  
Cell Functions ◽  
Processing Module ◽  
Biological Circuits ◽  
Operational Range ◽  
Genetic Modulators

Abstract BackgroundSynthetic biological circuits are widely utilized to control microbial cell functions. Natural and synthetic riboswitches are attractive classes of sensor modules for use in synthetic biological applications. However, tuning the dose-response parameters of riboswitch circuits is challenging because considerable understanding of riboswitch mechanism and screening of mutant libraries are generally required. Therefore, novel molecular parts and strategies for controlling the dose-response parameters of riboswitch circuits are needed.ResultsHere, we developed a toehold switch-based genetic modulator that combines a previously reported hybrid input construct, which consists of riboswitch and transcriptional repressor, and de-novo-designed riboregulators named as toehold switches. First, the introduction of a pair of toehold switch and trigger as a downstream signal-processing module resulted in a functional riboswitch circuit. Next, several optimization strategies that focused on the stoichiometric ratio of RNA components greatly improved the fold-change. Finally, further characterizations confirmed low leakiness and high orthogonality for multiple toehold switches, indicating its applicability in riboswitch circuits in a seamless manner.ConclusionsThe toehold switch-based genetic modulator improved the dynamic range and dramatically shifted the operational range compared to the previous sensors only with hybrid input construct. The programmable RNA-RNA interactions amenable to in silico design and optimization can facilitate further development of RNA-based genetic modulators for flexible tuning of riboswitch circuitry and synthetic biosensors.

Effects of different wind directions on ventilation of surrounding areas of two generic building configurations in Hong Kong

2021 ◽  
pp. 1420326X2110160
Author(s):  
Kai Yip Lee ◽  
Cheuk Ming Mak
Keyword(s):  
Wind Velocity ◽  
Natural Ventilation ◽  
Urban Environments ◽  
Air Pressure ◽  
Pressure Distributions ◽  
Air Intake ◽  
Dynamics Simulations ◽  
Surrounding Areas ◽  
Effective Use ◽  
Velocity Zone

This study investigated effects of incident wind angles on wind velocity distributions in wakes of two generic building configurations, namely, ‘T’- and ‘+’-shaped, and the air pressure distributions along their leeward walls by using computational fluid dynamics simulations. Results show that when the wind approaches laterally (90°) (vs. when the wind is direct (0°)), the downwind length and maximum bilateral width of the low-wind velocity zone in the wake of ‘T’-shaped building decrease by 11.5% and 37.9%, respectively. When the incident wind is oblique (45°) (vs. when it is direct), the length and width of this low-wind velocity zone in the wake of ‘+’-shaped building decrease by 15.0% and 30.9%, respectively. Furthermore, results show that the air pressure on the leeward walls of the ‘T’- and ‘+’-shaped buildings gradually decreases along with the building height. The resulting low-wind conditions on upper floors of buildings reduce the fresh air intake of their leeward units utilizing natural ventilation. It is particularly apparent in the case of direct approaching wind. Thus, the appropriate selection of building configurations and their orientations allows for the most effective use of wind to enhance ventilation in indoor and urban environments.

scholarly journals Development of a New Sr-O Parameterization to Describe the Influence of SrO on Iron-Phosphate Glass Structural Properties Using Molecular Dynamics Simulations

Materials ◽  
2021 ◽  
Vol 14 (15) ◽  
pp. 4326
Author(s):  
Pawel Goj ◽  
Aleksandra Wajda ◽  
Pawel Stoch
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Interatomic Potential ◽  
Glass Structure ◽  
Ion Pairs ◽  
Glass Network ◽  
Iron Phosphate ◽  
Phosphate Glasses ◽  
Potential Applications ◽  
Dynamics Simulations

Iron-phosphate glasses, due to their properties, have many potential applications. One of the most promising seems to be nuclear waste immobilization. Radioactive 90Sr isotope is the main short-lived product of fission and, due to its high solubility, it can enter groundwater and pose a threat to the environment. On the other hand, Sr is an important element in hard tissue metabolic processes, and phosphate glasses containing Sr are considered bioactive. This study investigated the effect of SrO addition on a glass structure of nominal 30Fe2O3-70P2O5 chemical composition using classical molecular dynamics simulations. To describe the interaction between Sr-O ion pairs, new interatomic potential parameters of the Buckingham-type were developed and tested for crystalline compounds. The short-range structure of the simulated glasses is presented and is in agreement with previous experimental and theoretical studies. The simulations showed that an increase in SrO content in the glass led to phosphate network depolymerization. Analysis demonstrated that the non-network oxygen did not take part in the phosphate network depolymerization. Furthermore, strontium aggregation in the glass structure was observed to lead to the non-homogeneity of the glass network. It was demonstrated that Sr ions prefer to locate near to Fe(II), which may induce crystallization of strontium phosphates with divalent iron.

scholarly journals Insights into the deactivation of 5-bromouracil after ultraviolet excitation

2017 ◽  
Vol 375 (2092) ◽  
pp. 20160202 ◽  
Author(s):  
Francesca Peccati ◽  
Sebastian Mai ◽  
Leticia González
Keyword(s):  
Gas Phase ◽  
Ground State ◽  
Surface Hopping ◽  
Ultraviolet Excitation ◽  
Quantum Chemistry Calculations ◽  
Electronic Structure Methods ◽  
Dna Strands ◽  
Potential Applications ◽  
Adiabatic Dynamics ◽  
Dynamics Simulations

5-Bromouracil is a nucleobase analogue that can replace thymine in DNA strands and acts as a strong radiosensitizer, with potential applications in molecular biology and cancer therapy. Here, the deactivation of 5-bromouracil after ultraviolet irradiation is investigated in the singlet and triplet manifold by accurate quantum chemistry calculations and non-adiabatic dynamics simulations. It is found that, after irradiation to the bright ππ * state, three main relaxation pathways are, in principle, possible: relaxation back to the ground state, intersystem crossing (ISC) and C–Br photodissociation. Based on accurate MS-CASPT2 optimizations, we propose that ground-state relaxation should be the predominant deactivation pathway in the gas phase. We then employ different electronic structure methods to assess their suitability to carry out excited-state dynamics simulations. MRCIS (multi-reference configuration interaction including single excitations) was used in surface hopping simulations to compute the ultrafast ISC dynamics, which mostly involves the 1 n O π * and 3 ππ * states. This article is part of the themed issue ‘Theoretical and computational studies of non-equilibrium and non-statistical dynamics in the gas phase, in the condensed phase and at interfaces’.

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