抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) and molecular mechanics generalized Born surface area (MM/GBSA) are arguably very popular methods for binding free energy prediction since they are more accurate than most scoring functions of molecular docking and less computationally demanding than alchemical free energy methods. MM/PBSA and MM/GBSA have been widely used in biomolecular studies such as protein folding, protein-ligand binding, protein-protein interaction, etc. In this review, methods to adjust the polar solvation energy and to improve the performance of MM/PBSA and MM/GBSA calculations are reviewed and discussed. The latest applications of MM/GBSA and MM/PBSA in drug design are also presented. This review intends to provide readers with guidance for practically applying MM/PBSA and MM/GBSA in drug design and related research fields.

End-Point Binding Free Energy Calculation with MM/PBSA and MM/GBSA: Strategies and Applications in Drug Design

Rapid progress in identifying biomarkers that are hallmarks of disease has increased demand for high-performance detection technologies. Implementation of electrochemical methods in clinical analysis may provide an effective answer to the growing need for rapid, specific, inexpensive, and fully automated means of biomarker analysis. This Review summarizes advances from the past 5 years in the development of electrochemical sensors for clinically relevant biomolecules, including small molecules, nucleic acids, and proteins. Various sensing strategies are assessed according to their potential for reaching relevant limits of sensitivity, specificity, and degrees of multiplexing. Furthermore, we address the remaining challenges and opportunities to integrate electrochemical sensing platforms into point-of-care solutions.

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Electrochemical Methods for the Analysis of Clinically Relevant Biomolecules

Developing powerful, simple and low-cost DNA amplification techniques is of great significance to bioanalysis and biomedical research Thus far, many signal amplification strategies have been developed, such as polymerase chain reaction (PCR), rolling circle amplification (RCA), and DNA strand displacement amplification (SDA) In particular, hybridization chain reaction (HCR), a type of toehold-mediated strand displacement (TMSD) reaction, has attracted great interest because of its enzyme-free nature, isothermal conditions, simple protocols, and excellent amplification efficiency In a typical HCR, an analyte initiates the cross-opening of two DNA hairpins, yielding nicked double helices that are analogous to alternating copolymers As an efficient amplification platform, HCR has been utilized for the sensitive detection of a wide variety of analytes, including nucleic acids, proteins, small molecules, and cells In recent years, more complicated sets of monomers have been designed to develop nonlinear HCR, such as branched HCR and even dendritic systems, achieving quadratic and exponential growth mechanisms In addition, HCR has attracted enormous attention in the fields of bioimaging and biomedicine, including applications in fluorescence in situ hybridization (FISH) imaging, live cell imaging, and targeted drug delivery In this review, we introduce the fundamentals of HCR and examine the visualization and analysis techniques for HCR products in detail The most recent HCR developments in biosensing, bioimaging, and biomedicine are subsequently discussed with selected examples Finally, the review provides insight into the challenges and future perspectives of HCR

Hybridization chain reaction: a versatile molecular tool for biosensing, bioimaging, and biomedicine

Dynamic DNA nanotechnology, a subfield of DNA nanotechnology, is concerned with the study and application of nucleic acid strand-displacement reactions. Strand-displacement reactions generally proceed by three-way or four-way branch migration and initially were investigated for their relevance to genetic recombination. Through the use of toeholds, which are single-stranded segments of DNA to which an invader strand can bind to initiate branch migration, the rate with which strand displacement reactions proceed can be varied by more than 6 orders of magnitude. In addition, the use of toeholds enables the construction of enzyme-free DNA reaction networks exhibiting complex dynamical behavior. A demonstration of this was provided in the year 2000, in which strand displacement reactions were employed to drive a DNA-based nanomachine (Yurke, B.; et al. Nature 2000, 406, 605–608). Since then, toehold-mediated strand displacement reactions have been used with ever increasing sophistication and the field of dynam...

Principles and Applications of Nucleic Acid Strand Displacement Reactions

We have designed programmable DNA-based nanoswitches whose closing/opening can be triggered over specific different pH windows. These nanoswitches form an intramolecular triplex DNA structure through pH-sensitive parallel Hoogsteen interactions. We demonstrate that by simply changing the relative content of TAT/CGC triplets in the switches, we can rationally tune their pH dependence over more than 5 pH units. The ability to design DNA-based switches with tunable pH dependence provides the opportunity to engineer pH nanosensors with unprecedented wide sensitivity to pH changes. For example, by mixing in the same solution three switches with different pH sensitivity, we developed a pH nanosensor that can precisely monitor pH variations over 5.5 units of pH. With their fast response time (<200 ms) and high reversibility, these pH-triggered nanoswitches appear particularly suitable for applications ranging from the real-time monitoring of pH changes in vivo to the development of pH sensitive smart nanomaterials.

/pdf/programmable-ph-triggered-dna-nanoswitches-fzonycyq5v.pdf

Programmable pH-triggered DNA nanoswitches.

Triplex nucleic acids have recently attracted interest as part of the rich "toolbox" of structures used to develop DNA-based nanostructures and materials. This Review addresses the use of DNA triplexes to assemble sensing platforms and molecular switches. Furthermore, the pH-induced, switchable assembly and dissociation of triplex-DNA-bridged nanostructures are presented. Specifically, the aggregation/deaggregation of nanoparticles, the reversible oligomerization of origami tiles and DNA circles, and the use of triplex DNA structures as functional units for the assembly of pH-responsive systems and materials are described. Examples include semiconductor-loaded DNA-stabilized microcapsules, DNA-functionalized dye-loaded metal-organic frameworks (MOFs), and the pH-induced release of the loads. Furthermore, the design of stimuli-responsive DNA-based hydrogels undergoing reversible pH-induced hydrogel-to-solution transitions using triplex nucleic acids is introduced, and the use of triplex DNA to assemble shape-memory hydrogels is discussed. An outlook for possible future applications of triplex nucleic acids is also provided.

Triplex DNA Nanostructures: From Basic Properties to Applications.

Selective configuration control of plasmonic nanostructures using either top-down or bottom-up approaches has remained challenging in the field of active plasmonics. We demonstrate the realization of DNA-assembled reconfigurable plasmonic metamolecules, which can respond to a wide range of pH changes in a programmable manner. This programmability allows for selective reconfiguration of different plasmonic metamolecule species coexisting in solution through simple pH tuning. This approach enables discrimination of chiral plasmonic quasi-enantiomers and arbitrary tuning of chiroptical effects with unprecedented degrees of freedom. Our work outlines a new blueprint for implementation of advanced active plasmonic systems, in which individual structural species can be programmed to perform multiple tasks and functions in response to independent external stimuli.

/pdf/selective-control-of-reconfigurable-chiral-plasmonic-11z398ve7m.pdf

Selective control of reconfigurable chiral plasmonic metamolecules

A wide range of molecular devices with nanoscale dimensions have been recently designed to perform a variety of functions in response to specific molecular inputs. Only limited examples, however, utilize antibodies as regulatory inputs. In response to this, here we report the rational design of a modular DNA-based nanomachine that can reversibly load and release a molecular cargo on binding to a specific antibody. We show here that, by using three different antigens (including one relevant to HIV), it is possible to design different DNA nanomachines regulated by their targeting antibody in a rapid, versatile and highly specific manner. The antibody-powered DNA nanomachines we have developed here may thus be useful in applications like controlled drug-release, point-of-care diagnostics and in vivo imaging.

/pdf/antibody-powered-nucleic-acid-release-using-a-dna-based-21vo15kfyv.pdf

Antibody-powered nucleic acid release using a DNA-based nanomachine

The availability of sensors able to rapidly detect SARS-CoV-2 directly in biological fluids in a single step would allow performing massive diagnostic testing to track in real time and contain the spread of COVID-19. Motivated by this, here, we developed an electrochemical aptamer-based (EAB) sensor able to achieve the rapid, reagentless, and quantitative measurement of the SARS-CoV-2 spike (S) protein. First, we demonstrated the ability of the selected aptamer to undergo a binding-induced conformational change in the presence of its target using fluorescence spectroscopy. Then, we engineered the aptamer to work as a bioreceptor in the EAB platform and we demonstrated its sensitivity and specificity. Finally, to demonstrate the clinical potential of the sensor, we tested it directly in biological fluids (serum and artificial saliva), achieving the rapid (minutes) and single-step detection of the S protein in its clinical range.

Andrea Idili

Papers

Programmable pH-triggered DNA nanoswitches.

Triplex DNA Nanostructures: From Basic Properties to Applications.

Selective control of reconfigurable chiral plasmonic metamolecules

Antibody-powered nucleic acid release using a DNA-based nanomachine

Rapid and Efficient Detection of the SARS-CoV-2 Spike Protein Using an Electrochemical Aptamer-Based Sensor.