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Cellulose/collagen composites have been widely used in biomedicine and tissue engineering. Interfacial interactions are crucial in determining the final properties of cellulose/collagen composite. Molecular dynamics simulations were carried out to gain insights into the interactions between cellulose and collagen. It has been found that the structure of collagen remained intact during adsorption. The results derived from umbrella sampling showed that (110) and ([Formula: see text]) faces exhibited the strongest affinity with collagen (100) face came the second and (010) the last, which could be attributed to the surface roughness and hydrogen-bonding linkers involved water molecules. Cellulose planes with flat surfaces and the capability to form hydrogen-bonding linkers produce stronger affinity with collagen. The occupancy of hydrogen bonds formed between cellulose and collagen was low and not significantly contributive to the binding affinity. These findings provided insights into the interactions between cellulose and collagen at the molecular level, which may guide the design and fabrication of cellulose/collagen composites.

Early diagnosis of rheumatoid arthritis (RA) is crucial to prevent deterioration and improve the prognosis of disease outcome. However, current clinical diagnostic methods are unable to achieve accurate and early detection of RA. In this work, we designed an activatable organic nanoprobe (

Electrochromic devices (ECDs) are in high demand for many applications; however, there is no ideal method to achieve the full recycling of the substrate and the functional layer in ECDs. Currently, it is still challenging to access ECDs with excellent electrochromic property, good degradability, and facile recycling capability. In this study, high-performance ECDs are successfully fabricated by using poly(3,4-ethylene dioxythiophene):poly(styrenesulfonate) as the functional layer and transparent gelatin film (TGF) derived from pigskin as the substrate. Compared with PET films or PET-based ECDs, the optical transmittance of TGF and the coloration efficiency of our ECDs could be increased by 3.2 and 41.4%, respectively, showing a great potential to replace conventional plastic-based ECDs. Furthermore, the TGF not only showed good biodegradability but also could be regenerated via a simple process without the loss of desirable properties. In addition, the functional layer and substrate can be easily separated in water due to the adjusted interactions of the interface and the unique property of gelatin, which may open a new path for fabricating green electronics.

The accurate detection of related biomarkers at early stage is crucial in diagnosis and therapy of cancer. Small molecule fluorescence probes stand out acting as efficient tools to detect biomolecules, especially biomacromolecules. Herein, a new probe that features excimer formation has been designed to detect cancer-related biomarker alkaline phosphatase(ALP). The probe shows high sensitivity to ALP with a low limit detection of 0.13 U/L and high selectivity with resistance to the interference in the complex physiological system. Furthermore, this probe presents good biocompatibility with negligible cytotoxicity and displays remarkable cell imaging functions, which allows for its application in biosystems. Theoretical simulation validates the high affinity of the probe with ALP and depicts the details of the interaction modes, which provides the possible mechanisms underlying the efficient detection of the probe in atomic level. The study of synthesis, properties and applications of the activatable emissive excimers not only enriches the tools to detect ALP, but also provides a new strategy to comprehend the pathogenic mechanism of enzyme-related diseases. Ministry of Education (MOE) Nanyang Technological University This work was supported by the National Natural Science Foundation of China(Nos.21904105, 22074120), the Fund of Nanyang Technological University, Singapore(No.NTU-SUG: M4081627.120) and the Singapore Ministry of Education, Academic Research Fund Tier 1(Nos.2019-T1-002-045, 2018-T1-001-173) and Academic Research Fund Tier 2(No.MOE2018-T2-2-042).

Cellulose/collagen composites have been widely used in biomedicine and tissue engineering. Interfacial interactions are crucial in determining the final properties of cellulose/collagen composite. Molecular dynamics simulations were carried out to gain insights into the interactions between cellulose and collagen. It has been found that the structure of collagen remained intact during adsorption. The results derived from umbrella sampling showed that (110) and (1-10) faces exhibited the strongest affinity with collagen, (100) face came the second and (010) the last, which could be attributed to the surface roughness and hydrogen-bonding linkers involved water molecules. Cellulose planes with flat surfaces and the capability to form hydrogen-bonding linkers produce stronger affinity with collagen. The occupancy of hydrogen bonds formed between cellulose and collagen was low and not significantly contributive to the binding affinity. These findings provided insights into the interactions between cellulose and collagen at the molecular level, which may guide the design and fabrication of cellulose/collagen composites.

Cellulose nanomaterials, such as cellulose nanocrystals (CNCs), have received enormous attention in various material research fields due to their unique properties and green/sustainable nature, among other qualities. Herein, we report hollow-type annular cellulose nanocrystals (HTA-CNCs), which are generated by following a high-intensity ultrasonic treatment. The advanced aberration-corrected transmission electron microscopy results reveal that HTA-CNCs exhibit ring structures with a typical diameter of 10.0-30.0 nm, a width of 3.0-4.0 nm, and a thickness of 2.0-5.0 nm, similar to those of elementary crystallites. The X-ray diffraction measurements show that the as-prepared HTA-CNCs maintain the cellulose I structure. The changes in structure and hydrogen-bonding characteristics of HTA-CNCs are further determined based on the FT-IR results after deconvolution fitting, showing that three types of hydrogen bonds decrease and the content of free OH increases in HTA-CNCs compared with those in the original CNCs. Furthermore, molecular dynamics simulation is carried out to support the experimental study. The formation of HTA-CNCs might be attributed to the structural change and entropy increase. The hollow-type annular CNCs may have broad value-added applications as cellulose nanomaterials in different fields.

Photoacoustic imaging (PAI) has attracted increasing attention both in basic research and clinical applications. PAI in the second near-infrared (NIR-II) window shows deeper penetration depth, better spatial resolution, higher maximum permissible exposure, and lower background noise than PAI in the first near-infrared (NIR-I) window. By introducing contrast agents, NIR-II PAI enables visualization of biological processes occurring at depths of several centimeters. Herein, we review a variety of contrast agents ranging from inorganic materials to organic materials and their further development as activatable NIR-II PAI probes to change their signals in response to a biomarker of interest. The physical and biochemical characteristics of the existing photoacoustic contrast agents are discussed, with their potential applications highlighted. Finally, potential challenges and prospects in the investigation of NIR-II PAI contrast agents in biomedical research are discussed.

Hydrogen sulfide (H2S) is a vital endogenous signal molecule that exerts critical physiological functions such as biological regulation and cytoprotection. Despite significant progress in developing H2S donors, site-specific delivery and controllable release of H2S in biological systems remain a key challenge. Herein, we develop new Cys-triggered fluorescent H2S donor Pro-S that is composed of a dicyanoisophorone-based near-infrared (NIR) fluorescent dye and a thiocarbamate moiety. The H2S donor releases H2S under the attack of Cys, accompanied by the release of a fluorescent reporter, which enables the real-time capturing of H2S by fluorescence spectroscopy or microscopy. Pro-S exhibits strong NIR fluorescence enhancement (70-fold), excellent controllable H2S release (30 min), high H2S release efficiency (62%), and well live-cell compatibility, allowing for visualization of H2S release in cells and zebrafish. Moreover, Pro-S presents a good effect of anti-inflammation in RAW 264.7 cells. This work provides a new idea for the design of H2S donors, which may be beneficial to the comprehension of the potential mechanism of inflammation and optimization of treatment strategies.

Despite widespread use of heterogeneous Pd catalysts in Suzuki-Miyaura coupling reactions, detailed roles of Pd, especially the nature of its active species, are still a topic of controversial debate. While some studies showed an active surface of Pd nanoparticles or nanoclusters acting heterogeneously, others claimed soluble Pd species leached from the metallic Pd to be active species which are homogeneous in nature. Besides, within the homogeneous mechanism, how the Pd leaches and promotes the cross-coupling reaction is then another question that needs to be addressed. It could be envisioned that if the soluble Pd species and solid-phase Pd are physically separated, the mechanism of Suzuki-Miyaura coupling could then be confirmed through examining the catalytic activity in different reaction regions. Herein we use microporous Stöber silica as a membrane to separate the soluble Pd species from solid Pd and conduct size-selective reactions which allow the passage of leaching Pd species, but not of reactants or products larger than the membrane aperture. With this strategy, we have been able to differentiate the surface reaction from the solution cross-coupling. We find that the leached Pd species are the only genuine catalytic intermediate in the cross-coupling reactions. We also confirm that oxidative addition of aryl halides to the solid Pd leads to leaching of the soluble Pd species which is necessary to promote Suzuki-Miyaura reactions.

Theranostics that integrates diagnosis and treatment modalities has attracted great attention due to its abilities of personalized therapy and real-time monitoring of therapeutic outcome. Such a theranostic paradigm requires agents to simultaneously possess the capabilities of targeting, imaging, and treatment. Activatable molecular agents (AMAs) are promising for cancer theranostics, as they show a higher signal-to-noise ratio (SNR), real-time detection of cancer-associated biomarkers, lower normal tissue toxicity, and a higher therapeutic effect. This perspective summarizes the recent advancements of AMAs, which include imaging-guided chemotherapy, imaging-guided photodynamic therapy, and imaging-guided photothermal therapy. The molecular design principles, theranostic mechanisms, and biomedical applications of AMAs are described, followed by a discussion of potential challenges of AMAs in cancer theranostics., Activatable molecualr agents that intergrate diagnosis and treatment modalities have attracted great attention due to its abilities of personalized therapy and real-time monitoring of therapeutic outcome.

Melatonin helps to maintain circadian rhythm, exerts anticancer activity, and plays key roles in regulation of glucose homeostasis and energy metabolism. Glycosylation, a form of metabolic flux from glucose or other monosaccharides, is a common post-translational modification. Dysregulated glycosylation, particularly O-GlcNAcylation, is often a biomarker of cancer cells. In this study, elevated O-GlcNAc level in bladder cancer was inhibited by melatonin treatment. Melatonin treatment inhibited proliferation and migration and enhanced apoptosis of bladder cancer cells. Proteomic analysis revealed reduction in cyclin-dependent-like kinase 5 (CDK5) expression by melatonin. O-GlcNAc modification determined the conformation of critical T-loop domain on CDK5 and further influenced the CDK5 stability. The mechanism whereby melatonin suppressed O-GlcNAc level was based on decreased glucose uptake and metabolic flux from glucose to UDP-GlcNAc, and consequent reduction in CDK5 expression. Melatonin treatment, inhibition of O-GlcNAcylation by OSMI-1, or mutation of key O-GlcNAc site strongly suppressed in vivo tumor growth. Our findings indicate that melatonin reduces proliferation and promotes apoptosis of bladder cancer cells by suppressing O-GlcNAcylation of CDK5.

Activation of signal transducer and activator of transcription 3 (STAT3) is associated with hypoxia-induced epithelial-mesenchymal transition (EMT). Activation of STAT3 requires its phosphorylated form, and STAT3 can also be post-translationally modified by O-GlcNAcylation. Dynamic regulation of STAT3 O-GlcNAcylation in relation to STAT3 phosphorylation remains poorly understood. We observed, based on chemical enzyme labeling and click chemistry methods in combination with mass spectrometric analysis, that O-GlcNAcylation of STAT3 is significantly reduced under hypoxia. Results of functional experiments indicated that O-GlcNAcylation maintains stability of STAT3 and prevents its degradation via ubiquitination during hypoxia-induced EMT. O-GlcNAcylation of STAT3 facilitated its phosphorylation. Following STAT3 phosphorylation, existing STAT3 O-GlcNAcylation was antagonistically released. Our experimental findings, in combination with structure modeling, indicate that O-GlcNAcylation of STAT3 at residue T717 is essential for its phosphorylation at Y705. In contrast, mutation of STAT3 at phosphorylation site Y705 had no effect on its O-GlcNAcylation. O-GlcNAcylation and phosphorylation of STAT3 evidently occur in a strict sequential order under hypoxia-induced EMT. Dynamic regulation of STAT3 function clearly involves crosstalk between O-GlcNAcylation and phosphorylation. O-GlcNAcylation of STAT3 at T717 facilitates EMT process by promoting STAT3 phosphorylation, and provides a potential therapeutic target that may be useful in anticancer drug design.

The interactions of complement receptor 2 (CR2) and the degradation fragment C3d of complement component C3 mediate the innate and adaptive immune systems. Due to the importance of C3d-CR2 interaction in the design of vaccines, many studies have indicated the interactions are pH-dependent. Moreover, C3d-CR2 interactions at pH 5.0 are unknown. To investigate the molecular mechanism of pH-regulating C3d-CR2 interaction, molecular dynamics simulations for C3d-CR2 complex in different pH are performed. Our results revealed that the protonation of His9 in C3d at pH 6.0 slightly weakens C3d-CR2 association as reducing pH from 7.4 to 6.0, initiated from a key hydrogen bond formed between Gly270 and His9 in C3d at pH 6.0. When reducing pH from 6.0 to 5.0, the protonation of His33 in C3d weakens C3d-SCR1 association by changing the hydrogen-bond network of Asp36, Glu37, and Glu39 in C3d with Arg13 in CR2. In addition, the protonation of His90 significantly enhances C3d-SCR2 association. This is because the enhanced hydrogen-bond interactions of His90 with Glu63 and Ser69 of the linker change the conformations of the linker, Cys112-Asn116 and Pro87-Gly91 regions. This study uncovers the molecular mechanism of the mediation of pH on C3d-CR2 interaction, which is valuable for vaccine design.

Hydrogen sulfide (H

Small-molecular fluorescence sensors have become promising detection tools in many fields attributing to their high sensitivity, excellent temporal and spatial resolution, and low cytotoxicity. However, high concentration or aggregation-induced fluorescence quenching effect has usually hindered the development of traditional fluorescence dyes. Herein, a new fluorophore cyanovinylene dye BMZ with excimer emission property has been constructed. It shows an obvious enhanced and red-shift emission upon aggregation in aqueous solution, which overmatches the conventional pyrene with longer absorption and emission wavelengths. Using this unique optical property, a new fluorescence probe BMZ-Gal has been developed for trapping of β-galactosidase (β-Gal) activity with high selectivity, low limit of detection of 0.17 U, and rapid recognition, which is based on the β-Gal-induced formation of red-shift emitting excimer. β-Gal has a strong affinity for BMZ-Gal, which is verified through the Michaelis-Menten constants (Km, 1.87 μM) and the hydrolysis efficiencies (Kcat/Km, 1.78 × 103 M-1 s-1). Furthermore, the assay system has been successfully used for detecting endogenous β-Gal in living ovarian cancer cells and can passively targeted to identify β-Gal in organelle level and determine its subcellular location with satisfactory accuracy. We anticipate that the new fluorophore cyanovinylene dye herein may inaugurate new opportunities for the development of excimer emission sensors.

Constructing imprinting materials with high recognition and selectivity for protein is an always challenge in protein imprinting technology (PIT). In this work, upon the participating of a zwitterionic polymer chain (Poly (1-vinyl-3-sulfopropylimidazolium), PVSP), a lysozyme imprinted core-shell carbon microsphere (CFC-PVSP@MIPs) was prepared by combining template immobilization method and surface imprinting technology. The carboxyl-functionalized carbon microspheres as substrate provided the CFC-PVSP@MIPs satisfactory adsorption capacity (68.1 mg g−1), while the dopamine as a functional monomer and crosslinker allowed the imprinted microspheres to have a thin imprinted shell, thus endowing them a fast adsorption equilibrium rate (120 min). In addition, PVSP could be tightly bound to the imprinted layer through non-covalent interaction, which not only simplified the preparation process of CFC-PVSP@MIPs, but also reduced the non-specific adsorption of imprinted material on proteins. Therefore, the resulting CFC-PVSP@MIPs exhibited a more superior recognition ability towards lysozyme with imprinting factor value of 3.10, compared with the PVSP-free imprinted microsphere (imprinting factor value 1.93). Furthermore, benefiting from the characteristics of zwitterionic groups, CFC-PVSP@MIPs also revealed stronger selectivity in competitive adsorption studies of binary protein mixture samples. Consequently, the proposed strategy would be a promising and convenient way to obtain protein imprinted material with high recognition ability, thus would be conducive to further development and application of PIT.

Prion diseases are neurodegenerative disorders characterized by the aggregation of an abnormal form of prion protein. The interaction of prion protein and cellular membrane is crucial to elucidate the occurrence and development of prion diseases. Its fragment, residues 106-126, has been proven to maintain the pathological properties of misfolded prion and was used as a model peptide. In this study, explicit solvent molecular dynamics (MD) simulations were carried out to investigate the adsorption, folding and aggregation of PrP106-126 with different sizes (2-peptides, 4-peptides and 6-peptides) on the surface of both pure neutral POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) and negatively charged POPC/POPG (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol) (3:1) lipids. MD simulation results show that PrP106-126 display strong affinity with POPC/POPG but does not interact with pure POPC. The positively charged and polar residues participating hydrogen bonding with membrane promote the adsorption of PrP106-126. The presence of POPC and POPC/POPG exert limited influence on the secondary structures of PrP106-126 and random coil structures are predominant in all simulation systems. Upon the adsorption on the POPC/POPG surface, the aggregation states of PrP106-126 have been changed and more small oligomers were observed. This work provides insights into the interactions of PrP106-126 and membranes with different compositions in atomic level, which expand our understanding the role membrane plays in the development of prion diseases. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.

Biological gels generally require polymeric chains that produce long‐lived physical entanglements. Low molecular weight colloids offer an alternative to macromolecular gels, but often require ad‐hoc synthetic procedures. Here, a short biomimetic peptide composed of eight amino acid residues derived from squid sucker ring teeth proteins is demonstrated to form hydrogel in water without any cross‐linking agent or chemical modification and exhibits a stiffness on par with the stiffest peptide hydrogels. Combining solution and solid‐state NMR, circular dichroism, infrared spectroscopy, and X‐ray scattering, the peptide is shown to form a supramolecular, semiflexible gel assembled from unusual right‐handed 3_10‐helices stabilized in solution by π–π stacking. During gelation, the 3_10‐helices undergo conformational transition into antiparallel β‐sheets with formation of new interpeptide hydrophobic interactions, and molecular dynamic simulations corroborate stabilization by cross β‐sheet oligomerization. The current study broadens the range of secondary structures available to create supramolecular hydrogels, and introduces 3_10‐helices as transient building blocks for gelation via a 3_10‐to‐β‐sheet conformational transition., Advanced Science, 6 (21), ISSN:2198-3844

It was observed in experiments that the catalytic domain (CD) of Trichoderma reesei Cel7A (TrCel7A) hydrolyzes crystalline cellulose in a processive manner, but the underlying binding mechanism is still unknown. Here, through replica-exchange molecular dynamics simulations, we find that the loading and sucking-in process of the cellulose chain into CD is entropy-driven and enthalpy-unfavorable, which firmly relate to the desolvation of the binding channel of CD. During the loading process, hydrophobic interactions play a dominant role because several aromatic residues have been identified to guide the cellulose chain processing. At the active site, a transition from enthalpy- to entropy-driven is detected for the driving force. Such a finding reveals the indispensability of the catalytic reaction of the glycosidic bond to provide the energy to drive the movements of the cellulose chain. Our study reveals the interaction pictures between the cellulose chain and TrCel7A at the atomic level, which helps better understand the catalytic mechanism of TrCel7A. This work was supported by the National Natural Science Foundation of China under Grant 11874238 and Shandong Provincial Natural Science Foundation under Grant ZR2018MA043. The authors also acknowledge the support from the Fundamental Research Funds of Shandong University and State Key Laboratory of Microbial Technology Open Projects Fund (Project No. M2017-03).

The active metabolite GS-461203 of hepatitis C virus (HCV) non-structural protein 5B (NS5B) inhibitor sofosbuvir can stall RNA synthesis or replication by competitively inhibiting the natural substrate nucleoside triphosphate like UTP. Unfortunately, S282T mutant can lead to the resistance to sofosbuvir. Here, the detailed binding mechanism and unbinding process of GS-461203 and UTP to HCV NS5B were unraveled by using conventional molecular dynamics (MD) simulation and steered molecular dynamics (SMD) simulation. Our simulation results demonstrate that both polar and nonpolar interactions are favorable for GS-461203 and UTP binding. Meanwhile, we also identified the key residues responsible for GS-461203 and UTP binding in NS5B-RNA together with the three unbinding process steps including translation, reversal of base and ribose and complete divorce. The 2′-fluoro-2′-C-methyl ribose of GS-461203 can form stronger polar and nonpolar interactions with residues S282 and I160 than UTP. The results can also explain the reason why GS-461203 can effectively be incorporated into RNA synthesis or replication. In the S282T mutant system, the binding affinity attenuation of UTP relative to wild type HCV NS5B is less than that of GS-461203. The obtained binding and unbinding mechanism of HCV NS5B with the inhibitor GS-461203 and substrate in our work will provide useful guidance for the development of new and effective HCV NS5B inhibitors with low resistance.

S-Palmitoylation is a key regulatory mechanism controlling protein targeting, localization, stability, and activity. Since increasing evidence shows that its disruption is implicated in many human diseases, the identification of palmitoylation sites is attracting more attention. However, the computational methods that are published so far for this purpose have suffered from a poor balance of sensitivity and specificity; hence, it is difficult to get a good generalized prediction ability on an external validation set, which holds back the further analysis of associations between disruption of palmitoylation and human inherited diseases. In this work, we present a reliable identification method for protein S-palmitoylation sites, called SeqPalm, based on a series of newly composed features from protein sequences and the synthetic minority oversampling technique. With only 16 extracted key features, this approach achieves the most favorable prediction performance up to now with sensitivity, specificity, and Matthew's correlation coefficient values of 95.4%, 96.3%, and 0.917, respectively. Then, all known disease-associated variations are studied by SeqPalm. It is found that 243 potential loss or gain of palmitoylation sites are highly associated with human inherited disease. The analysis presents several potential therapeutic targets for inherited diseases associated with loss or gain of palmitoylation function. There are even biological evidence that are coordinate with our prediction results. Therefore, this work presents a novel approach to discover the molecular basis of pathogenesis associated with abnormal palmitoylation. SeqPalm is now available online at http://lishuyan.lzu.edu.cn/seqpalm , which can not only annotate the palmitoylation sites of proteins but also distinguish loss or gain of palmitoylation sites by protein variations.

Hydrazine has been applied diffusely in most of the chemical industry; however, it is a hazardous environmental pollutant and highly toxic to organisms. Selective, rapid, and sensitive detection of hydrazine thus becomes absolutely necessary in both biological and environmental sciences. Accordingly, fluorescence probes for hydrazine have been paid great attention in recent years. Disclosed here is the near-infrared (NIR) fluorescence probe with a turn-on fluorescent probe CyJ based on the structure-emission property relationships of the NIR dyes containing an acetyl group as the recognizing moiety. This new probe not only can be readily prepared, but also shows excellent sensing properties. First and most important of all, CyJ is highly selective for N2H4 over various anions, cations, and other amino compounds and has a low limit of detection (LOD) of hydrazine (5.4 ppb as fluorescence sensor and 6.1 ppb as UV sensor). Besides, CyJ exhibited a dramatic increase in fluorescence at λmax = 706 nm in the presence of N2H4, and it offers a rapid, colorimetric and vapor sensing detection process for N2H4 in both aqueous solution and diluted human serum. Furthermore, CyJ has good cell-membrane permeability and low cytotoxicity. In addition, we have successfully applied the CyJ to visualize N2H4 in live mouse and, for the first time, in tissues such as the liver, lung, kidney, heart, and spleen.

With increasing interest in optical in vivo imaging, there is a corresponding increase in demand for near-infrared (NIR) dyes. Such probes can be used, for example, to detect intracellular GSH, which would be helpful for understanding the mechanisms of diseases. In this work, we report a cyanine-based fluorescent probe that undergoes biothiol-promoted specific O-S cleavage and subsequent self-immolation through intramolecular 1,6-elimination. In addition, we investigated the cell viability of the system and successfully applied the probe to living cells, in vivo, and in various tissues.

Natural polyphenols are one of the most actively investigated categories of amyloid inhibitors, and resveratrol has recently been reported to inhibit and remodel the human islet amyloid polypeptide (hIAPP) oligomers and fibrils. However, the exact mechanism of its action is still unknown, especially for the full-length hIAPP1-37. To this end, we performed all-atom molecular dynamics simulations for hIAPP1-37 pentamer with and without resveratrol. The obtained results show that the binding of resveratrol is able to cause remarkable conformational changes of hIAPP1-37 pentamer, in terms of secondary structures, order degree, and morphology. By clustering analysis, two possible binding sites of resveratrol on the hIAPP1-37 pentamer were found, located at the grooves of the top and bottom surfaces of β-sheet layer, respectively. After the binding free energy calculation and residue energy decomposition, it can be concluded that the bottom site is the more possible one, and that the nonpolar interactions act as the driving force for the binding of hIAPP1-37 to resveratrol. In addition, Arg11 is the most important residue for the binding of resveratrol. The full understanding of inhibitory mechanism of resveratrol on the hIAPP1-37 oligomer, and the identification of its binding sites on this protein are helpful for the future design and discovery of new amyloid inhibitors.

Synthetic water channels offer great promise to replace natural aquaporins (AQPs) for making new‐generation biomimetic membranes for water treatment. However, the water permeability of the current synthetic water channels is still far below that of AQPs. Here, peptide‐attached (pR)‐pillar[5]arene (pR‐PH) channels are reported to mimic the high permeability of AQPs. It is demonstrated that the pR‐PH channels with an open pore can transport water smoothly and efficiently. The pR‐PH channels are competitive with AQPs in terms of water permeability and are much superior to diastereomer peptide‐attached (pS)‐pillar[5]arene (pS‐PH) and other reported synthetic water channels. The exceptional water‐transport properties of the pR‐PH channels are further demonstrated in a composite polymeric membrane that incorporates the nanochannels into the top selective layer. This membrane gives a significantly improved water flux while retaining high salt rejection. The results establish a tangible foundation for developing highly efficient artificial water channel‐based biomimetic membrane for water purification applications. Economic Development Board (EDB) National Research Foundation (NRF) Public Utilities Board (PUB) Accepted version The authors thank Prof. William B. Krantz from University of Colorado for comments on the manuscript and for editing the text. This work was supported by PUB, Singapore’s National Water Agency and a grant from the Singapore National Research Foundation (EWI 1501-IRIS-04). The funding support from the Singapore Economic Development Board to the Singapore Membrane Technology Centre (SMTC) is gratefully acknowledged.

The fragment 106-126 of prion protein exhibits similar properties to full-length prion. Experiments have shown that the A117V mutation enhances the aggregation of PrP106-126, while the H111S mutation abolishes the assembly. However, the mechanism of the change in the aggregation behavior of PrP106-126 upon the two mutations is not fully understood. In this study, replica exchange molecular dynamics simulations were performed to investigate the conformational ensemble of the WT PrP106-126 and its two mutants A117V and H111S. The obtained results indicate that the three species are all intrinsically disordered but they have distinct morphological differences. The A117V mutant has a higher propensity to form β-hairpin structures than the WT, while the H111S mutant has a higher population of helical structures. Furthermore, the A117V mutation increases the hydrophobic solvent accessible surface areas of PrP106-126 and the H111S mutation reduces the exposure of hydrophobic residues. It can be concluded that the difference in populations of β-hairpin structures and the change of hydrophobic solvent accessible areas may induce the different aggregation behaviors of the A117V and the H111S mutated PrP106-126. Understanding why the two mutations have contrary effects on the aggregation of PrP106-126 is very meaningful for further elucidation of the mechanism underlying aggregation and design of inhibitor against aggregation process.

The near-infrared (NIR) fluorescence sensor for rapid, selective, and sensitive detection of cystenine (Cys) is of great importance in both biological and environmental sciences. Herein, we report a specific probe with turn-on fluorescence property, visible color change with naked-eye, and large wavelength shift on UV spectra for highly selective detection of Cys over homocysteine (Hcy) and glutathione (GSH) in both HEPES buffer (10 mM, pH 7.4) and diluted human serum. The probe based on the conjugate addition-cyclization reaction has a low limit of detection to Cys (0.16 μM as NIR fluorescence sensor and 0.13 μM as UV sensor). Kinetic study indicated that the probe has a very rapid response to Cys, owing to the much higher pseudo-first-order reaction constant with Cys (299 M(-1) s(-1)) than with Hcy (1.29 M(-1) s(-1)) or GSH (0.53 M(-1) s(-1)). Upon addition of Cys to a solution of the probe, the color changed from purple to cyan, with the maximum wavelength shifting from 582 to 674 nm in the UV spectrum and a fluorescence emission at 697 nm appearing. It has been successfully applied for determination of Cys in diluted serum and bioimaging of Cys in living cells with low cell toxicity.

The palindromic region AGAAAAGA (PrP113–120) in prion is highly amyloidogenic and very critical in the structural conversion of cellular prion protein to its pathogenetic form. In this region, there is an important point mutation A117V, which is closely related to the occurrence of Gerstmann–Straussler–Scheinker Syndrome. However, the detailed knowledge about the effects of the A117V mutation on the folding and aggregation of the palindromic sequences is still lacking. To investigate the impacts of A117V mutation on the earliest steps along the PrP113–120 aggregation pathway, replica exchange molecular dynamics simulations of the monomer, 2- and 4-peptide systems of PrP113–120 and its A117V mutant were carried out. The simulations of monomers indicate that both WT and the A117V mutated PrP113–120 are mostly random coils with helical structures transiently populated. Differently, the A117V mutation enhances the intrinsic disorder of PrP113–120. The simulations of 2- and 4-peptide systems of the two species show that the A117V mutation increases the sheet contents and the populations of oligomers, which may be attributed to the enhancement of inter-peptide backbone hydrogen bonding interactions and side chain hydrophobic interactions. Overall, the study provides structural insights into the impacts of the A117V mutation on the folding and assembly of the palindromic sequences, which might be helpful to elucidate the mechanism underlying prion disease and the origin of the Gerstmann–Straussler–Scheinker Syndrome.

Prion diseases are marked by cerebral accumulation of the abnormal isoform of the prion protein. A fragment of prion protein composed of residues 106-126 (PrP106-126) exhibits similar properties to full length prion and plays a key role in the conformational conversion from cellular prion to its pathogenic pattern. Soluble oligomers of PrP106-126 have been proposed to be responsible for neurotoxicity. However, the monomeric conformational space and initial oligomerization of PrP106-126 are still obscure, which are very important for understanding the conformational conversion of PrP106-126. In this study, replica exchange molecular dynamics simulations were performed to investigate monomeric and dimeric states of PrP106-126 in implicit solvent. The structural diversity of PrP106-126 was observed and this peptide did not acquire stable structure. The dimeric PrP106-126 also displayed structural diversity and hydrophobic interaction drove the dimerization. To further study initial oligomerization of PrP106-126, 1 µs conventional molecular dynamics simulations of trimer and tetramer formation were carried out in implicit solvent. We have observed the spontaneous formation of several basic oligomers and stable oligomers with high β-sheet contents were sampled in the simulations of trimer and tetramer formation. The β-hairpin formed in hydrophobic tail of PrP106-126 with residues 118-120 in turn may stabilize these oligomers and seed the formation oligomers. This study can provide insight into the detailed information about the structure of PrP106-126 and the dynamics of aggregation of monomeric PrP106-126 into oligomers in atomic level.

Prion diseases are associated with misfolding and aggregation of prion protein (PrP). Cellular prion protein contains a disulfide bond linking Cys residues at positions 179 and 214. It has been proposed that this disulfide bond plays an important role in the conversion between cellular (PrP(C)) and the scrapie form of prion protein (PrP(Sc)). To probe the role of this disulfide bond in the stability and folding of prion protein, we employed molecular dynamics simulations to study the reduced prion protein and a variant of PrP in which the two cysteines were replaced by alanines residues. The simulations highlighted the changes that occurred upon breakage of the disulfide bond. Breakage of the disulfide bond resulted in a shift of H1, elongation of the native β-sheet and perturbation of the hydrophobic core of huPrP. The changes are similar to the conformational transitions of prion protein in low pH, in denaturing conditions or with pathogenic mutations, which indicate that rupture of the disulfide bond may lead to the misfolding of prion protein.

The central event in the pathogenesis of prion protein (PrP) is a profound conformational change from its α-helical (PrPC) to its β-sheet-rich isoform (PrPSc). Many single amino acid mutations of PrP are associated with familial prion diseases, such as D202N, E211Q, and Q217R mutations located at the third native α-helix of human PrP. In order to explore the underlying structural and dynamic effects of these mutations, we performed all-atom molecular dynamics (MD) simulations for the wild-type (WT) PrP and its mutants. The obtained results indicate that these amino acid substitutions have subtle effects on the protein structures, but show large changes of the overall electrostatic potential distributions. We can infer that the changes of PrP electrostatic surface due to the studied mutations may influence the intermolecular interactions during the aggregation process. In addition, the mutations also affect the thermodynamic stabilities of PrP.

Background Prion diseases are associated with a conformational switch for PrP from PrP C to PrP Sc . Many genetic mutations are linked with prion diseases, such as mutations T188K/R/A with fCJD. Scope of review MD simulations for the WT PrP and its mutants were performed to explore the underlying dynamic effects of T188 mutations on human PrP. Although the globular domains are fairly conserved, the three mutations have diverse effects on the dynamics properties of PrP, including the shift of H1, the elongation of native β-sheet and the conversion of S2–H2 loop to a 3 10 helix. Major conclusions Our present study indicates that the three mutants for PrP may undergo different pathogenic mechanisms and the realistic atomistic simulations can provide insights into the effects of disease-associated mutations on PrP dynamics and stability, which can enhance our understanding of how mutations induce the conversion from PrP C to PrP Sc . General significance Our present study helps to understand the effects of T188K/R/A mutations on human PrP: despite the three pathogenic mutations almost do not alter the native structure of PrP, but perturb its stability. This instability may further modulate the oligomerization pathways and determine the features of the PrP Sc assemblies.

Nanomaterials (NMs) have been widely used in the biomedical field. To explore the biological effects of graphene as one of the most widely used NMs, we studied the adsorption behavior and induced conformational changes of proteins representing different secondary structures on graphene: β-strands (WW domain), mixed α/β structure (BBA protein), and α-helices (λ-repressor). Our results indicate these model proteins were adsorbed onto the graphene surface quickly and tightly, however, varied degrees of conformational changes were observed. During the adsorption process, we found the β motif is a stiffer structural unit than the α-helix. Moreover, the level of conformational changes of the proteins is related not only to their sequence and structural properties but also to their orientation. Overall, from the different levels of intermolecular interaction, the protein adsorption was driven by van der Waals, hydrophobic and π–π stacking interactions. Our work suggests that classical molecular dynamics simulations and MM-GBSA calculations can provide useful information about the dynamics and energetics of the adsorption of proteins onto graphene. We believe that these findings will help us to further understand the adsorption of proteins on hydrophobic carbon nanomaterials at the atomic level.