CASTpFold: Computed Atlas of Surface Topography of the universe of protein Folds.

Geometric and topological properties of protein structures, including surface pockets, interior cavities and cross channels, are of fundamental importance for proteins to carry out their functions. Computed Atlas of Surface Topography of proteins (CASTp) is a widely used web server for locating, delineating, and measuring these geometric and topological properties of protein structures. Recent developments in AI-based protein structure prediction such as AlphaFold2 (AF2) have significantly expanded our knowledge on protein structures. Here we present CASTpFold, a continuation of CASTp that provides accurate and comprehensive identifications and quantifications of protein topography. It now provides (i) results on an expanded database of proteins, including the Protein Data Bank (PDB) and non-singleton representative structures of AlphaFold2 structures, covering 183 million AF2 structures; (ii) functional pockets prediction with corresponding Gene Ontology (GO) terms or Enzyme Commission (EC) numbers for AF2-predicted structures and (iii) pocket similarity search function for surface and protein-protein interface pockets. The CASTpFold web server is freely accessible at https://cfold.bme.uic.edu/castpfold/.

Maternal high fat diet programs spatial learning and central leptin signaling in mouse offspring in a sex-specific manner.

Environmental factors in early life have been demonstrated to increase the risk of neurodevelopmental disorders in offspring, especially the deficiency of the cognitive ability. Leptin has emerged as a key hormone that conveys information on energy stores, but there is growing appreciation that leptin signaling may also play an important role in neurodevelopment. The present study aimed to investigate whether maternal HFD exposure impairs the offspring learning and memory through the programming of central leptin system. We observed that hippocampus-dependent learning and memory were impaired in male but not female offspring from HFD-fed maternal ancestors (C57BL/6 mice), as assessed by novel object recognition and Morris water maze tests. Moreover, the chromatin immunoprecipitation results revealed the maternal HFD consumption led to the increasement in the binding of the histone marker H3K9me3 in male offspring, which mediates gene silencing in the leptin receptor promoter region. Furthermore, there was an increase in the expression of the histone methylase SUV39H1 in male but not female offspring, which regulates H3K9me3. Additionally, it has been observed that IL-6 and IL-1 also could lead to similar alternations when acting on cultured hippocampal neurons in vitro. Taken together, our data suggest that maternal HFD consumption influences male offspring hippocampal cognitive performance in a sex-specific manner, and central leptin signaling may serve as the cross-talk between maternal diet and cognitive impairment in offspring.

CASTpFold: Computed Atlas of Surface Topography of the universe of protein Folds.

Geometric and topological properties of protein structures, including surface pockets, interior cavities, and cross channels, are of fundamental importance for proteins to carry out their functions. Computed Atlas of Surface Topography of proteins (CASTp) is a widely used web server for locating, delineating, and measuring these geometric and topological properties of protein structures. Recent developments in AI-based protein structure prediction such as AlphaFold2 (AF2) have significantly expanded our knowledge on protein structures. Here we present CASTpFold, a continuation of CASTp that provides accurate and comprehensive identifications and quantifications of protein topography. It now provides (i) results on an expanded database of proteins, including the Protein Data Bank (PDB) and non-singleton representative structures of AlphaFold2 structures, covering 183 million AF2 structures; (ii) functional pockets prediction with corresponding Gene Ontology (GO) terms or Enzyme Commission (EC) numbers for AF2-predicted structures; and (iii) pocket similarity search function for surface and protein-protein interface pockets. The CASTpFold web server is freely accessible at https://cfold.bme.uic.edu/castpfold/.

Tubeimosides are pan-coronavirus and filovirus inhibitors that can block their fusion protein binding to Niemann-Pick C1.

SARS-CoV-2 and filovirus enter cells via the cell surface angiotensin-converting enzyme 2 (ACE2) or the late-endosome Niemann-Pick C1 (NPC1) as a receptor. Here, we screened 974 natural compounds and identified Tubeimosides I, II, and III as pan-coronavirus and filovirus entry inhibitors that target NPC1. Using in-silico, biochemical, and genomic approaches, we provide evidence that NPC1 also binds SARS-CoV-2 spike (S) protein on the receptor-binding domain (RBD), which is blocked by Tubeimosides. Importantly, NPC1 strongly promotes productive SARS-CoV-2 entry, which we propose is due to its influence on fusion in late endosomes. The Tubeimosides' antiviral activity and NPC1 function are further confirmed by infection with SARS-CoV-2 variants of concern (VOC), SARS-CoV, and MERS-CoV. Thus, NPC1 is a critical entry co-factor for highly pathogenic human coronaviruses (HCoVs) in the late endosomes, and Tubeimosides hold promise as a new countermeasure for these HCoVs and filoviruses.

Anion-Counterion Strategy toward Organic Cocrystal Engineering for Near-Infrared Photothermal Conversion and Solar-Driven Water Evaporation.

An anion-counterion strategy is proposed to construct organic mono-radical charge-transfer cocrystals for near-infrared photothermal conversion and solar-driven water evaporation. Ionic compounds with halogen anions as the counterions serve as electron donors, providing the necessary electrons for efficient charge transfer with unchanged skeleton atoms and structures as well as the broad red-shifted absorption (200-2000 nm) and unprecedented photothermal conversion efficiency (~90.5 %@808 nm) for the cocrystals. Based on these cocrystals, an excellent solar-driven interfacial water evaporation rate up to 6.1±1.1 kg ⋅ m-2 ⋅ h-1 under 1 sun is recorded due to the comprehensive evaporation effect from the cocrystal loading in polyurethane foams and chimney addition, such performance is superior to the reported results on charge-transfer cocrystals or other materials for solar-driven interfacial evaporation. This prototype exhibits the great potential of cocrystals prepared by the one-step mechanochemistry method in practical large-scale seawater desalination applications.

Primary Structural Units "D+A-" Ion Pairs Dominating Near-Infrared Photothermal Conversion of Organic Ionic Cocrystals.

The specific stacking mode of D/A blocks is often considered to largely determine the physicochemical properties of cocrystals. However, this rule may fail when encountering a large degree of (integer or near-integer) charge transfer situations. Herein, we explore the extensive correlations between the possible smallest structural units, stacking modes, and near-infrared photothermal conversion (NIR-PTC) properties of F4TCNQ-based cocrystals with typical features of integer-charge-transfer. Surprisingly, these cocrystals with distinct stacking modes display analogous D-A interactions, broad red-shift absorption, ultrafast (1-3 ps) relaxation dynamics of excited states, and excellent NIR-PTC properties. This supports that the resulting "D+A-" ion pairs from integer-charge-transfer may serve as the primary structural units beneath the secondary stacking modes to dominate the property of cocrystals. The stacking modes play an important but only secondary role. This work provides new insights into the structure-dynamics-property correlations and modular design of organic cocrystals for PTC and other applications.

Predicting Pathology of Missense Mutations through Protein-Specific Evolutionary Pattern.

Missense mutations, which are single base pair genetic alternation resulting in a different amino acid, are among the most common occurring variants in exon regions of the human genome and may lead to diseases. Thus to assess the effects of missense mutations, it is essential to investigate the evolutionary history of the protein under selection pressures. In this study, we employ a continuous-time Markov model to investigate the evolutionary patterns in protein sequences and a Bayesian Markov chain Monte Carlo method to estimate the substitution rates for protein of interest, from which we obtain scoring matrices. Specifically, we examined the evolutionary patterns of protein sequences containing missense mutations using a species tree to define the phylogeny of the protein of interest. We thoroughly studied the evolutionary pattern of human muscle glycogen phosphorylase containing 127 known missense mutations, and identified characteristic evolutionary patterns in 63 proteins with 2,238 missense mutations, including both deleterious and neutral effects. Our results show that the estimated protein-specific evolutionary pattern-based scoring matrices (PSM) lead to higher sensitivity in detecting the pathological effects of missense mutations, compared to the general evolutionary pattern-based scoring matrix of Blosum62 (BL62) matrix. By incorporating PSM, the performance of a recently released structure-based model SPRI for evaluating missense mutations is further improved.

Mechanochemistry toward Organic "Salt" via Integer-Charge-Transfer Cocrystal Strategy for Rapid, Efficient, and Scalable Near-Infrared Photothermal Conversion.

Invited for this month's cover is the group of Shun-Li Chen and Ming-De Li at the Shantou University. The image shows that one electron can be transferred easily from donor to acceptor unit to obtain integer-charge-transfer cocrystals for realizing high-efficient solar-harvesting and photothermal conversion. The Research Article itself is available at 10.1002/cssc.202300644.

Mechanochemistry toward Organic "Salt" via Integer-Charge-Transfer Cocrystal Strategy for Rapid, Efficient, and Scalable Near-Infrared Photothermal Conversion.

Inspired by the concept of ionic charge-transfer complexes for the Mott insulator, integer-charge-transfer (integer-CT) cocrystals are designed for NIR photo-thermal conversion (PTC). With amino-styryl-pyridinium dyes and F4TCNQ (7,7',8,8'-Tetracyano-2,3,5,6-tetrafluoroquinodimethane) serving as donor/acceptor (D/A) units, integer-CT cocrystals, including amorphous stacking "salt" and segregated stacking "ionic crystal", are synthesized by mechanochemistry and solution method, respectively. Surprisingly, the integer-CT cocrystals are self-assembled only through multiple D-A hydrogen bonds (C-H⋅⋅⋅X (X=N, F)). Strong charge-transfer interactions in cocrystals contribute to the strong light-harvesting ability at 200-1500 nm. Under 808 nm laser illumination, both the "salt" and "ionic crystal" display excellent PTC efficiency beneficial from ultrafast (∼2 ps) nonradiative decay of excited states. Thus integer-CT cocrystals are potential candidates for rapid, efficient, and scalable PTC platforms. Especially amorphous "salt" with good photo/thermal stability is highly desirable in practical large-scale solar-harvesting/conversion applications in water environment. This work verifies the validity of the integer-CT cocrystal strategy, and charts a promising path to synthesize amorphous PTC materials by mechanochemical method in one-step.