Journal of Biomolecular Structure & Dynamics最新文献

Viral infections in plants are a big threat to agriculture and the economy. Though the viral infection mechanism is well documented, the cell-to-cell trafficking of the virus is poorly understood. The plant virus is known to encode movement protein (MP) for trafficking the virus from an infected cell to a healthy cell. The movement protein is known to increase plant cells' size exclusion limit (SEL) of plasmodesmata (PD). However, the exact mechanism of the viral trafficking remained unclear. In this study, we proposed a possible mechanism of viral trafficking by using Sesbania mosaic virus (SeMV) as a model system. The movement protein and RNA-dependent RNA polymerase (RdRp) of SeMV were modeled using the ab initio method. It is also known that MP binds with VPg in the movement process and RdRp requires P10 for replication. The models of VPg and P10 were extracted from the structure of polyprotein 2a. The complexes MP-VPg and RdRp-P10 were built with the help of molecular docking and were subjected to molecular dynamic simulation to get stable complexes. The trafficking complex (MP+VPg + RdRp + P10) was obtained by performing the molecular docking of these two complexes. Through MDS, the stability of the trafficking complex was confirmed. For the first time, a trafficking complex was proposed to understand its role in navigation of the viral complex through the host's plasmodesmata.

Sphingosine Kinase 1 (SPHK1), observed to be overexpressed in an array of human malignancies, plays a pivotal role in modulating essential cellular activities throughout the process of tumor formation. Consequently, SPHK1 represents a promising therapeutic target, offering novel approaches to tumor treatment. Here, the structure-activity relationship was researched by using CoMFA and CoMSIA models. Both CoMFA (q²=0.621; n = 10; r²=0.992) and CoMSIA (q²=0.585; n = 7; r²=0.967) demonstrated satisfactory predictive capabilities. The structure-activity relationship of the compounds was analyzed by the counter maps of various fields. Further on, the compounds were interfaced with SPHK1 using the Surfex-Dock method to elucidate their interactive characteristics. Findings reveal that the binding is predominantly reliant on van der Waals, carbon-hydrogen bonds and hydrophobic interactions. Furthermore, the potential activities and ADME/T properties of six novel compounds were predicted utilizing 3D-QSAR models and online tools. The newly designed compounds were validated to have better activities and suitable ADME/T properties. In addition, molecular dynamics (MD) simulation further revealed that key residues, such as Ala339, Ala170, Ala115, Asp81, Gly342, Phe288 Ser164, Phe188, Ile170, etc. This study offers a roadmap to the discovery and design of innovative SPHK1 inhibitors.

Despite the testing of various small molecules and new drug entities, tuberculosis still represents a major health burden given the fact that it kills > 40.000 cases every single day. In the recent years, antimicrobial peptides (AMP) were proved their extraordinary activity against different bacterial species. In the present study, we examined the peptidome of Arabian camel milk proteins as AMP through computer-aided drug development approaches. Five proteins from Arabian camel milk sequences were downloaded from UniProt database followed by in silico digestion using AHPP server. The generated peptides were assessed for their anti-TB activity, biochemical properties, allergenicity, toxicity and membrane penetrability. Peptides passed fulfilled these criteria were then subjected to molecular docking via HPEPDOCK 2 and CABS-dock tools. Afterward, molecular dynamics (MD) were performed for best docked complex to assess the stability. Of the generated peptidome, only four peptides proved anti-TB activity, non-allergen, non-toxic and classified as cell-penetrating peptides. The five peptides were the best in terms of docking to thymidylate kinase and found to be stable after 120 ns of MD simulations as reflected by the low RMSD and RMSF change (< 0.5 nm). The putative peptidome of Arabian camel milk proteins is a potential AMP against M. tuberculosis but needs in vitro experimentation.

Interleukin-4-induced gene 1 (IL4I1) is an L-phenylalanine oxidase. As the primary enzyme responsible for degrading tryptophan, IL4I1 generates indole metabolites and kynurenic acid, which act as crucial endogenous ligands to activate the aryl hydrocarbon receptor (AHR). This activation enhances tumor survivability while suppressing the body's anti-tumor immune response. Consequently, IL4I1 is now recognized as a promising new target for drug development in the realm of cancer immunomodulation. In this study, we employed a strategy combining AlphaFold2 with molecular dynamics (MD) simulations to model receptor conformations our docking model achieved a regression fit with an R² coefficient of 0.34, providing a robust framework for structure-based virtual screening aimed at identifying potential IL4I1 inhibitors. We then applied this structure-based virtual screening method to a compound library. After further MD simulation and following Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculation of binding free energy and ADMET analysis, five candidate IL4I1 inhibitors were obtained. This study provides an effective in silico approach for the identification of IL4I1 inhibitors and offers a valuable reference for the virtual screening of inhibitors targeting other proteins without known structures.

The nucleophile elbow is a well-known structural motif, which exists in proteins with catalytic triads and contains a catalytic nucleophile and the first node of an oxyanion hole. Here, we show that structural similarities of proteins with the nucleophile elbow extend beyond simple nucleophile elbow motifs. The motifs are incorporated into larger conserved structural organizations, the ElbowFlankOxy networks, incorporating motifs and flanking residues and networks of conserved interactions. A detailed structural analysis shows two major types of ElbowFlankOxy networks, depending on the formation of the oxyanion hole. Additionally, the ElbowFlankOxy networks show three classes: Class 1-2-3, 3-1-2, and 2-3-1, defined by the order in which the catalytic nucleophile and key interacting residues are located in the amino acid sequence, giving rise to six ElbowFlankOxy network variations. This makes it possible to properly position homologous non-catalytic, non-standard, and unusual catalytic triad active sites of proteins with the nucleophile elbow within the fold classification.

The quest for sustainable solutions to plastic pollution has driven research into plastic-degrading enzymes, offering promising avenues for polymer recycling applications. However, enzymes derived from natural sources often exhibit suboptimal thermostability, hindering their industrial viability. Protein engineering techniques have emerged as a powerful approach to enhance the desired properties of these biocatalysts. This study aims to conduct a comprehensive analysis of the thermostability of Vibrio palustris PETase (VpPETase) through an integrated computational approach encompassing homology modeling, site-specific molecular docking, molecular dynamics (MD) simulations, and comparative evaluation of a single-point mutation (V195F) against the wild-type enzyme. Homology modeling was used to predict VpPETase model using multiple templates. Model quality was rigorously assessed using Ramachandran plot analysis, ProSA, Verify 3D, and ERRAT. Molecular docking elucidated the catalytic region comprising residues His149, Asp117, and Ser71, while highlighting the pivotal roles of His149, Tyr1, and Ser71 in substrate binding affinity. MD simulations at various temperatures revealed higher stability at 313.15 K over a 100 ns trajectory, as evidenced by analyses of root-mean-square deviation (RMSD), radius of gyration (Rg), solvent-accessible surface area (SASA), hydrogen bonding, and root-mean-square fluctuation (RMSF). The V195F mutant exhibited a slight increase in stability compared to wild-type. While this study provides valuable insights into the thermostability of VpPETase, further investigations, including experimental validation of thermostability enhancements and in vitro characterization, are warranted to fully exploit the potential of this enzyme for industrial applications in plastic recycling.

The potential sesquiterpene lactone groups from the Vernonia genus; namely vernolide-A, vernolide-B, and vernodalin, have been reported for anticancer effects by downregulating cancer promoter proteins. Nevertheless, prior investigations have failed to identify the target proteins that are associated with the compounds' actions. Subsequently, the present investigation attempts to identify the target proteins associated with cancer. The number of candidate target proteins predicted by our molecular docking study for vernolide-A, vernolide-B, and vernodalin were one, five, and seven, respectively. Vernolide-A, vernolide-B, and vernodalin were predicted to have the most selective and attractive interactions with candidate target proteins; such as p38α, PGEP2R, and HSP90α, respectively. In addition, our MD simulation study revealed that the compounds' effects on the residual flexibility were not substantial. This suggested that their relative binding-free energy was similar to that of well-established ligands; including PD169316, dinoprostone, and Pu-H54. We also addressed the potential molecular mechanisms that may be associated with compounds in this report. Vernolide-A, vernolide-B, and vernodalin may potentially inhibit the proliferation, survival, angiogenesis, and migration of cancer cells through their strong affinity for a variety of cancer-related molecules. Additional laboratory experimental designs; including in vitro and in vivo studies, are suggested to further our computational findings.

The Tobacco Mosaic Virus (TMV) is a critical plant virus that can cause a significant drop in crop yield. To understand how recombinant coat-protein impacts the affinity and assembly of TMV's subunits, research is being conducted to assess the effect of recombinant protein on virus resistance. To develop a recombinant coat-protein that can lower TMV infection rates in plants, a design strategy was employed that involves creating defective viral subunits leading to incorrect assembly. This method is similar to using defective puzzle pieces that form incorrect connections resulting in disrupted viral assembly, ultimately affecting the production of mature virus particles. The study investigated the effect of mutations on one side of the Tobacco mosaic virus coat-protein using molecular modeling and dynamics simulation techniques. The simulation showed that the recombinant subunit had lower flexibility (between 0.15 to 0.20 nm) compared to the other subunits (between 0.45 to 0.75 nm), which was attributed to the smaller loop area. The study suggests an effective recombinant coat-protein with the potential to prevent virus infection by disrupting the coat-protein assembly process. This approach can be used to design a plant vaccine against viruses. Developing a recombinant protein can also provide benefits to plants such as protection from pests and enhancement of growth and productivity.

Caspase-6 (CASP6) is an effector caspase that has been marked to possess various pathological attributes associated with neurodegeneration. It is widely expressed in the neurodegenerative brain and peripheral tissues. It plays a vital role in apoptotic cell death and also performs non-apoptotic functions like axon pruning which contribute to the degeneration of neurons. Increment in active CASP6 levels in the cerebrospinal fluid has been observed during inflammation and has been linked to the early onset of Alzheimer's disease (AD). In the current study, a novel CASP6 inhibitor was identified with the help of integrated target-based and ligand-based drug-designing approaches. Various molecular features of US9 (PDB ID 8EG6) were used to generate models. The pharmacophore models were evaluated using the EF value, GH score, and percentage yield to select the best-suited model. The best model was used to screen the ZINC-15 database to obtain virtual hits. The undesirable compounds were eliminated using various nodes in KNIME workflow. The resulting compounds were further subjected to docking-based virtual screening (DBVS) to find the lead compounds. Further, the molecular docking studies were carried out in three stages, followed by pharmacokinetic property prediction and toxicity studies. The top two virtual hits, i.e. ZINC000012563650 and ZINC000069415222, were considered for molecular dynamics simulation studies. Compound ZINC000069415222 was found to possess better stability, drug-like properties, and lower toxicity under simulated conditions. Thus, ZINC000069415222 was identified as a potential CASP6 inhibitor that could be further explored experimentally as an anti-AD drug.

Dengue is a major global health challenge, caused by the dengue virus (DENV) and transmitted through the Aedes aegypti mosquito. The four DENV serotypes (DENV1-4) infect about 400 million people annually. The non-structural protein 5 (NS5) is the most conserved DENV protein, crucial for viral replication. This study aims to elucidate the replication and pathogenesis mechanisms of DENV by targeting tyrosine-based motifs and YXXΦ-like tetrapeptides in the NS5 protein across all serotypes. We employed computational tools to identify and analyze tyrosine-based motifs (TM) and YXXΦ-like tetrapeptides within the NS5 protein. The structural characteristics of these motifs were determined using the AlphaFold2 web server. Additionally, we investigated post-translational modifications (PTMs) within these motifs to assess their potential roles in pathogenesis and immune response. Our analysis revealed various TM and YXXΦ-like tetrapeptides structurally conserved across the DENV serotypes. Several PTM sites were identified within these motifs, suggesting their involvement in virulence, enhanced propagation, and modulating the host immune system. The identified TM and tetrapeptides hold significant promise as targets for vaccine development against DENV. They potentially regulate key viral functions and immune evasion mechanisms. Molecular dynamics (MD) simulation analysis of conserved TM and YXXΦ-like tetrapeptides revealed distinct stability patterns. However, further in vivo and in vitro studies are needed to validate these findings and fully explore their therapeutic potential.