Journal of Biomolecular Structure & Dynamics最新文献

Alzheimer's disease (AD) progression is strongly linked to conformational changes of amyloid-β42 (Aβ42) in neuronal membranes. This study examined the influence of pH on Aβ42 conformation in 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) membranes using Raman spectroscopy, circular dichroism (CD), and molecular dynamics (MD) simulations. At acidic pH (5.5), Aβ42 predominantly adopted α-helical structures (∼75-80%), whereas neutral (pH 7.4) and alkaline conditions (pH 9.5) reduced α-helical content to ∼48-58% and ∼44-47%, respectively, with a corresponding rise in random-coil structures (∼20-36%). Across all pH conditions, β-sheet content remained minimal, although MD trajectories indicated transient β-bridge contacts suggestive of early aggregation. MD analyses revealed modest pH-dependent perturbations in bilayer thickness and lipid order. Consistency across experimental and computational methods highlights pH as a critical modulator of Aβ42 structural dynamics in membranes, providing mechanistic insight into its neurotoxic potential and informing future therapeutic strategies.

Transforming Growth Factor Beta (TGF-B) signalling plays a central role in maintaining vascular homeostasis, regulating extracellular matrix production, and controlling pulmonary vascular remodelling. Disruption of this pathway has been closely associated with pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD). Genetic variations, particularly non-synonymous single-nucleotide polymorphisms (nsSNPs), in key genes of the TGF-B cascade can lead to structural or functional alterations in the encoded proteins, thereby affecting pathway regulation and disease outcomes. In this study, nsSNPs in TGFB1, TGFBR1, TGFBR2, SMAD2, SMAD3, and SMAD4 were analysed using multiple computational tools including SIFT, PolyPhen2, PANTHER, PhD-SNP, MetaSNP, PredictSNP2, SNAP2, CADD, REVEL, and MutPred2 to predict deleterious variants. ConSurf was used to evaluate evolutionary conservation, and ProtParam assessed physicochemical changes between wild-type and mutant proteins. Protein structural models for wild-type and mutant variants were generated using I-TASSER and validated through Ramachandran plots. Furthermore, protein-protein docking and molecular dynamics (MD) simulations were conducted to investigate the structural stability and binding effects between TGF-B and its receptor, TGFBRII. A total of 42 high-confidence deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) were identified across the six genes, with specific variants, such as R156C of TGFB and N384S of TGFBRII, showing major destabilising effects on receptor conformation, and E313D of TGFB inducing structural compaction that may impair signal transduction. Overall, these computational findings suggest that deleterious nsSNPs in the TGF-B signalling components may alter protein stability and disrupt pathway communication, potentially influencing PH-associated COPD pathogenesis and offering future avenues for therapeutic targeting.

Skeletal dysplasia is an ensemble of hereditary conditions that impact bone and cartilage formation, leading to aberrant skeletal growth and proportions. Such illnesses can affect the limbs, spine, and skull, and they can produce a wide range of symptoms, from minor to severe. Filamin A and B are functionally analogous proteins, exhibiting structural resemblance and playing crucial role in the formation of cellular cytoskeleton. Objective of the research was to employ experimental and computational approaches to investigate the contribution of Filamins in skeletal dysplasias. Whole exome sequencing lead to the identification of two mutations involved in a spectrum of skeletal dysplasias with predominant spine and articular association. Here we report two families from Pakistan with distinct mutations in FLNA protein (R196W) causing otopalatodigital syndrome-1 or metaepishyseal dysplasia with short stature, prominent facial dysmorphism including hypertelorism, frontal bossing, down-slanting parpebral fissures and depressed nasal bridge. While novel, homozygous, nonsense FLNB mutation (p.C1081*) is causing Spondylocarpotarsal synostosis syndrome (SCT), an exceptionally rare skeletal disorder marked by disproportionate short stature, spinal deformities, and other associated features like dental enamel hypoplasia, joint laxity, and conductive hearing loss. In silico structural and functional analysis of mutant filamins provide compelling proof for their role in the progression of skeletal dysplasias. Screened variants have not only affected the protein's three-dimensional structure dramatically but also resulted in loss of functional domains, leading to aberrant interactions with binding proteins and progression of disease.

The complex regulatory network of proteins in Pseudomonas aeruginosa controls pathogenesis and cellular sustainability. Phosphorylation in Pseudomonas play a central role in this regulation. Functional amyloids in Pseudomonas (Fap) expression influences the global proteome, suggesting its influence on the protein-interaction network. The preliminary exploration of Fap interactome through immunoprecipitation/mass spectrometry (IP/MS) were enriched for phosphokinase proteins. This called forth for phosphoproteomics which revealed three proteins of the Fap operon, FapD, FapB, and FapF were found in multi-phosphorylated state. In silico phosphorylation at experimentally determined positions of Fap protein structures provided insight into structural changes. Phosphorylation of FapD reinforces protein-protein interaction ability by increasing protein binding residues and flexibility of interfacial domains. Phosphorylated FapB affects the stability of the aggregating core by regulating the exposure and flexibility of the aggregation-prone regions. FapF in the phosphorylated form displayed structural changes in regions that functionally assist transportation process. Multi-site phosphorylation can generate inter-/intra - regulon network that can explain how expression of Fap influences global proteome. Multisite phosphorylation of Fap proteins is tailored for specific protein modulations that can provide functional adaptability and assist successful amyloid biogenesis.

Polyethylene terephthalate (PET) is highly resistant to biodegradation, posing significant environmental risks. Fortunately, enzymatic degradation of PET offers a sustainable and eco-friendly approach to mitigating this waste, requiring a deeper understanding of the enzymatic PET hydrolysis' binding modes and molecular mechanisms. This study evaluated the efficiency of lipase KV1 (LipKV1) variants in enhancing PET degradation through a comprehensive computational approach. Docking results revealed that variants Var9_PET (-6.2 kcal/mol), Var18_PET (-6.0 kcal/mol), and Var181_PET (-6.0 kcal/mol) exhibited higher binding affinities than the wild-type (-2.5 kcal/mol). Molecular dynamics simulations highlighted their remarkable stability and flexibility, supported by consistent RMSD (0.30 - 0.35 nm) and RMSF values (0.05 - 0.32 nm). Favorable Rg values (1.79 - 1.82 nm) also pointed to their compact and stable protein folding, while the SASA results showed reduced solvent exposure in the variants. The PET was tightly anchored within their hydrophobic active sites, with hydrogen bond distances remaining close to ∼0.25 nm. Var18 displayed the highest hydrogen bond occupancy for the key residue Ala216 (9.75%) than the wild-type (catalytic Ser165, 2.84%). Principal Component Analysis further revealed enhanced flexibility and dynamic motion in the lipase variants, suggesting improved adaptability for PET hydrolysis. These observations corresponded with the MM-PBSA results, showing marginally lower binding free energies for Var18_PET (-31.47 ± 0.54 kcal/mol) and Var181_PET (-31.58 ± 2.71 kcal/mol) than the wild-type (-29.24 ± 1.14 kcal/mol). Conclusively, the in silico findings underscore the LipKV1 variants' enhanced PET-binding affinity for microplastic degradation, warranting further experimental effectiveness validation.

Plasmodium falciparum, the causative agent of the most lethal form of human malaria, harbors numerous uncharacterized proteins whose functions remain unexplored yet may be central to its survival and pathogenicity. Among its specialized organelles, food vacuole plays pivotal role in hemoglobin-catabolism, heme-detoxification, nutrient-assimilation and pharmacodynamic-interactions, thereby representing critical therapeutic target. However, numerous food vacuole-associated proteins remain uncharacterized. In this study, multiple bioinformatics tools were employed to comprehensively characterize a hypothetical food vacuole-associated protein, PF11_0364 (designated PfHDDCP). Conserved domain analysis identified HotDog fold, hallmark of acyl-CoA thioesterases, suggesting its possible role in lipid metabolism. 3D structural model of PfHDDCP was generated using I-TASSER and evaluated with PROCHECK and ProSA. Over 90% of residues were located in favored regions of Ramachandran plot, and ProSA Z-score fell within the range typical of native protein structures, indicating good model quality. Domain analysis via NCBI-CDD identified two putative ligand-binding sites in PfHDDCP. Molecular docking using HDOCK and AutoDock predicted that Acetyl-CoA and Acyl Carrier Protein, canonical substrates of thioesterases, bind at Binding-Site 1, which corresponds to the predicted catalytic site. In contrast, antimalarial compounds were predicted to bind at Binding-Site 2, distinct secondary pocket, suggesting possible allosteric site that may interfere with substrate binding. Molecular dynamics simulations performed with Desmond indicated stable PfHDDCP-ligand complexes and ligand-induced conformational changes, supporting model of ligand-mediated functional modulation. Although these results offer preliminary computational insights into structure, function, and druggability of PfHDDCP, they remain predictive and require experimental validation to confirm the proposed enzymatic activity and therapeutic relevance.

DNA receptor site remain a crucial class of anticancer agents for many researchers. Literature revealed extensive data explaining different involving such data to control anticancer behavior. However, the structural limitations and adverse effects of existing drugs, such as doxorubicin, necessitate the development of novel agents. To address these challenges, a series of 25 linker-based purine/pyrimidine derivatives were designed and after screening through ADMET properties, compounds (4-9) were synthesized (Compounds 1-3 were taken from Literature), and well-characterized. Further, docking analysis was carried out for compounds (1-9) towards various DNA receptor sites, which were compared with doxorubicin. The most efficient compounds 1 and 5 were taken to explore DNA binding and anticancer potential. These compounds feature strategically modified linker regions to enhance stability within the DNA duplex. Computational studies, including molecular docking and MD simulations, extensively explored the structural interactions of these compounds with DNA. Compounds 1 and 5 exhibit stable interactions with linker, particularly acetamide in compound 1 is playing a key role in binding affinity and groove fitting. Notably, compound 1 maintained strong and stable interaction with both DNA strands compared to compound 5 and doxorubicin, suggesting its potential as efficient ligands. Further, FT-IR confirmed intercalation in compound 1 with carbonyl frequency reduction, while its low IC₅₀ of 42.17 µM highlighted strong anticancer potential. Overall, this study presents a structurally refined approach to DNA receptor site, offering valuable insights for designing next-generation anticancer agents with optimized therapeutic potential.

The MPZ (Myelin Protein Zero) gene, located on chromosome 1q23.3, plays a crucial role in myelin sheath formation and maintenance. Mutations in the MPZ protein are linked to demyelinating neuropathies, yet the structural and functional consequences of these mutations remain unclear. This study aims to identify and analyze the impact of nonsynonymous single nucleotide polymorphisms (nsSNPs) on the structure and function of the MPZ protein using in silico approaches. Seven sequence-based predictive tools (SIFT, PANTHER, SNP&GO, Fathmm, PhD-SNP, SNAP, MetaSNP) and five structure-based tools (I-Mutant, DynaMut, CupSAT, muPRO, iStable) were used to identify harmful nsSNPs. Molecular dynamics simulations using GROMACS further evaluated the structural and conformational effects of high-risk mutations. The screening process identified G123S and N131K as high-risk mutations. Molecular dynamics simulations revealed that the G123S mutation significantly destabilizes the MPZ protein by reducing conformational flexibility and inducing compaction. Increased root mean square deviations and localized flexibility in the G123S mutant suggest potential disruption of functional dynamics. In contrast, the N131K mutation, while reducing flexibility, preserved structural similarity to the wild-type MPZ protein, indicating a milder impact. These findings suggest that nsSNP-induced structural alterations in MPZ may negatively impact protein stability and function, potentially contributing to neuropathies. Further experimental validation is necessary to confirm these computational predictions.

The challenge in vaccine development, along with drug resistance issues, has encouraged the search for new anti-influenza drugs targeting different viral proteins. Hemagglutinin (HA) glycoprotein, crucial in the viral replication cycle, has emerged as a promising therapeutic target. CBS1117 and JNJ4796 were reported to exhibit similar potencies against infectious group 1 influenza, which included H1 and H5 HAs; however, their potencies were significantly reduced against group 2 HA. This study aims to explore the molecular binding mechanisms and group specificity of these fusion inhibitors against both group 1 (H5) and group 2 (H3) HA influenza viruses using molecular dynamics simulations. CBS1117 and JNJ4796 exhibit stronger interactions with key residues within the H5 HA binding pocket compared to H3-ligand complexes. Hydrogen bonding and hydrophobic interactions involving residues, such as H38₁, Q40₁, T325₁ (H5-CBS1117), T318₁ (H5-JNJ4796), W21₂, I45₂, V48₂, and V52₂ predominantly contribute to stabilizing H5-ligand systems. In contrast, these interactions are notably weakened in H3-inhibitor complexes. Predicted protein-ligand binding free energies align with experimental data, indicating CBS1117 and JNJ4796's preference for heterosubtypic group 1 HA binding. Understanding the detailed atomistic mechanisms behind the varying potencies of these inhibitors against the two HA groups can significantly contribute to the development and optimization of effective HA fusion inhibitors. To accomplish this, the knowledge of the transition of HA from its pre- to post-fusion states, the molecular size of ligands, and their potential binding regions, could be carefully considered.

The transforming growth factor beta (TGF-β) signaling pathway is believed to play essential roles in several physiological activities, including cancer. TGF-β receptor type I (TBR-I) is a key membrane receptor protein in the TGF-β signaling pathway, which relates to many intracellular biological effects. In recent years, cold atmospheric plasma (CAP) has been found to have promising prospects in selective anticancer therapy and has confirmed its essential role in the TGF-β signaling pathway. However, the ambiguous effect of CAP-induced electric field (EF) on TBR-I still limits the application of CAP in clinical therapy. Molecular dynamics is applied to assess the effect of EF on the structure of the extracellular domain of TBR-I using a series of indicators and methods, and then we discuss the ligand binding ability of TBR-I. Results show that moderate EF intensities' structural restraints may contribute to the structural stability and ligand-binding ability of TBR-I, but an EF higher than 0.1 V/nm will be harmful. What's more, EF induces a change in the docking interface of TBR-I, showing the conformation and position of special sequences of residues decide the ligand binding surface. The relevant results suggest that CAP-induced EF plays a crucial role in receptor-receptor interaction and provides significant guidelines for EF-related anticancer therapy.