Molecular Modeling Research Articles

Construction of molecular subtype and prognostic model for gastric cancer based on nucleus-encoded mitochondrial genes

Construction of molecular subtype and prognostic model for gastric cancer based on nucleus-encoded mitochondrial genes

Exploring the Molecular Interaction Between NR2E3 and NR1D1 in Retinitis Pigmentosa: A Docking and Molecular Dynamics Study

ABSTRACTBackground and AimsRetinitis pigmentosa (RP) is a hereditary retinal disorder that gradually leads to vision loss due to photoreceptor cell degeneration. This study aims to investigate the clinical features and genetic underpinnings of RP within a large Iranian family. Our focus centered on mutations in the NR2E3 gene, which plays a critical role in the development and maintenance of the retina.MethodsTwenty‐five family members showed symptoms of RP, and fourteen of them underwent clinical examinations conducted by geneticists and ophthalmologists. The DNA samples of five individuals diagnosed with RP from the family were subjected to whole‐exome sequencing (WES) as part of the study. The candidate variant identified through WES was subsequently confirmed using bidirectional sequencing in additional family members. Additionally, in silico analysis, including molecular modeling, protein–protein docking, and molecular dynamics simulation (MD), was employed to assess potential pathogenic effects associated with the candidate variants.ResultsOphthalmic examination revealed night blindness, which is a common symptom among affected individuals. Genetic analysis identified a homozygous missense variant (c.934G>A/p.R311Q) in NR2E3 exon 6, which co‐segregates with other affected family members. Furthermore, molecular docking analysis indicated potential disruption in the binding affinity between NR2E3 and NR1D1 proteins. In‐depth, molecular dynamics analysis, considering parameters such as RMSD, RMSF, and hydrogen bonding, revealed notable differences between normal and mutant protein complexes.ConclusionExploring the molecular interaction between NR2E3 and NR1D1 provides new insights into the pathogenic mechanism of the p.R311Q mutation in RP.

On the Nature of the Out-Of-Plane Distortions in Subporphyrins.

The field of subporphyrins has garnered great interest in recent years owing to its unique structure and associated properties. They exhibit spectroscopic features similar to porphyrins and find applications in various optoelectronic devices, photodynamic therapy etc. Most of the synthesized subporphyrins have boron coordination with an axial ligand and exhibits a bowl-shaped geometry. The first isolation of a stable free-base subporphyrin is achieved recently with mesityl groups at two of the meso positions and anthracene at the other. X-ray studies reveal a markedly non-planar structure different from the bowl shape and is attributed to the steric hindrance of the inner N-H bonds. Herein, we report a systematic quantum chemical investigation assisted by symmetry principles on molecular models to characterize the out-of-plane (OOP) distortions observed so far in subporphyrins and unveil the electronic reasons. Correlation of the frontier molecular orbital (FMO) landscape between the D4h porphyrin and D3h subporphyrin gives insight into their electronic structure relative to one another and the nature of OOP distortions. Further the effect of a π-donor cum σ-acceptor substituent at the meso/beta positions of the subporphyrin ring as well as the impact of boron incorporation in the central cavity on the OOP distortions are also discussed.

Linearly Scaling Molecular Dynamic Modeling To Simulate Picosecond Laser Ablation of a Silicon Carbide Crystal.

A molecular dynamics model for picosecond laser ablation of nanoscale silicon carbide crystals was established by linearly scaling the laser focal diameter, and the correlation between the molecular dynamic simulation of the nanoscale and the experimental reproduction of the microscale was achieved. The calculation accuracy of the molecular dynamic model was verified by ablating the surface of silicon carbide wafers with a laser pulse width of 37 ps. On this basis, this paper further investigated the influence of the laser pulse width and fluence on the surface ablation damage and modification width, threshold, and lattice temperature. The results showed that, when the laser pulse width is higher than 10 ps, the silicon carbide damage threshold increases with increasing the pulse width, while the modification threshold is almost unaffected by the pulse width. In addition, the influence of crystal orientation has been studied, and laser irradiation along the [1-100] crystal orientation induces a higher peak temperature, larger damage, and modification width and threshold, followed by irradiation along the [0001] crystal orientation and lowest along the [11-20] crystal orientation. Finally, with the linear scaling value increasing, the spatial distribution of the laser energy field deviates more from the actual situation, resulting in the calculated results being more consistent with the experimental results. Through this paper, it is demonstrated that this linearly scaled molecular dynamics model can be used to study laser ablation results over tens of micrometers.

Structural Insights into the Mechanism of a Polyketide Synthase Thiocysteine Lyase Domain.

Polyketide synthases (PKSs) are renowned for the structural diversity of the polyketide natural products they produce, but sulfur-containing functionalities are rarely installed by PKSs. We previously characterized thiocysteine lyase (SH) domains involved in the biosynthesis of the leinamycin (LNM) family of natural products, exemplified by LnmJ-SH and guangnanmycin (GnmT-SH). Here we report a detailed investigation into the PLP-dependent reaction catalyzed by the SH domains, guided by a 1.8 Å resolution crystal structure of GnmT-SH. A series of elaborate substrate mimics were synthesized to answer specific questions garnered from the crystal structure and from the biosynthetic logic of the LNM family of natural products. Through a combination of bioinformatics, molecular modeling, in vitro assays, and mutagenesis, we have developed a detailed model of acyl carrier protein (ACP)-tethered substrate-SH, and interdomain interactions, that contribute to the observed substrate specificity. Comparison of the GnmT-SH structure with archetypical PLP-dependent enzyme structures revealed how Nature, via evolution, has modified a common protein structural motif to accommodate an ACP-tethered substrate, which is significantly larger than any of those previously characterized. Overall, this study demonstrates how PLP-dependent chemistry can be incorporated into the context of PKS assembly lines and sets the stage for engineering PKSs to produce sulfur-containing polyketides.

Single-Nucleus and Spatial Transcriptomics Revealing Host Response Differences Triggered by Mutated Virus in Severe Dengue

Dengue virus (DENV) infection causes various disease manifestations ranging from an asymptomatic state to severe, life-threatening dengue. Despite intensive research, the molecular mechanisms underlying the abnormal host responses and severe disease symptoms caused by evolved DENV strains is not fully understood. First, the spatial structure of mutant DENV was compared via in silico molecular modeling analysis. Second, employing single-nucleus and spatial RNA sequencing, we analyzed and verified transcriptome samples in uninfected, mild (NGC group), and severe (N10 group) liver tissues from murine models. In this study, we obtained a cumulatively mutated DENV-2 N10 with enhanced capability of replication and pathogenicity post 10 serial passages in Ifnra−/− mice. This variant caused severe damage in the liver, as compared with other organs. Furthermore, mutated DENV infection elicited stronger responses in hepatocytes. The critical host factor Nrg4 was identified. It dominated mainly via the activation of the NRG/ErbB pathway in mice with severe symptoms. We report on evolved N10 viruses with changes observed in different organisms and tissue. This evolutionary variant results in high replicability, severe pathogenicity, and strong responses in murine. Moreover, the host responses may play a role by activating the NRG/ErbB signaling pathway. Our findings provide a realistic framework for defining disturbed host responses at the animal model level that might be one of the main causes of severe dengue and the potential application value.

Wybrane aspekty przeciwwirusowej aktywności flawonoidów względem SARS-CoV-2

Coronaviruses cause diseases of the respiratory tract, gastrointestinal tract and central nervous system, which threaten human health and contribute to economic losses. Innovative production technologies make it possible to use bioactive compounds as antiviral agents. Most fruits, vegetables and plant products contain flavonoids. Numerous studies have demonstrated the health-promoting effect of this group of compounds resulting from their antioxidant potential. The activity of an antioxidant in the body is the result of many factors that modulate the reactivity and physicochemical properties, among which the chemical structure is the most important. Bioinformatics tools using molecular modeling often precede research using in vitro and in vivo methods. The aim of this review is to present the mechanism of antiviral action of flavonoids against SARS-CoV-2, responsible for COVID-19. Studies using virtual molecular docking models were collected to test the affinity of flavonoids for key proteins of the SARS-CoV-2 virus replication cycle. Among the flavonoids with antiviral activity, the most active were apigenin, luteolin, isorhamnetin, kaempferol, myricetin, quercetin, hesperetin, naringenin and genistein. Food products with a high content of these compounds are indicated.

Benzocarbazoledinones as SARS-CoV-2 Replication Inhibitors: Synthesis, Cell-Based Studies, Enzyme Inhibition, Molecular Modeling, and Pharmacokinetics Insights

Endemic and pandemic viruses represent significant public health challenges, leading to substantial morbidity and mortality over time. The COVID-19 pandemic has underscored the urgent need for the development and discovery of new, potent antiviral agents. In this study, we present the synthesis and anti-SARS-CoV-2 activity of a series of benzocarbazoledinones, assessed using cell-based screening assays. Our results indicate that four compounds (4a, 4b, 4d, and 4i) exhibit EC50 values below 4 μM without cytotoxic effects in Calu-3 cells. Mechanistic investigations focused on the inhibition of the SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) have used enzymatic assays. Notably, compounds 4a and 4b showed Mpro inhibition activity with IC50 values of 0.11 ± 0.05 and 0.37 ± 0.05 µM, respectively. Furthermore, in silico molecular docking, physicochemical, and pharmacokinetic studies were conducted to validate the mechanism and assess bioavailability. Compound 4a was selected for preliminary drug-likeness analysis and in vivo pharmacokinetics investigations, which yielded promising results and corroborated the in vitro and in silico findings, reinforcing its potential as an anti-SARS-CoV-2 lead compound.

Melt Expansion and Thermal Transitions of Semiconducting Polymers in Thin Films

AbstractThe molecular self‐organization and reorganization and thus volumetric and density changes during structural relaxation and melting of modern organic semi‐conducting materials remains largely unknown, particularly in the device relevant thin film geometry where the initial state may be structurally quenched away from equilibrium. Here, the apparent mass‐thickness of a range of semi‐conducting polymeric or molecular model materials systems is measured through in situ ellipsometry. Surprisingly, the volume changes upon melting correlate inversely, with a few exceptions, to the quality of crystallinity found via x‐ray methods (i.e., directly correlate with the paracrystalline g‐parameter) rather than the melting enthalpy that is possibly a proxy for the degree of crystallinity. This study also observes changes in orientation and/or density due to segmental relaxation during the first heat, thus complementing other characterization methods that measure relaxation or reorganization transitions. Semiconducting materials exhibit very large melt expansion and a richer phase‐behavior compared to commodity polymers, presumably due to their complex chemical structure. The results delineate an important and novel structure‐function relation that, together with simulations constrained by these results, will lead to better rational design of semi‐conducting materials.

Novel Nordaucane Sesquiterpenoid and Sesquiterpene Lactone From Laserpitium Species: Isolation, Structure Elucidation, InVitro, InVivo, and In Silico Evaluation as Anticancer Agents.

This study explores the cytotoxic activity-guided isolation of the underground parts of Laserpitium hispidum M. Bieb and Laserpitium petrophilum Boiss. & Heldr., which have not been previously investigated. The aim is to isolate and evaluate bioactive compounds from Laserpitium L. species with anticancer potential. This study involves bioactivity-guided isolation and structural studies of the pure compounds utilizing NMR, UV-Vis, IR spectroscopies, and HRMS. The cytotoxic activity of the isolated compounds was evaluated invitro and invivo, whereas molecular modeling, docking, and ADME predictions were conducted using Schrödinger software. The study isolated phenylpropanoids (laserine (1), latifolone (2), myristicin (3)), sterol (stigmasterol (4)), polyenes (falcarindiol (5)), sesquiterpene lactone (11-hydroxybadkhyzin (6)), and nordaucane sesquiterpene (norlasidiol angelate (7)) from L. hispidum, whereas L. petrophilum yielded 10β-acetoxy-8α-angeloyloxy-6αH,7αH-guaian-3-en-12,6-olide (8), 10β-acetoxy-8α-senecioyloxy-6αH,7αH-guaian-3-en-6,12-olide (9) and acetylisomontanolide (10). Molecular docking simulations revealed stable interactions between compounds 7 and 9 with estrogen receptor α (ERα) and vascular endothelial growth factor receptor 2 (VEGFR2), with compound 7 showing superior stability and binding affinity. In silico ADME predictions indicated favorable pharmacokinetic properties, including high oral absorption. Compounds 7 and 9, representing new nordaucane and sesquiterpene lactones, have not been previously reported. Invitro cytotoxicity revealed that compound 7 exhibits potent anti-cancer activity against MCF-7 cells, whereas compound 9 showed reduced cytotoxicity. Invivo testing in Caenorhabditis elegans supported these findings, suggesting safety and efficacy in organisms. In silico results emphasize the potential of these compounds, with compound 7 promising due to its stability and strong binding affinity.

A Hollowed-Out Heterometallic Cluster for Catalytic Knoevenagel Condensation.

Lanthanide-containing clusters are synthetically Lanthanide-containing clusters are synthetically challenging and with significant chemical and materials applications.Herein, two isostructural heterometallic clusters of the formula (NO3)12@[Ln132Ni78(OH)292(IDA)48(CH3COO)96(NO3)12(H2O)78]Cl44·xH2O·yCH3OH(IDA = iminodiacetate; Ln = Gd1,x= 110,y= 0; Ln = Eu2,x= 95,y= 40)were obtained via co-hydrolysis of Ln3+(Gd3+orEu3+) and Ni2+in the presence of iminodiacetate(IDA). Crystallographic studies show that each features a truncated tetrahedral core of Ln132Ni78within which avoid of 5.5 Å in diameter; connecting the central cage and its exterior are four trumpet-like passageways surface-decorated with dinuclear units of [Gd(μ3-OH)2Gd]. Mass spectroscopic analyses indicate that both clusters maintained their structural integrity in aqueous solution, with cryo-electron microscopyproviding the most convincing visual evidence in support of the cluster's solution stability. Size-selective Knoevenagel condensation, believed to occur in the passageways on the basis of experimental and molecular modeling results,was achieved in the presence of1. The application of 1as a uniquely structured molecular reactor and a recyclable heterogeneous catalyst was further illustrated by the one-pot three-component synthesis of biologically and pharmaceutically significant4H-pyran derivatives.

A Hollowed‐Out Heterometallic Cluster for Catalytic Knoevenagel Condensation

Lanthanide‐containing clusters are synthetically Lanthanide‐containing clusters are synthetically challenging and with significant chemical and materials applications. Herein, two isostructural heterometallic clusters of the formula (NO3)12@[Ln132Ni78(OH)292(IDA)48(CH3COO)96(NO3)12(H2O)78]Cl44·xH2O·yCH3OH (IDA = iminodiacetate; Ln = Gd 1, x = 110, y = 0; Ln = Eu 2, x = 95, y = 40) were obtained via co‐hydrolysis of Ln3+ (Gd3+ or Eu3+) and Ni2+ in the presence of iminodiacetate (IDA). Crystallographic studies show that each features a truncated tetrahedral core of Ln132Ni78 within which a void of 5.5 Å in diameter; connecting the central cage and its exterior are four trumpet‐like passageways surface‐decorated with dinuclear units of [Gd(μ3‐OH)2Gd]. Mass spectroscopic analyses indicate that both clusters maintained their structural integrity in aqueous solution, with cryo‐electron microscopy providing the most convincing visual evidence in support of the cluster's solution stability. Size‐selective Knoevenagel condensation, believed to occur in the passageways on the basis of experimental and molecular modeling results, was achieved in the presence of 1. The application of 1 as a uniquely structured molecular reactor and a recyclable heterogeneous catalyst was further illustrated by the one‐pot three‐component synthesis of biologically and pharmaceutically significant 4H‐pyran derivatives.

STK19 positions TFIIH for cell-free transcription-coupled DNA repair.

In transcription-coupled nucleotide excision repair (TC-NER), stalled RNA polymerase II (RNA Pol II) binds CSB and CRL4CSA, which cooperate with UVSSA and ELOF1 to recruit TFIIH. To explore the mechanism of TC-NER, we recapitulated this reaction invitro. When a plasmid containing a site-specific lesion is transcribed in frog egg extract, error-free repair is observed that depends on CSB, CRL4CSA, UVSSA, and ELOF1. Repair also requires STK19, a factor previously implicated in transcription recovery after UV exposure. A 1.9-Å cryo-electron microscopy structure shows that STK19 binds the TC-NER complex through CSA and the RPB1 subunit of RNA Pol II. Furthermore, AlphaFold predicts that STK19 interacts with the XPD subunit of TFIIH, and disrupting this interface impairs cell-free repair. Molecular modeling suggests that STK19 positions TFIIH ahead of RNA Pol II for lesion verification. Our analysis of cell-free TC-NER suggests that STK19 couples RNA Pol II stalling to downstream repair events.

Molecular models of PM6 for non-fullerene acceptor organic solar cells: How DAD and ADA structures impact charge separation and charge recombination.

The quadrupole moment of a non-fullerene acceptor (NFA) generated by the constituent electron donor (D) and acceptor (A) units is a significant factor that affects the charge separation (CS) and charge recombination (CR) processes in organic photovoltaics (OPVs). However, its impact on p-type polymer domains remains unclear. In this study, we synthesized p-type molecules, namely acceptor-donor-acceptor (ADA) and donor-acceptor-donor (DAD), which are components of the benchmark PM6 polymer (D: benzodithiophene and A: dioxobenzodithiophene). Planar heterojunction films, a model of bulk heterojunction, were prepared using ADA, DAD, and PM6 as the bottom p-type layers and Y6 NFA as the top n-type layer. Flash-photolysis time-resolved microwave conductivity, femtosecond transient absorption spectroscopy, and quantum mechanical calculations were employed to probe the charge carrier dynamics. Our findings reveal that while the subtle difference in quadrupole moment and energy gradient of the p-type materials has a minimal influence on CS, the molecular type (ADA or DAD) significantly affects the bulk CR. This study expands the understanding of how the p-type component and its conformation at the p/n interface impact the CS and CR in OPVs, highlighting the critical role of molecular donors in optimizing device performance.

Molecular modeling and cytotoxic activity studies of oxirane-2-carboxylate derivatives

In this study, five 3-aryloxirane-2-carboxylate derivatives were prepared, and the antiproliferative activities of molecules were screened in lung and colon cancer cell lines. The results showed that molecules had antiproliferative activity on cancerous cells with IC50 values under 100 µM. Furthermore, all of the molecules were found to have a much higher cytotoxic effect than cisplatin in colon cancer cells. The interactions of the relatively active compounds to the crucial enzyme in cancer cell proliferation, cyclin-dependent kinase 1 (CDK1), were investigated using molecular docking. The stability of the resulting CDK1-compound complexes procured from the docking was also assessed through molecular dynamics (MD) simulations. Then, the binding affinity of compounds 2-3a and 2-3c to the target enzyme was computed by MMPBSA. The molecular docking study demonstrated that the two most active compounds could bind to the enzyme. The binding potential of 2-3a is anticipated to be higher as it had one more conventional hydrogen bond and a slightly lower binding energy than compound 2-3c. The MD simulation study exhibited that the two compounds formed a stable complex with the enzyme. On the other hand, the MMPBSA energy computation implicated a slightly higher binding affinity for compound 2-3c toward the enzyme. Furthermore, electrical and frontier molecular orbital analysis of all of the tested compounds was conducted by density functional theory (DFT) studies. Compound 2-3a is anticipated to be the most chemically stable as it gave the highest energy gap value in the DFT analysis.

New targets and biomarkers for doxorubicin-induced cardiotoxicity in humans: implications drawn from toxicogenomic data and molecular modelling

The doxorubicin-induced cardiotoxicity continues to be a life-threatening adverse effect in the clinic. Doxorubicin-induced acute cardiotoxicity is reversible, whereas chronic cardiotoxicity is irreversible, leading to dilated cardiomyopathy and heart failure. The aim of this study was to identify the molecular mechanisms associated with doxorubicin metabolites in doxorubicin-induced chronic cardiotoxicity. For this purpose, literature searches and in silico toxicogenomic analyses were conducted using various tools, including the Comparative Toxicogenomic Database, GeneMANIA, Metascape, MIENTURNET, ChEA3, and AutoDock. Additionally, molecular dynamics simulations were performed for 500 ns using Schrödinger software to assess the stability and dynamics of the representative docked complexes. We observed that doxorubicin biotransformed into five metabolites in the human heart and identified 11 common genes related to doxorubicin, its metabolites, dilated cardiomyopathy, and heart failure. Our findings revealed that doxorubicin and its metabolites primarily exhibited binding affinity to the beta-1 adrenergic receptor and fatty acid synthase. Furthermore, we identified several key transcription factors, especially the Homeobox protein Nkx-2.6, and hsa-miR-183-3p associated with this cardiotoxicity. Finally, we observed that, in addition to doxorubicinol, 7-deoxidoxorubicinone, another metabolite of doxorubicin, may also contribute to this cardiotoxicity. These findings contribute to our understanding of the processes underlying doxorubicin-induced chronic cardiotoxicity.

Synthesis and antitumor evaluation of glycyrrhetinic acid-dithiocarbamate hybrids.

Glycyrrhetinic acid (GA) is a naturally occurring triterpene compound. The aim of this study was to employ the pharmacophore hybrid strategy to merge GA with various dithiocarbamates and obtain novel compounds with better antitumor activities. We present a two-step synthetic protocol wherein the GA derivative underwent reaction with carbon disulfide and various secondary amines in a one-pot manner under mild conditions, facilitating the preparation of a series of structurally novel GA-dithiocarbamate derivatives. Bioassay screening revealed that the representative compound 3c demonstrated the capacity to reduce the mitochondrial membrane potential in Hep3B and Huh-7 cells, induce nuclear apoptosis, inhibit invasion and migration, and prompt both early and late apoptosis. Furthermore, our research findings indicated that this apoptotic phenomenon may be associated with the expression of Bcl-2, Bax, Bak, PARP, and cleaved-PARP proteins. Utilizing network pharmacology for predicting core targets and signaling pathways of compound 3c for hepatocellular carcinoma (HCC) treatment involved employing molecular docking models to demonstrate high affinity between compound and target protein. In conjunction with Western blot analysis, compound 3c may impact HCC through the PI3K-AKT-mTOR pathway.

Insight on novel sulfamoylphenyl pyrazole derivatives as anticancer carbonic anhydrase inhibitors.

As another part continue for our previous study, variable substituted pyrazoles bearing sulfamoylphenyl moiety were synthesized and screened against two cancer related human carbonic anhydrase (hCA) isoforms and acetazolamide (AAZ) used as a reference standard. Some compounds as 4e and 6c manifested a promising inhibitory activity against both isoforms (KI = 0.072, 0.081 and 0.073, 0.095 µM), respectively. While others as 4a and 5e showed inhibitory activity against hCA IX only (KI = 0.062, 0.04 µM) or against hCA XII only as compound 5b (KI = 0.106 µM) compared to AAZ (KI = 0.065, 0.046 µM), respectively. Also, the anticancer efficacy against 60 cancer cell lines for the target compounds was assessed, and the most promising ones were 4d and 5a-d. Further investigation of the anticancer activity of 5b on MCF-7 cell line explored (IC50 = 5.21 µM) compared to doxorubicin (IC50 = 11.58 µM). Moreover, compound 5b was exposed to cell cycle analysis and apoptotic assay on MCF-7 breast cancer cell line under both normal and hypoxic conditions at its IC50 concentration with elevation of total apoptotic cells % in MCF-7 relative to the control cells; respectively. Finally, molecular modelling simulations rationalized the in vitro testing results.

STK19 facilitates the clearance of lesion-stalled RNAPII during transcription-coupled DNA repair.

Transcription-coupled DNA repair (TCR) removes bulky DNA lesions impeding RNA polymerase II (RNAPII) transcription. Recent studies have outlined the stepwise assembly of TCR factors CSB, CSA, UVSSA, and transcription factor IIH (TFIIH) around lesion-stalled RNAPII. However, the mechanism and factors required for the transition to downstream repair steps, including RNAPII removal to provide repair proteins access to the DNA lesion, remain unclear. Here, we identify STK19 as a TCR factor facilitating this transition. Loss of STK19 does not impact initial TCR complex assembly or RNAPII ubiquitylation but delays lesion-stalled RNAPII clearance, thereby interfering with the downstream repair reaction. Cryoelectron microscopy (cryo-EM) and mutational analysis reveal that STK19 associates with the TCR complex, positioning itself between RNAPII, UVSSA, and CSA. The structural insights and molecular modeling suggest that STK19 positions the ATPase subunits of TFIIH onto DNA in front of RNAPII. Together, these findings provide new insights into the factors and mechanisms required for TCR.

M630L MUTATION DISRUPTS THE STRUCTURE CONFORMATION OF BRUTON TYROSINE KINASE (BTK) DOMAIN IN PATIENT WITH X-LINKED AGAMMAGLOBULINEMIA: INSIGHTS FROM IN SILICO

X-Linked Agammaglobulinemia (XLA) is a rare inherited disease, attributed to mutations found in the Bruton Tyrosine Kinase (BTK) gene. This research outlines the application of Molecular Modelling and Simulation to predict the effects of a novel non-synonymous Single Nucleotide Polymorphism (nsSNP) reported in the BTK kinase domain protein of a male XLA patient. The mutation at position c.1888A>T causes a substitution of p.M630L within the kinase domain of the BTK protein. Functional assessment using in silico prediction tools (SIFT, Polyphen-2, PROVEAN, MutationAssessor, PANTHER, FATHMM, MutPred and MutationTaster) predicted the mutation to be deleterious, potentially disrupting both the structure and function of the protein. Nevertheless, the mutation is not located at the active site of the kinase domain. Consequently, the molecular dynamics (MD) simulations were performed to investigate the impact of amino acid substitution to the three-dimensional (3D) conformational structure of the BTK protein, contributing to the disease phenotype observed in the reported patient. MD analysis, clustering analysis and Principle Component Analysis (PCA) revealed that the 3D conformational structure of the kinase domain of mutant protein to be more compact and rigid compared to the wildtype. Given that the alterations in protein structure can influence their functional characteristics, the p.M630L mutation within the BTK protein kinase domain might disrupt the protein function, potentially impeding the maturation of B cells and contributing to the onset of XLA disease.