Search Results (48)

The relationship between protein structure and function is intrinsically interconnected, as the structure of a protein directly determines its functional properties. To investigate the effects of temperature and pressure on protein function, this study employed ethyl carbamate (EC) hydrolase as a model food enzyme and conducted molecular dynamics (MD) simulations under varying temperature and pressure levels to elucidate its structure–function relationship. By systematically analyzing the dynamic changes in root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), hydrogen bonding, catalytic pocket conformation, and packing density under different temperature and pressure conditions, we revealed the structural adaptability of EC hydrolase. Furthermore, we analyzed the characteristics of EC hydrolase using molecular dynamics simulations with temperature and pressure levels, as well as conformational bias-based computer-aided engineering, providing both theoretical and experimental foundation for the adaptability mechanisms of enzymes under extreme conditions. Full article

Background/Objectives: Pomegranate (Punica granatum) peel, often discarded as waste, contains abundant bioactive compounds such as polyphenols, vitamins, flavonoids, tannins, anthocyanins, and many more. This contributes to remarkable bioactivities, including anticancer, anti-inflammatory, antioxidant, antibacterial, and antifungal properties. Pancreatic cancer is a deadly cancer with a 9% survival rate. Its aggressiveness, invasiveness, quick metastasis, and poor prognosis significantly decrease the survival rate. Thus, we aim to explore pomegranate peel as a possible alternative medication for treating pancreatic cancer through virtual methods. Methods: Firstly, bioactive compounds were collected from multiple databases and screened for oral bioavailability (OB) ≥ 0.3 and drug likeness (DL) ≥ 0.18 scores. Simultaneously, network pharmacology was employed to extract the most probable targets for pancreatic cancer. Further computational analyses were performed, including molecular docking, molecular dynamics simulation, and in silico pharmacokinetics evaluation. Results: Consequently, the top 10 key targets from network analysis were AKT1, IL6, TNF, SRC, STAT3, EGFR, BCL2, HSP90AA1, HIF1A, and PTGS2. However, only AKT1, EGFR, BCL2, HSP90AA1, and PTGS2 exhibited strong binding affinities with pomegranate compounds, which are significantly declared in affected cells to enhance cancer progression. Outcomes from molecular dynamics simulations, particularly RMSD, RMSF, hydrogen bonding, and radius of gyration (Rg), confirmed stable interactions between 1-O-Galloyl-beta-D-glucose, epicatechin, phloridzin, and epicatechin gallate with respective target proteins. Conclusions: This suggests that pomegranate peels hold anticancer bioactive compounds for treating pancreatic cancer. Surprisingly, most compounds adhere to Lipinski’s and Pfizer’s rules and display no toxicity. However, as this study relies entirely on computational methods, experimental validation is necessary to confirm these findings and assess real-world efficacy and potential side effects. Full article

This study employs Density Functional Theory (DFT) and Molecular Dynamics (MD) simulations to investigate interactions between water molecules and Poly(N-isopropylacrylamide) (PNIPAM). DFT reveals preferential water binding sites, with enhanced binding energy observed in the linker zone. Quantum Theory of Atoms in Molecules (QTAIM) and electron localization function (ELF) analyses highlight the roles of hydrogen bonding and steric hindrance. MD simulations unveil temperature-dependent hydration dynamics, with structural transitions marked by changes in the radius of gyration (Rg) and the radial distribution function (RDF), aligning with DFT findings. Our work goes beyond prior studies by combining a DFT, QTAIM and MD simulations approach across different PNIPAM monomer-to-30mer structures. It introduces a systematic quantification of pseudo-saturation thresholds and explores water clustering dynamics with structural specificity, which have not been previously reported in the literature. These novel insights establish a more complete molecular-level picture of PNIPAM hydration behavior and temperature responsiveness, emphasizing the importance of amide hydrogen and carbonyl oxygen sites in hydrogen bonding, which weakens above the lower critical solution temperature (LCST), resulting in increased hydrophobicity and paving the way for understanding water sorption mechanisms, offering guidance for future applications such as dehumidification and atmospheric water harvesting. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder marked by the progressive accumulation of amyloid-β (Aβ) plaques and tau protein tangles in the brain. These pathological aggregates interfere with neuronal function, leading to the disruption of cognitive processes, particularly memory. The deposition of Aβ forms senile plaques, while tau protein, in its hyperphosphorylated state, forms neurofibrillary tangles, both of which contribute to the underlying neurodegeneration observed in AD. Rosmarinic acid (RosA), a natural compound found in plants such as Rosmarinus officinalis, is known for its antioxidant, anti-inflammatory, and antimicrobial properties. Due to its ability to cross the blood–brain barrier, RosA holds promise as a nutritional supplement that may support brain health. In this study, molecular dynamics (MD) simulations were used to investigate the impact of RosA on the structural stability of Aβ peptides. The results indicated that the addition of RosA increased the instability of Aβ, as evidenced by an increase in the Root Mean Square Deviation (RMSD), a decrease in the Radius of Gyration (Rg), and an expansion of the Solvent Accessible Surface Area (SASA). This destabilization is primarily attributed to the disruption of native hydrogen bonds and hydrophobic interactions in the presence of two RosA molecules. The free energy landscape (FEL) analysis and MM-PBSA (Poisson-Boltzmann Surface Area Mechanics) results further support the notion that RosA can effectively bind to the hydrophobic pocket of the protein, highlighting its potential as a nutritional component that may contribute to maintaining brain health and function. Full article

Sinomenine (SIN) is a drug for the treatment of rheumatoid arthritis, most of which is administered orally, but it is prone to adverse gastrointestinal effects. Gel can overcome the gastrointestinal adverse effects caused by oral administration. In this paper, a multiscale computational pharmaceutics strategy was developed to guide the systematic study of formulation factors of a SIN gel and, further, to guide the formulation design. A molecular dynamics (MD) simulations method was utilized to successfully screen the optimal prescription of SIN gel and to elucidate the molecular mechanisms affecting the quality of SIN gel. The optimal prescription was 3.0% of SIN, 1.0% of Carbopol (Cp), 30% of Ethanol (Eth), 5.0% of Glycerine (Gly) and 10.0% of Menthol (Men). The influence mechanism can be explained by the combination of multiple parameters, such as the microstructure diagram, the radius of gyration (Rg) and the radial distribution function (RDF). In vitro transdermal studies were carried out using a modified Franz diffusion cell method to evaluate the quality of the screened and reference prescriptions. The results showed that the cumulative penetration and penetration rate of the screening of prescription were better than the reference formulation. Most important of all, the simulation results are in good agreement with the in vitro release experiment, indicating that the strategy has good applicability. This study was able to accurately optimize the formulation and elucidate the molecular mechanism, which would provide a reference for further research on SIN and gel. Full article

Bombyx mori silk fibroin is a promising biopolymer with notable mechanical strength, biocompatibility, and potential for diverse biomedical applications, such as tissue engineering scaffolds, and drug delivery. These properties are intrinsically linked to the structural characteristics of silk fibroin, making it essential to understand its molecular stability under varying environmental conditions. This study employed molecular dynamics simulations to examine the structural stability of silk I and silk II conformations of silk fibroin under changes in temperature (298 K to 378 K) and pressure (0.1 MPa to 700 MPa). Key parameters, including Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and Radius of Gyration (R_g) were analyzed, along with non-bonded interactions such as van der Waals and electrostatic potential energy. Our findings demonstrate that both temperature and pressure exert a destabilizing effect on silk fibroin, with silk I exhibiting a higher susceptibility to destabilization compared to silk II. Additionally, pressure elevated the van der Waals energy in silk I, while temperature led to a reduction. In contrast, electrostatic potential energy remained unaffected by these environmental conditions, highlighting stable long-range interactions throughout the study. Silk II’s tightly packed β-sheet structure offers greater resilience to environmental changes, while the more flexible α-helices in silk I make it more susceptible to structural perturbations. These findings provide valuable insights into the atomic-level behavior of silk fibroin, contributing to a deeper understanding of its potential for applications in environments where mechanical or thermal stress is a factor. The study underscores the importance of computational approaches in exploring protein stability and supports the continued development of silk fibroin for biomedical and engineering applications. Full article

Nano- and micro-sized vesicular and colloidal structures mediate cell–cell communication. They are important players in the physiology of plants, animals, and humans, and are a subject of increasing interest. We investigated the effect of three surfactants, N-cetylpyridinium chloride (CPC), sodium dodecyl sulfate (SDS), and Triton X-100 (TX100), and two anionic polyelectrolytes, sodium polystyrene sulfonate (NaPSS) and sodium polymethacrylate (NaPMA), on nanoliposomes. In addition, the effect of SDS and TX100 on selected biological membranes (erythrocytes and microalgae) was investigated. The liposomes were produced by extrusion and evaluated by microcalorimetry and light scattering, based on the total intensity of the scattered light (I_tot), hydrodynamic radius (R_h), radius of gyration (R_g), shape parameter p (=R_h/R_g,0), and polydispersity index. The EPs shed from erythrocytes and microalgae Dunaliella tertiolecta and Phaeodactylum tricornutum were visualized by scanning electron microscopy (SEM) and analyzed by flow cytometry (FCM). The R_h and I_tot values in POPC liposome suspensions with added CPC, SDS, and TX100 were roughly constant up to the respective critical micelle concentrations (CMCs) of the surfactants. At higher compound concentrations, I_tot dropped towards zero, whereas R_h increased to values higher than in pure POPC suspensions (R_h ≈ 60–70 nm), indicating the disintegration of liposomes and formation of larger particles, i.e., various POPC–S aggregates. Nanoliposomes were stable upon the addition of NaPSS and NaPMA, as indicated by the constant R_h and I_tot values. The interaction of CPC, SDS, or TX100 with liposomes was exothermic, while there were no measurable heat effects with NaPSS or NaPMA. The SDS and TX100 increased the number density of EPs several-fold in erythrocyte suspensions and up to 30-fold in the conditioned media of Dunaliella tertiolecta at the expense of the number density of cells, which decreased to less than 5% in erythrocytes and several-fold in Dunaliella tertiolecta. The SDS and TX100 did not affect the number density of the microalgae Phaeodactylum tricornutum, while the number density of EPs was lower in the conditioned media than in the control, but increased several-fold in a concentration-dependent manner. Our results indicate that amphiphilic molecules need to be organized in nanosized particles to match the local curvature of the membrane for facilitated uptake. To pursue this hypothesis, other surfactants and biological membranes should be studied in the future for more general conclusions. Full article

Isocitrate dehydrogenase 1 (IDH1) is a necessary enzyme for cellular respiration in the tricarboxylic acid cycle. Mutant isocitrate dehydrogenase 1 (mIDH1) has been detected overexpressed in a variety of cancers. mIDH1 inhibitor ivosidenib (AG-120) was only approved by the Food and Drug Administration (FDA) for marketing, nevertheless, a range of resistance has been frequently reported. In this study, several mIDH1 inhibitors with the common backbone pyridin-2-one were explored using the three-dimensional structure–activity relationship (3D-QSAR), scaffold hopping, absorption, distribution, metabolism, excretion (ADME) prediction, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, R² = 0.980, Q² = 0.765) and comparative molecular similarity index analysis (CoMSIA, R² = 0.997, Q² = 0.770) were used to build 3D-QSAR models, which yielded notably decent predictive ability. A series of novel structures was designed through scaffold hopping. The predicted pIC₅₀ values of C3, C6, and C9 were higher in the model of 3D-QSAR. Additionally, MD simulations culminated in the identification of potent mIDH1 inhibitors, exhibiting strong binding interactions, while the analyzed parameters were free energy landscape (FEL), radius of gyration (Rg), solvent accessible surface area (SASA), and polar surface area (PSA). Binding free energy demonstrated that C2 exhibited the highest binding free energy with IDH1, which was −93.25 ± 5.20 kcal/mol. This research offers theoretical guidance for the rational design of novel mIDH1 inhibitors. Full article

In the dynamic field of radiopharmaceuticals, innovating targeted agents for cancer diagnosis and therapy is crucial. Our study enriches this evolving landscape by evaluating the potential of radioiodinated anastrozole ([¹²⁵I]anastrozole) and radioiodinated epirubicin ([¹²⁵I]epirubicin) as targeting agents against MTHFD2-driven tumors. MTHFD2, which is pivotal in one-carbon metabolism, is notably upregulated in various cancers, presenting a novel target for radiopharmaceutical application. Through molecular docking and 200 ns molecular dynamics (MD) simulations, we assess the binding efficiency and stability of [¹²⁵I]anastrozole and [¹²⁵I]epirubicin with MTHFD2. Molecular docking illustrates that [¹²⁵I]epirubicin has a superior binding free energy (∆G_bind) of −41.25 kJ/mol compared to −39.07 kJ/mol for [¹²⁵I]anastrozole and −38.53 kJ/mol for the control ligand, suggesting that it has a higher affinity for MTHFD2. MD simulations reinforce this, showing stable binding, as evidenced by root mean square deviation (RMSD) values within a narrow range, underscoring the structural integrity of the enzyme–ligand complexes. The root mean square fluctuation (RMSF) analysis indicates consistent dynamic behavior of the MTHFD2 complex upon binding with [¹²⁵I]anastrozole and [¹²⁵I]epirubicin akin to the control. The radius of gyration (RG) measurements of 16.90 Å for MTHFD2-[¹²⁵I]anastrozole and 16.84 Å for MTHFD2-[¹²⁵I]epirubicin confirm minimal structural disruption upon binding. The hydrogen bond analysis reveals averages of two and three stable hydrogen bonds for [¹²⁵I]anastrozole and [¹²⁵I]epirubicin complexes, respectively, highlighting crucial stabilizing interactions. The MM-PBSA calculations further endorse the thermodynamic favorability of these interactions, with binding free energies of −48.49 ± 0.11 kJ/mol for [¹²⁵I]anastrozole and −43.8 kJ/mol for MTHFD2-. The significant contribution of Van der Waals and electrostatic interactions to the binding affinities of [¹²⁵I]anastrozole and [¹²⁵I]epirubicin, respectively, underscores their potential efficacy for targeted tumor imaging and therapy. These computational findings lay the groundwork for the future experimental validation of [¹²⁵I]anastrozole and [¹²⁵I]epirubicin as MTHFD2 inhibitors, heralding a notable advancement in precision oncology tools. The data necessitate subsequent in vitro and in vivo assays to corroborate these results. Full article

Malaria is one of the infectious illnesses causing a public health burden worldwide. Plasmodium vivax (P. vivax) is the most prevalent malaria parasite in Asia and Asia Pacific. P. vivax is resistant to sulfadoxine–pyrimethamine (SP) and mefloquine. This resistance makes it extremely difficult to control and eradicate due to its ability to survive in the liver and reactivate if the person infected has a weakened immune system. Thus, this study aims to inhibit P. vivax via targeting Duffy-binding protein (DBP) with active compounds from Hops (Humulus lupulus). The inhibition of DBP is essential to reduce malaria invasion of human red blood cells. We performed a quality assessment and prediction of the active site of DBP to determine the effectiveness and prediction of ligands in inhibiting DBP. Furthermore, the mechanism and structural stability of active compounds against DBP were evaluated using a combination of molecular docking and molecular dynamics simulation and a density-functional theory (DFT) study. The results showed that rutin had the highest binding of 8.852 kcal/mol. However, after the molecular dynamics simulation was run for 50 ns, the ligand 6-prenylnaringenin via MM-PBSA calculation showed the most positive value of 106.760 kJ/mol. In addition, 6-prenylnaringenin is the most stable ligand via the analysis of root-mean-square deviation backbone (RMSDBb), root-mean-square deviation c-alpha (RMSDCa), root-mean-square fluctuation (RMSF), solvent-accessible surface area (SASA), radius of gyration (Rg), and the hydrogen bond formation. We conclude that 6-prenylnaringenin has a tight and stable bond with the targeted DBP protein. Finally, we propose the use of 6-prenylnaringenin as a potential antimalarial compound via in silico studies. Full article

Starch retrogradation is a complex process involving changes in the multi-scale structure. In particular, the particle order of retrograded starch is unclear. In this study, we measured the radius of gyration (R_g) and radius of particles (R) of retrograded starch using small-angle X-ray scattering. Retrograded starch included various R_g, and the values of R_g depended on the length and state of the starch chains. With time, the standard deviations of R decreased due to the increase in particle uniformity. Based on these results, a new method for assessing the degree of starch retrogradation was established from the perspective of the particle order. The accuracy of the new method was verified through differential scanning calorimetry and scanning electron microscopy. The microstructures of the samples indicated that the retrograded starch granules contained substructures (primary particles) of different sizes. This study provides a new perspective for analyzing the structure of retrograded starch. Full article

We provide promising computational (in silico) data on phytochemicals (compounds 1–10) from Arabian Peninsula medicinal plants as strong binders, targeting 3-chymotrypsin-like protease (3CL^Pro) and papain-like proteases (PL^Pro) of SARS-CoV-2. Compounds 1–10 followed the Lipinski rules of five (RO5) and ADMET analysis, exhibiting drug-like characters. Non-covalent (reversible) docking of compounds 1–10 demonstrated their binding with the catalytic dyad (CYS145 and HIS41) of 3CL^Pro and catalytic triad (CYS111, HIS272, and ASP286) of PL^Pro. Moreover, the implementation of the covalent (irreversible) docking protocol revealed that only compounds 7, 8, and 9 possess covalent warheads, which allowed the formation of the covalent bond with the catalytic dyad (CYS145) in 3CL^Pro and the catalytic triad (CYS111) in PL^Pro. Root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and radius of gyration (Rg) analysis from molecular dynamic (MD) simulations revealed that complexation between ligands (compounds 7, 8, and 9) and 3CL^Pro and PL^Pro was stable, and there was less deviation of ligands. Overall, the in silico data on the inherent properties of the above phytochemicals unravel the fact that they can act as reversible inhibitors for 3CL^Pro and PL^Pro. Moreover, compounds 7, 8, and 9 also showed their novel properties to inhibit dual targets by irreversible inhibition, indicating their effectiveness for possibly developing future drugs against SARS-CoV-2. Nonetheless, to confirm the theoretical findings here, the effectiveness of the above compounds as inhibitors of 3CL^Pro and PL^Pro warrants future investigations using suitable in vitro and in vivo tests. Full article

In response to the urgent demand for innovative antibiotics, theoretical investigations have been employed to design novel analogs. Because griseofulvin is a potential antibacterial agent, we have designed novel derivatives of griseofulvin to enhance its antibacterial efficacy and to evaluate their interactions with bacterial targets using in silico analysis. The results of this study reveal that the newly designed derivatives displayed the most robust binding affinities towards PBP2, tyrosine phosphatase, and FtsZ proteins. Additionally, molecular dynamics (MD) simulations underscored the notable stability of these derivatives when engaged with the FtsZ protein, as evidenced by root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and solvent-accessible surface area (SASA). Importantly, this observation aligns with expectations, considering that griseofulvin primarily targets microtubules in eukaryotic cells, and FtsZ functions as the prokaryotic counterpart to microtubules. These findings collectively suggest the promising potential of griseofulvin and its designed derivatives as effective antibacterial agents, particularly concerning their interaction with the FtsZ protein. This research contributes to the ongoing exploration of novel antibiotics and may serve as a foundation for future drug development efforts. Full article

Alpha synuclein (α-Syn) is a neuronal protein encoded by the SNCA gene and is involved in the development of Parkinson’s disease (PD). The objective of this study was to examine in silico the functional implications of non-synonymous single nucleotide polymorphisms (nsSNPs) in the SNCA gene. We used a range of computational algorithms such as sequence conservation, structural analysis, physicochemical properties, and machine learning. The sequence of the SNCA gene was analyzed, resulting in the mapping of 42,272 SNPs that are classified into different functional categories. A total of 177 nsSNPs were identified within the coding region; there were 20 variants that may influence the α-Syn protein structure and function. This identification was made by employing different analytical tools including SIFT, PolyPhen2, Mut-pred, SNAP2, PANTHER, PhD-SNP, SNP&Go, MUpro, Cosurf, I-Mut, and HOPE. Three mutations, V82A, K80E, and E46K, were selected for further examinations due to their spatial positioning within the α-Syn as determined by PyMol. Results indicated that these mutations may affect the stability and function of α-Syn. Then, a molecular dynamics simulation was conducted for the SNCA wildtype and the four mutant variants (p.A18G, p.V82A, p.K80E, and p.E46K). The simulation examined temperature, pressure, density, root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), solvent-accessible surface area (SASA), and radius of gyration (Rg). The data indicate that the mutations p.V82A, p.K80E, and p.E46K reduce the stability and functionality of α-Syn. These findings highlight the importance of understanding the impact of nsSNPs on α-syn structure and function. Our results required verifications in further protein functional and case–control studies. After being verified these findings can be used in genetic testing for the early diagnosis of PD, the evaluation of the risk factors, and therapeutic approaches. Full article

Insulating cotton was used to change the airflow temperature in the exhaust pipe of a diesel engine, and soot particles at different positions in the exhaust pipe under different operating conditions were collected. The morphologies and microstructures of soot particles were observed by high-resolution transmission electron microscopy (HRTEM). The characteristic parameters, including the mean primary particle diameter (d_p), radius of gyration of soot aggregate (R_g), fractal dimension of soot particle (D_f), carbon layer spacing (D_s), and carbon layer torsion resistance (T_f), were statistically analyzed. The changes in each characteristic parameter before and after adding insulating cotton were compared. After installing the cotton, soot particles still grew through surface chemical reactions and physical processes in the diesel exhaust pipe, the agglomeration becomes more and more prevalent, the particle size increased, and D_f increased. The increase in the airflow temperature in the exhaust pipe promoted the surface growth of primary soot particles and enhanced the turbulence, which made the chain-like soot particles more likely to reunite under the action of turbulent eddies. Consequently, R_g decreased and D_f increased. Furthermore, the average D_s and T_f of primary soot particles deceased, especially under high loads. This indicated that the increase in the temperature of the exhaust pipe was conducive to the graphitization of primary soot particles. Full article