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At least 19 recordsLinked to original sources
PubMed2023

Discussion on the mechanism of Lingguizhugan Decoction in treating hypertension based on network pharmacology and molecular simulation technology.

To explore the mechanism of Lingguizhugan Decoction in treating hypertension based on network pharmacology and molecular simulation. The active ingredients and potential targets were screened by the Systematic Pharmacological Analysis Platform of Traditional Chinese Medicine (TCMSP). Hypertension-related targets were obtained from OMIM and GeneCards databases. Common targets between drug and hypertension were screened in the Venny platform. A protein-protein interaction (PPI) network was constructed in the STRING database using intersection targets. Key targets in PPI network were analyzed by Cytoscape. R language program was used for Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Finally, the binding abilities of the main active ingredients to critical targets were verified by molecular simulation. Naringenin, quercetin, kaempferol, and β-sitosterol in Lingguizhugan Decoction, and potential targets such as STAT3, AKT1, TNF, IL6, JUN, PTGS2, MMP9, CASP3, TP53, and MAPK3, were screened out. KEGG Enrichment analysis revealed that the common targets of Lingguizhugan Decoction and hypertension are mainly involved in the lipid and atherosclerosis signaling pathway, AGE-RAGE signaling pathway in diabetic complications, fluid shear stress and atherosclerosis, and IL17 signaling pathway. The molecular simulation results showed that naringenin-MAPK3, quercetin-MMP9, quercetin-PTGS2, and quercetin-TP53 were the top four in the docking scores. Naringenin-MAPK3 and quercetin-MMP9 were stable, with binding free energies of -27.97 ± 1.41 kcal/mol and -21.15 ± 3.17 kcal/mol, respectively. The possible mechanism of Lingguizhugan Decoction in treating hypertension is characterized of multi-component, multi-target, and multi-pathway.Communicated by Ramaswamy H. Sarma.

Network Pharmacology↗
PubMed1990

Using molecular dynamics simulations on crambin to evaluate the suitability of different continuum dielectric and hydrogen atom models for protein simulations.

Molecular dynamics simulations of enzymes with enough explicit waters of solvation to realistically account for solute-solvent interactions can burden the computational resources required to perform the simulation by more than two orders of magnitude. Since enzyme simulations even with an implicit solvation model can be imposing for a supercomputer, it is important to assess the suitability of different continuum dielectric models for protein simulations. A series of 100-picosecond molecular dynamics simulations were performed on the X-ray crystal structure of the protein crambin to examine how well computed structures, obtained using seven continuum dielectric and two hydrogen atom models, agreed with the X-ray structure. The best level of agreement between computed and experimental structures was obtained using a constant dielectric of 2 and the all-hydrogen model. Continuum dielectric models of 1, 1r, and 2r also led to computed structures in reasonably good agreement with the X-ray structure. In all cases, the all-hydrogen model gave better agreement than the united atom model, although, in one case, the difference was not significant. Dielectric models of 4, 80, and 4r with either hydrogen model yielded significantly poorer fits. It is especially noteworthy that the observed trends did not semiquantitatively converge until about 50 picoseconds into the simulations, suggesting that validation studies for protein calculations based on energy minimizations or short simulations should be viewed with caution.

Computer Simulation↗
PubMed1992

The fine structure of two DNA dodecamers containing the cAMP responsive element sequence and its inverse. Nuclear magnetic resonance and molecular simulation studies.

1H and 31P n.m.r. (nuclear magnetic resonance) spectroscopy have been used in conjunction with molecular simulation to determine the structure of two DNA dodecamers. The first of these, CATGACGTCATG, contains the octameric sequence CRE (cAMP responsive element), while the second is the reversed sequence, GTACTGCAGTAC. Structure determination was based on both NOESY (nuclear Overhauser spectroscopy) derived distances and COSY (correlated spectroscopy) dihedral angle data. Access to the 31P spectra also allowed the epsilon backbone angles to be determined. Considerable care was taken in deriving structural parameters from the n.m.r. data and an excellent level of agreement is obtained with the simulated conformations. Both dodecamers are found to belong to the B-DNA family; however, there is a striking difference between the CRE sequence and its inverse, the former conformation alone showing a strong structural heterogeneity.

Base Sequence↗
PubMed1992

The conformational behaviour of complexes of alpha-cyclodextrin with p-chlorophenol and p-hydroxybenzoic acid in water as studied by molecular dynamics simulations.

Molecular dynamics simulations were performed to obtain information about the conformational behaviour and stabilization of alpha-cyclodextrin (alpha CD) complexes in water. Simulations of p-chlorophenol and p-hydroxybenzoic acid in alpha CD showed that the complex is a very flexible system. The guest compound rotates inside the cavity and partly moves in and out. alpha CD continuously adapts its conformation to the orientation of the guest compound (or vice versa): the hexagon of the glycosidic oxygen atoms is stretched parallel to the plane of the aromatic ring of the guest compound during 80% of the simulation. This suggests that Van der Waals interactions play an important role in the stabilization of the complex. Each intramolecular hydrogen bond between neighbouring glucose units is formed during 30-80% of the simulation. Hydrogen bonds between alpha CD and the guest compound, on the other hand, are rarely formed. Thus, intermolecular hydrogen bonding seems to play a minor role in the stabilization of alpha CD complexes.

Chlorophenols↗
PubMed1992

Cholesterol in model membranes. A molecular dynamics simulation.

Molecular dynamics simulations of a model membrane with inserted cholesterol molecules have been performed to study the perturbing influence of cholesterol. In the fluid phase of a lipid bilayer at 13 mol% concentration of cholesterol, local ordering of the hydrocarbon chains is induced. This perturbation decays with the distance from the cholesterol, and the effect extends 1.25 nm. It can be monitored in several ways, e.g., by an order parameter corresponding to deuterium nuclear magnetic resonance quadrupolar splittings, by the fraction of gauche bonds, or by the local bilayer thickness. At constant surface density, the local ordering is accompanied by disordering of the bulk phase, and, consequently, the net ordering effect is small. After compressing the system laterally in accordance with experimentally known surface areas, the bulk order parameters agree with those of a pure system, and the average order parameters are in accordance with experimental data. The necessity for this lateral compression is supported by calculated lateral pressures. At lower cholesterol concentration (3%), no direct perturbing effect is observed. A smaller lateral pressure than in a pure system indicates that the system with cholesterol is expected to have a smaller surface area, which would result in an increase of the order parameters, thus accounting for the experimental observations. The lack of spatial variation is, however, puzzling and may indicate a cooperative ordering effect.

Cholesterol↗
PubMed2026

Decoding TnsC Filament Assembly in CRISPR-Associated Transposons Using Interpretable Deep Learning and Molecular Simulations.

CRISPR-associated transposons (CASTs) enable programmable DNA integration, yet how the TnsC regulator forms processive filaments on DNA to coordinate RNA-guided transposition in type V-K CAST systems remains unknown. Here, we integrate large-scale molecular simulations, interpretable deep learning using graph attention networks (GATs), and causal inference analyses to define the molecular determinants of TnsC filament nucleation and elongation. We show that TnsC nucleates by inducing localized DNA deformation that propagates along extended filaments, with Granger causality revealing that TnsC motions precede and predict DNA deformation. Interpretable GAT models demonstrate that elongation is determined during early recognition between incoming and DNA-bound subunits, followed by structural reorganization that regenerates the recruitment interface and enables processive assembly. These results elucidate the molecular mechanism of processive TnsC filament assembly and explain why isolated TnsC filaments preferentially elongate in the 5' → 3' direction, while accessory transposition factors can reshape the interaction landscape and alter filament growth polarity. Together, these findings advance our understanding of CAST function and inform the engineering of programmable DNA integration platforms. Beyond CAST systems, this work introduces an interpretable GAT approach as a general and transferable deep learning strategy for uncovering molecular mechanisms in biological systems, while demonstrating the power of causal inference for dissecting directional relationships in molecular dynamics.

Deep Learning↗
PubMed2026

Zhiling Jiangya decoction treats hypertension in rats: An integrative study of network pharmacology, immune infiltration, molecular simulation, and 16S rDNA sequencing.

OBJECTIVE: This study integrated network pharmacology, immune infiltration analysis, molecular docking, molecular dynamics simulation, ADMET prediction, 16S rDNA sequencing, and rat experiments to elucidate the potential mechanisms underlying the antihypertensive effects of Zhiling Jiangya Decoction (ZLJYD). METHODS: Active compounds and their potential targets were screened from the PubChem, TCMSP, NovoPro, and SwissTargetPrediction databases. Hypertension-related targets were retrieved from the OMIM and GeneCards databases, and overlapping targets were identified. The STRING database and Cytoscape 3.10.1 software were used to construct a protein-protein interaction network and a herb-component-target-disease network. Gene Ontology functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed to identify the key biological processes and signaling pathways involved. Using the CIBERSORT algorithm combined with correlation analysis, we investigated the association between key targets and immune cell infiltration. Molecular docking, molecular dynamics simulations, and ADMET predictions were performed to assess the binding stability and pharmacokinetic properties of the main compounds with their corresponding targets. Finally, the antihypertensive efficacy of ZLJYD was validated using a spontaneously hypertensive rat model, and alterations in gut microbiota were analyzed using 16S rDNA sequencing. RESULTS: A total of 123 active compounds and 267 hypertension-related targets of ZLJYD were identified. Enrichment analysis revealed that these targets were primarily associated with the PI3K-Akt signaling pathway and lipid and atherosclerosis pathways. Immune infiltration analysis suggested that the therapeutic effects of ZLJYD may involve the regulation of follicular helper T cells, naïve B cells, and naïve CD4⁺ T cells. Molecular docking and dynamics simulations supported the stable binding of key compounds to their target proteins, while ADMET predictions indicated favorable pharmacokinetic properties and safety profiles. Rat experiments demonstrated that ZLJYD significantly reduced blood pressure in spontaneously hypertensive rats, partially alleviated gut microbiota dysbiosis, and altered microbial community structure and phylogenetic diversity. CONCLUSION: This study systematically elucidates the potential mechanisms underlying the antihypertensive effects of ZLJYD through multiple components, targets, and pathways, particularly immune regulation and gut microbiota remodeling. These findings provide mechanistic insights into its potential therapeutic application.

16S rDNA sequencing↗
PubMed1991

Cooperative ligand reorientations in cytochrome c3: a molecular dynamics simulation.

Molecular dynamics simulations of a tetraheme cytochrome c3 were performed to investigate dynamic aspects of the motion of the axial heme iron ligands. It was found that persistent transitions between alternate axial imidazole orientations of the histidine incorporated in the CXXCH heme binding sequence occurred via correlated motions. The correlated motions involved virtually all of the atoms comprising the polypeptide backbone of the heme binding sequence as well as the histidine imidazole side-chain.

Amino Acid Sequence↗
PubMed1991

FASTRUN: a special purpose, hardwired computer for molecular simulation.

We describe the design, construction, and performance of a special purpose, hardwired accelerator for molecular mechanical calculations called FASTRUN. The processor was designed at Columbia University in 1984, constructed in the Instrumentation Division of Brookhaven National Laboratory, and delivered to Columbia in final form in 1989. It was rendered functional for molecular mechanics in early 1990. Together with its host Star array processor, FASTRUN has a measured performance for molecular dynamics simulations which compares favorably with present day supercomputers. The hardware replication cost of FASTRUN is on the order of $100,000.00.

Computer Simulation↗
PubMed2025

Design of nanobody targeting SARS-CoV-2 spike glycoprotein using CDR-grafting assisted by molecular simulation and machine learning.

The design of proteins capable effectively binding to specific protein targets is crucial for developing therapies, diagnostics, and vaccine candidates for viral infections. Here, we introduce a complementarity-determining region (CDR) grafting approach for designing nanobodies (Nbs) that target specific epitopes, with the aid of computer simulation and machine learning. As a proof-of-concept, we designed, evaluated, and characterized a high-affinity Nb against the spike protein of SARS-CoV-2, the causative agent of the COVID-19 pandemic. The designed Nb, referred to as Nb Ab.2, was synthesized and displayed high-affinity for both the purified receptor-binding domain protein and to the virus-like particle, demonstrating affinities of 9 nM and 60 nM, respectively, as measured with microscale thermophoresis. Circular dichroism showed the designed protein's structural integrity and its proper folding, whereas molecular dynamics simulations provided insights into the internal dynamics of Nb Ab.2. This study shows that our computational pipeline can be used to efficiently design high-affinity Nbs with diagnostic and prophylactic potential, which can be tailored to tackle different viral targets.

Spike Glycoprotein, Coronavirus↗
PubMedDate not supplied

Molecular simulation and drug design.

Computer simulation techniques have become a major tool in the analysis of biomolecular properties and behaviour. These techniques are used extensively in drug and protein design projects, because they can provide information that is complementary to experimental data. Molecular mechanics methods such as energy minimization and molecular dynamics are among the most commonly used simulation techniques for the study of biomolecules. We present here a brief description of some molecular mechanics methods and a few applications examples for biomacromolecules and biomolecular complexes.

Computer Simulation↗
PubMed1992

Application of restrained minimization, simulated annealing and molecular dynamics simulations for the conformational analysis of oligosaccharides.

The purpose of the present study was to determine the confidence with which the small number of 1H NMR nuclear Overhauser effect (NOE) distance constraints measurable across glycosidic linkages in oligosaccharides could be used for solution conformational analysis. This was assessed by use of these constraints in restrained molecular mechanical minimization of the tetrasaccharide Gal beta 1----4(Fuc alpha 1----3)Glc-NAc beta 1----3Gal, a model compound of the Lewis-X antigenic determinant. This presents a particularly severe test case in view of extreme resonance overlap and a dearth of inter-residue distance constraints. It is concluded that these constraints, when used in conventional restrained minimization, result in the generation of 'virtual conformations' and local minima about glycosidic linkages. However, these restraints are nevertheless found to be useful in the initial stages of a conformational analysis strategy involving restrained minimization combined with dynamical simulated annealing to define more accurately the global minimum energy configuration, together with molecular dynamics simulation to explore conformational mobility about this minimum. Theoretical ROE values calculated over the time course of the MD simulation, using a formalism appropriate for the time scale of the internal motion, are compared with those obtained experimentally in the oligosaccharide.

Carbohydrate Conformation↗
PubMed1990

Dynamic properties of the first enzymatic reaction steps of porcine pancreatic elastase. How rigid is the active site of the native enzyme? Molecular dynamics simulation.

Two molecular dynamics simulations (100 and 50 ps) of native porcine pancreatic elastase i.e., without bound substrate and with the active site hydrated by a dome of water (630 molecules) have been performed. Dynamical properties of the catalytic tetrad have been examined. While relative conformations of the Asp 102, His 57, and Ser 214 are rather stable in time, the side chain of Ser 195 undergoes several conformational changes. No preferences are observed for the formation of a hydrogen bond between the O gamma-H group (Ser 195) and nitrogen N, (His 57). A cluster of ordered water molecules effectively competes with the H-O gamma group (Ser 195) and thereby prevents the formation of this H bond, which is generally agreed to be crucial for catalysis.

Animals↗
PubMed1989

Superoxide dismutase: fluctuations in the structure and solvation of the active site channel studied by molecular dynamics simulation.

The molecular dynamics (MD) simulation of superoxide dismutase (SOD) in water is carried out for a total of 23 ps. The simulation system is a 26 A sphere centered at the active site of SOD, including 1602 atoms from SOD and 1761 water molecules. There is no gross deviation from the x-ray structure for the average MD structure. The structure and potential fluctuations around the active site are examined. The results provide new insight to the interactions between SOD and its substrate superoxide.

Binding Sites↗
PubMedDate not supplied

Disaccharide conformational flexibility. II. Molecular dynamics simulations of sucrose.

Molecular dynamics simulations have been used to study the motions in vacuum of the disaccharide sucrose. Ensembles of trajectories were calculated for each of the five local minimum energy conformations identified in the adiabatic conformational energy mapping of this molecule. The model sucrose molecules were found to exhibit a variety of motions, although the global minimum energy conformation was found to be dynamically stable, and no transitions away from this structure were observed to occur spontaneously. In all but one of these vacuum trajectories, the intramolecular hydrogen bond between residues was maintained, in accord with recent nmr studies of this molecule in aqueous solution. Considerable flexibility of the furanoid ring was found in the trajectories. No "flips" to the opposite puckering for this ring were found in the simulations starting from the global minimum, although such a transition was observed for a trajectory initiated with one of the higher local minimum energy conformations. Overall, the observed structural fluctuations were consistent with the experimental picture of sucrose as a relatively rigid molecule.

Carbohydrate Conformation↗