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PubMed2004

Prediction of ligand binding affinity and orientation of xenoestrogens to the estrogen receptor by molecular dynamics simulations and the linear interaction energy method.

Exposure to environmental estrogens has been proposed as a risk factor for disruption of reproductive development and tumorigenesis of humans and wildlife (McLachlan, J. A.; Korach, K. S.; Newbold, R. R.; Degen, G. H. Diethylstilbestrol and other estrogens in the environment. Fundam. Appl. Toxicol. 1984, 4, 686-691). In recent years, many structurally diverse environmental compounds have been identified as estrogens. A reliable computational method for determining estrogen receptor (ER) binding affinity is of great value for the prediction of estrogenic activity of such compounds and their metabolites. In the presented study, a computational model was developed for prediction of binding affinities of ligands to the ERalpha isoform, using MD simulations in combination with the linear interaction energy (LIE) approach. The linear interaction energy approximation was first described by Aqvist et al. (Aqvist, J.; Medina, C.; Samuelsson, J. E. A new method for predicting binding affinity in computer-aided drug design. Protein Eng. 1994, 7, 385-391) and relies on the assumption that the binding free energy (DeltaG) depends linearly on changes in the van der Waals and electrostatic energy of the system. In the present study, MD simulations of ligands in the ERalpha ligand binding domain (LBD) (Shiau, A. K.; Barstad, D.; Loria, P. M.; Cheng, L.; Kushner, P. J.; Agard, D. A.; Greene, G. L. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998, 95, 927-937), as well as ligands free in water, were carried out using the Amber 6.0 force field (http://amber.scripps.edu/). Contrary to previous LIE methods, we took into account every possible orientation of the ligands in the LBD and weighted the contribution of each orientation to the total binding affinity according to a Boltzman distribution. The training set (n = 19) contained estradiol (E2), the synthetic estrogens diethylstilbestrol (DES) and 11beta-chloroethylestradiol (E2-Cl), 16alpha-hydroxy-E2 (estriol, EST), the phytoestrogens genistein (GEN), 8-prenylnaringenin (8PN), and zearalenon (ZEA), four derivatives of benz[a]antracene-3,9-diol, and eight estrogenic monohydroxylated PAH metabolites. We obtained an excellent linear correlation (r(2) = 0.94) between experimental (competitive ER binding assay) and calculated binding energies, with K(d) values ranging from 0.15 mM to 30 pM, a 5 000 000-fold difference in binding affinity. Subsequently, a test set (n = 12) was used to examine the predictive value of our model. This set consisted of the synthetic estrogen 5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol (THC), daidzein (DAI), equol (EQU) and apigenin (API), chlordecone (KEP), progesterone (PRG), several mono- and dihydroxylated PAH metabolites, and two brominated biphenyls. The predicted binding affinities of these estrogenic compounds were in very good agreement with the experimental values (average deviation of 0.61 +/- 0.4 kcal/mol). In conclusion, our LIE model provides a very good method for prediction of absolute ligand binding affinities, as well as binding orientation of ligands.

Animals↗
PubMed2004

Dynamic relationships among type IIa bacteriocins: temperature effects on antimicrobial activity and on structure of the C-terminal amphipathic alpha helix as a receptor-binding region.

Dynamic aspects of structural relationships among class IIa bacteriocins, which are antimicrobial peptides from lactic acid bacteria (LAB), have been examined by use of circular dichroism (CD), molecular dynamics (MD) simulations, and activity testing. Pediocin PA-1 is a potent class IIa bacteriocin, which contains a second C-terminal disulfide bond in addition to the highly conserved N-terminal disulfide bond. A mutant of pediocin PA-1, ped[M31Nle], wherein the replacement of methionine by norleucine (Nle) gives enhanced stability toward aerobic oxidation, was synthesized by solid-phase peptide synthesis to study the activity of the peptide in relation to its structure. The secondary structural analysis from CD spectra of ped[M31Nle], carnobacteriocin B2 (cbn B2), and leucocin A (leuA) at different temperatures suggests that the alpha-helical region of these peptides is important for target recognition and activity. Using molecular modeling and dynamic simulations, complete models of pediocin PA-1, enterocin P, sakacin P, and curvacin A in 2,2,2-trifluoroethanol (TFE) were generated to compare structural relationships among this class of bacteriocins. Their high sequence similarity allows for the use of homology modeling techniques. Starting from homology models based on solution structures of leuA (PDB code 1CW6) and cbnB2 (PDB code 1CW5), results of 2-4 ns MD simulations in TFE and water at 298 and 313 K are reported. The results indicate that these peptides have a common helical C-terminal domain in TFE but a more variable beta sheet or coiled N terminus. At elevated temperatures, pediocin PA-1 maintains its overall structure, whereas peptides without the second C-terminal disulfide bond, such as enterocin P, sakacin P, curvacin A, leuA, and cbnB2 experience partial disruption of the helical section. Pediocin PA-1 and ped[M31Nle] were found to be equally active at different temperatures, whereas the other peptides that lack the second C-terminal disulfide bond are 30-50 times less antimicrobially potent at 310 K (37 degrees C) than at 298 K (25 degrees C). These results indicate that the structural changes in the helical region observed at elevated temperatures account for the loss of activity of these peptides. The presence of C-terminal hydrophobic residues on one side of the amphipathic helix in class IIa bacteriocins is an important feature for receptor recognition and specificity toward particular organisms. This study assists in the understanding of structure-activity relationships in type IIa bacteriocins and demonstrates the importance of the conserved C-terminal amphipathic alpha helix for activity.

Amino Acid Sequence↗
PubMed2003

nth-Nearest-neighbor distribution functions of an interacting fluid from the pair correlation function: a hierarchical approach.

The paper presents a general formalism for the nth-nearest-neighbor distribution (NND) of identical interacting particles in a fluid confined in a nu-dimensional space. The nth-NND functions, W(n,r) (for n=1,2,3, em leader) in a fluid are obtained hierarchically in terms of the pair correlation function and W(n-1,r) alone. The radial distribution function (RDF) profiles obtained from the molecular dynamics (MD) simulation of Lennard-Jones (LJ) fluid is used to illustrate the results. It is demonstrated that the collective structural information contained in the maxima and minima of the RDF profiles being resolved in terms of individual NND functions may provide more insights about the microscopic neighborhood structure around a reference particle in a fluid. Representative comparison between the results obtained from the formalism and the MD simulation data shows good agreement. Apart from the quantities such as nth-NND functions and nth-nearest-neighbor distances, the average neighbor population number is defined. These quantities are evaluated for the LJ model system and interesting density dependence of the microscopic neighborhood shell structures are discussed in terms of them. The relevance of the NND functions in various phenomena is also pointed out.

Journal Article↗
PubMed1999

Structure investigation of amphiphilic cyclopeptides in isotropic and anisotropic environments-A model study simulating peptide-membrane interactions.

It has been proposed that the membrane allows a much more efficient binding of certain small or medium-sized amphiphilic messenger molecules to their receptor, not only by accumulation of the drug, but also by induction of orientations and conformations that are much more favorable for receptor docking than structures adopted in isotropic phases. A series of eight amphiphilic cyclic peptides containing lipophilic (L-alpha-aminodecanoic acid = Ada, L-alpha-aminohexadecanoic acid = Ahd, Nhdg = N-hexadecylglycine) and hydrophilic (Lys, Asp) amino acids were synthesized and examined by means of NMR spectroscopy and molecular dynamics (MD) simulations in isotropic (CDCl3) and membrane-mimicking anisotropic (SDS/H2O) solvents to study the influence of the environment on their individual conformations. NMR data of cyclo(-Gly1-D-Asp2-Ahd3-Ahd4-Asp5-Gly6+ ++-) (C4), cyclo(-Lys1-D-Pro2-Lys3-Ada4-Pro5-Ada6-) (C5) and cyclo(-Lys1-Pro2-Lys3-Ada4-D-Pro5-Ada6-) (C6) clearly indicate that those compounds are too rigid to perform a conformational change upon transition from an isotropic to an anisotropic environment. On the other hand, the experimental data of cyclo (-Gly1-Asp2-Ahd3-Ahd4-Asp5-Gly6-) (C1), cyclo(-Asp1-Ala2-Nhdg3-Ala4-D-Asp5-) (C7), and cyclo(-D-Asp1-Ala2-Nhdg3-Ala4-Asp5-) (C8) suggest highly flexible unstructured molecules in both environments. However, for cyclo(-Asp1-Asp2-Gly3-Ahd4-Ahd5-Gly6-) (C2) we observed a structure inducing effect of a membrane-like environment. The compound populates three different conformations in SDS/H2O, whereas in CDCI3 no preferred conformation can be detected. cyclo(-D-Asp1-Asp2-Gly3-Ahd4-Ahd5-Gly6-) (C3) clearly exhibits two different conformations with a shifted beta,beta-turn motif in CDCI3 and SDS/H2O solutions. The conformational change could be reproduced in a restraint-free MD simulation using the biphasic membrane mimetic CCl4/H2O. Our results give clear evidence that membrane interactions may not only lead to structure inductions, but can also induce major conformational changes in compounds already exhibiting a defined structure in isotropic solution.

Carbon Tetrachloride↗
PubMed2006

Conformational behavior of temporin A and temporin L in aqueous solution: a computational/experimental study.

Molecular dynamics (MD) simulations and circular dichroism (CD) experiments were carried out on aqueous temporin A and L, two short peptides belonging to an interesting class of natural substances known to be active mainly against Gram-positive/negative bacteria and fungi. Experimental results indicate the higher propensity of temporin L, with respect to temporin A, in forming alpha-helical structures. These results were revisited by long-timescale MD simulations, in which their alpha-helical propensity was investigated in the absence of trifluoroethanol. Results clearly show the higher stability of alpha-helix conformations in temporin L; moreover, an interestingly strong mechanical analogy emerges since both temporins show the same residue interval (from 7 to 10) as the most energetically accessible for alpha-helix formation. Such studies provide some intriguing structural and mechanical evidence that may help in better understanding and rationalizing the conformational behaviour of temporins in water solution and, ultimately, the inner principles of their microbial targets selectivity and mechanism of action at the level of cell membranes.

Amino Acid Sequence↗
PubMed2006

Three hydrolases and a transferase: comparative analysis of active-site dynamics via the BioSimGrid database.

Comparative molecular dynamics (MD) simulations enable us to explore the conformational dynamics of the active sites of distantly related enzymes. We have used the BioSimGrid (http://www.biosimgrid.org) database to facilitate such a comparison. Simulations of four enzymes were analyzed. These included three hydrolases and a transferase, namely acetylcholinesterase, outer-membrane phospholipase A, outer-membrane protease T, and PagP (an outer-membrane enzyme which transfers a palmitate chain from a phospholipid to lipid A). A set of 17 simulations were analyzed corresponding to a total of approximately 0.1 micros simulation time. A simple metric for active-site integrity was used to demonstrate the existence of clusters of dynamic conformational behaviour of the active sites. Small (i.e. within a cluster) fluctuations appear to be related to the function of an enzymatically active site. Larger fluctuations (i.e. between clusters) correlate with transitions between catalytically active and inactive states. Overall, these results demonstrate the potential of a comparative MD approach to analysis of enzyme function. This approach could be extended to a wider range of enzymes using current high throughput MD simulation and database methods.

Acetylcholinesterase↗
PubMed2004

Free energy perturbation study of water dimer dissociation kinetics.

An efficient approach is described for using accurate ab initio calculations to determine the rates of elementary condensation and evaporation processes that lead to nucleation of aqueous aerosols. The feasibility of the method is demonstrated in an application to evaporation rates of water dimer at 230 K. The method, known as ABC-FEP (ab initio/classical free energy perturbation), begins with a calculation of the potential of mean force for the dissociation (evaporation) of small water clusters using a molecular dynamics (MD) simulation with a model potential. The free energy perturbation is used to calculate how changing from the model potential to a potential calculated from ab initio methods would alter the potential of mean force. The difference in free energy is the Boltzmann-weighted average of the difference between the ab initio and classical potential energies, with the average taken over a sample of configurations from the MD simulation. In principle, the method does not require a highly accurate model potential, though more accurate potentials require fewer configurations to achieve a small sampling error in the free energy perturbation step. To test the feasibility of obtaining accurate potentials of mean force from ab initio calculations at a modest number of configurations, the free energy perturbation method has been used to correct the errors when some standard models for bulk water (SPC, TIP4P, and TIP4PFQ) are applied to water dimer. To allow a thorough exploration of sampling issues, a highly accurate fit to results of accurate ab initio calculations, known as SAPT-5s, as been used a proxy for the ab initio calculations. It is shown that accurate values for a point on the potential of mean force can be obtained from any of the water models using ab initio calculations at only 50 configurations. Thus, this method allows accurate simulations of small clusters without the need to develop water models specifically for clusters.

Aerosols↗
PubMed2001

Large vortex-like structure of dipole field in computer models of liquid water and dipole-bridge between biomolecules.

We propose a framework to describe the cooperative orientational motions of water molecules in liquid water and around solute molecules in water solutions. From molecular dynamics (MD) simulation a new quantity "site-dipole field" is defined as the averaged orientation of water molecules that pass through each spatial position. In the site-dipole field of bulk water we found large vortex-like structures of more than 10 A in size. Such coherent patterns persist more than 300 ps although the orientational memory of individual molecules is quickly lost. A 1-ns MD simulation of systems consisting of two amino acids shows that the fluctuations of site-dipole field of solvent are pinned around the amino acids, resulting in a stable dipole-bridge between side-chains of amino acids. The dipole-bridge is significantly formed even for the side-chain separation of 14 A, which corresponds to five layers of water. The way that dipole-bridge forms sensitively depends on the side-chain orientations and thereby explains the specificity in the solvent-mediated interactions between biomolecules.

Amino Acids↗
PubMed2003

Phase coexistence and dynamic properties of water in nanopores.

The dynamical properties of a confined fluid depend strongly on the (spatially varying) density. Its knowledge is therefore an important prerequisite for molecular-dynamics (MD) simulations and the analysis of experimental data. In a mixed Gibbs ensemble Monte Carlo (GEMC)/MD simulation approach we first apply the GEMC method to find possible phase states of water in hydrophilic and hydrophobic nanopores. The obtained phase diagrams evidence that a two-phase state is the most probable state of a fluid in incompletely filled pores in a wide range of temperature and level of pore filling. Pronounced variations of the average and local densities are observed. Subsequently, we apply constant-volume MD simulations to obtain water diffusion coefficients and to study their spatial variation along the pore radius. In general, water diffusivity slightly decreases in a hydrophilic pore and noticeably increases in a hydrophobic pore (up to about 40% with respect to the bulk value). In the range of gradual density variations the local diffusivity essentially follows the inverse density and the water binding energy. The diffusivity in the quasi-two-dimensional water layers near the hydrophilic wall decreases by 10 to 20% with respect to the bulk value. The average diffusivity of water in incompletely filled pore is discussed on the basis of the water diffusivities in the coexisting phases.

Computer Simulation↗
PubMed2004

A PELDOR-based nanometer distance ruler for oligonucleotides.

A pulsed electron paramagnetic resonance (EPR) spectroscopic ruler for oligonucleotides was developed using a series of duplex DNAs. The spin-labeling is accomplished during solid-phase synthesis of the oligonucleotides utilizing a palladium-catalyzed cross-coupling reaction between 5-iodo-2'-deoxyuridine and the rigid spin-label 2,2,5,5-tetramethyl-pyrrolin-1-yloxyl-3-acetylene (TPA). 4-Pulse electron double resonance (PELDOR) was then used to measure the intramolecular spin-spin distances via the dipolar coupling, yielding spin-spin distances of 19.2, 23.3, 34.7, 44.8, and 52.5 A. Employing a full-atom force field with explicit water, molecular dynamic (MD) simulations on the same spin-labeled oligonucleotides in their duplex B-form gave spin-spin distances of 19.6, 21.4, 33.0, 43.3, and 52.5 A, respectively, in very good agreement with the measured distances. This shows that the oligonucleotides adopt a B-form duplex structure also in frozen aqueous buffer solution. It also demonstrates that the combined use of site-directed spin-labeling, PELDOR experiments, and MD simulations can yield a microscopic picture about the overall structure of oligonucleotides. The technique is also applicable to more complex systems, like ribozymes or DNA/RNA-protein complexes, which are difficult to access by NMR or X-ray crystallography.

Base Sequence↗
PubMed2004

Oscillatory behavior of nanodroplets.

Molecular dynamics (MD) simulations were performed in order to investigate the phenomenon of free oscillations of nanodroplets and the extent to which the continuum theory for such oscillations holds at nanoscales. The effect of temperature on these oscillations is also studied. The surface tension, a key property for the phenomenon of interest, was evaluated and compared with the experimental values of argon, showing that with an appropriate choice of the cutoff distance in the MD simulations, it is possible to predict the surface tension with good approximation. Nanoscale capillary waves on the free surface of the droplet were observed and compared to continuum theoretical predictions of the same. The nanodroplet interface thickness calculated based on continuum theory for these waves agreed well with the molecular dynamics calculation of the interface thickness. The frequencies of the oscillation of the droplet were calculated for all the studied temperatures and compared with the classical continuum theory. Although the simulated system cannot be considered strictly as a continuum, a good overall agreement was found.

Journal Article↗
PubMed2005

Structural relaxation in the glass transition region of water.

We perform molecular dynamics (MD) simulations using the extended simple-point-charge (SPC/E) model for water to study the structural relaxation through the glass transition region. We follow the same standard protocol used in differential scanning calorimetry experiments. Specifically, we cool liquid configurations at different cooling rates to produce a glass, and then we heat the glass back to the liquid state. We also study aging effects in the glass before heating. We find that MD simulations can reproduce the phenomenology observed in experiments. We review the Tool-Narayanaswamy-Moynihan (TNM) phenomenological approach, introduced to describe the behavior of the specific heat upon heating glass to the liquid phase. The TNM approach requires, as an ansatz, an expression for the temperature dependence of the relaxation time. We compare the simulation results with the prediction of the TNM approach supplemented with two well-known expressions for the relaxation time: the Narayanaswamy-Moynihan (NM) and the Adam-Gibbs-Scherer (AGS) expressions. We find that, in the case of slow cooling rates, our simulations are well represented by the TNM approach, but only if the AGS expression is adopted. We also find that the TNM approach fails in the case of fast cooling rates for both NM and AGS expressions. Several attempts to provide more freedom to the fitting procedure by allowing the fitting parameters to depend on temperature, cooling, and/or heating rates do not improve the agreement between the simulation data and the TNM predictions.

Journal Article↗
PubMed2006

Domain motions of the Mip protein from Legionella pneumophila.

The homodimeric 45.6 kDa (total mass) Mip protein, a virulence factor from Legionella pneumophila, was investigated with solution NMR spectroscopy and molecular dynamics (MD) simulations. Two Mip monomers are dimerized via an N-terminal helix bundle that is connected via a long alpha-helix to a C-terminal FKBP domain in each subunit. More than 85% of the amino acids were identified in triple-resonance NMR spectra. (15)N relaxation analysis showed a bimodal distribution of R(1)/R(2) values, with the lower ratio in the N-terminal domain. Relaxation dispersion measurements confirmed that these reduced ratios did not originate from conformational exchange. Thus, two different correlation times (tau(c)) can be deduced, reflecting partly uncoupled motions of both domains. Relaxation data of a Mip(77)(-)(213) monomer mutant were similar to those observed in the dimer, corroborating that the FKBP domain, including part of the connecting helix, behaves as one dynamic entity. MD simulations (18 ns) of the Mip dimer also yielded two different correlation times for the two domains and thus confirm the independence of the domain motions. Principal component analysis of the dihedral space covariance matrix calculated from the MD trajectory suggests a flexible region in the long connecting helix that acts as a hinge between the two domains. Such motion provides a possible explanation of how Mip can bind to complex molecular components of the extracellular matrix and mediate alveolar damage and bacterial spread in the lung.

Bacterial Proteins↗
PubMed2006

Structure and hydrogen bonding in liquid and supercritical aqueous NaCl solutions at a pressure of 1000 bar and temperatures up to 500 degrees C: A comprehensive experimental and computational study.

The behavior of aqueous 1.1 M NaCl solution at a constant pressure of 1000 bar in the temperature range 25-500 degrees C has been studied with the use of IR absorption, Raman scattering, X-ray diffraction, and molecular dynamics (MD) simulations. The results are compared with the data for pure water under identical external conditions. The main purpose of the experimental and theoretical studies was to understand in what way an electrolyte dissolved in water influences the hydrogen bonding and structural features of water. As was found, the vibrational spectra show no essential difference between the properties of solution and pure water. However, the experimental pair correlation functions and the results of MD simulations present an evidence for very different nature of these substances. A characteristic feature of the structure of NaCl solution is a considerable contribution of strong O-H...Cl- bonds. As the temperature increases, the number of such bonds decreases partially due to a phenomenon of ion pairing, so that at high temperatures the properties of the solution become closer to the properties of water.

Computer Simulation↗
PubMed1997

NMR solution structure of a novel hirudin variant HM2, N-terminal 1-47 and N64-->V + G mutant.

The 64 amino acid hirudin-like peptide HM2 (Hirudinaria manillensis) is one of the agents known to specifically block the blood-clotting enzyme thrombin, and therefore is used as a potential pharmacological tool for the treatment of arterial and venous thrombosis. This peptide and its derivatives provide a new set of probes for studies aimed at elucidating the structural basis of the inhibition of alpha-thrombin. We used 581, 699, and 492 nmr-derived constraints respectively in a protocol employing simulated annealing, followed by restrained molecular dynamics and restrained energy minimization to derive the three-dimensional structures of HM2 and its mutants the HM2 (V + G) and the HM2 (1-47). HM2 consists of a well-defined core region of two double-stranded beta-sheet and a disordered C-terminus. These features are shared by other members of the hirudin family. The same type of folding has also been observed for recombinant hirudins whose structure has been determined in solution by nmr spectroscopy and in the structure of the complex hirudin-thrombin determined by x-ray diffraction. Molecular dynamics (MD) simulation methods were applied in the study of the structural and dynamic fluctuation properties of the hirudin derivatives solvated by 1625 and 1276 water molecules with periodic boundary conditions for HM2 and HM2 (1-47), respectively. Trajectories of 100 and 50 ps for the two unconstrained systems were generated at constant temperature and pressure. Analysis of the MD simulation shows that the structure of the peptide core is fairly rigid and stable in itself while the conformation of the C-terminal tail, which is involved in the inhibitory mechanism of thrombin, fluctuates and appears as a disordered region.

Amino Acid Sequence↗
PubMed2005

Comparative analysis of HIV-1 Tat variants.

HIV-1 Tat protein is a crucial element for viral replication; therefore, its inhibition might be exploited against the AIDS infection. To gain insights on the natural variability of this protein, we present a comparative investigation on the relationship between the primary sequences and the experimentally available three-dimensional structures from the HIV-1 Tat variants Z2, BRU, and MAL. Our computational tools include sequence conservation algorithms, structural analysis, electrostatic modeling, and molecular dynamics (MD) simulations. We find that two regions located between residues 10-18 and 41-52 display the highest primary sequence conservation, while the most conserved region among the available structures corresponds approximately to the segment between positions approximately 44 and 50. Furthermore, in spite of their large structural divergence, Tat variants share a common mode for long-range intramolecular interactions. Finally, the flexibility of the Z2, BRU, and MAL variants, as emerging from multinanosecond MD simulations, is rather similar. Based on this work, we conclude that the turnlike region between amino acids 44 and 50 is structurally most conserved, emerging as an important motif for pharmaceutical targeting aimed toward inhibiting Tat action.

Algorithms↗
PubMed2025

Integrated network pharmacology, molecular docking and experimental validation to investigate the mechanism of tannic acid in nasopharyngeal cancer.

Tannic acid (TA) is the primary bioactive component in the gallnut (Galla chinensis) and has exhibited the anticancer effects. However, the mechanism of its anti-cancer activity in nasopharyngeal carcinoma (NPC) remains unclear. This research aims to explore the underlying mechanism of TA in the treatment of nasopharyngeal cancer using network pharmacology, molecular docking and experimental validation. Firstly, the targets of TA and NPC were predicted and collected through databases, and the intersection targets were identified. Subsequently, protein-protein interaction (PPI) network analysis, Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes Genomes (KEGG) pathway enrichment analysis, molecular docking and molecular dynamics (MD) simulation were conducted to uncover the potential mechanisms of TA in treatment of NPC. Finally, in vitro experiments were utilized to verify the mechanism of TA with anticancer activity in NPC. The results of network pharmacology revealed 42 intersection targets between NPC-related targets and TA-related targets. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling was identified as the main target pathway of TA against NPC. Additionally, molecular docking and MD simulation confirmed the closely binding affinities of TA with AKT1. Furthermore, the results of in vitro experiments demonstrated that TA exerts anticancer activity against NPC by targeting the PI3K/AKT signaling pathway, leading to the suppression of cell proliferation. TA is a promising therapeutic candidate for NPC through PI3K/AKT signaling pathway. These results provide insights into the clinical application of TA, particularly when considered in combination with other therapeutic modalities.

Molecular Docking Simulation↗
PubMed2006

Transition between icosahedral and cuboctahedral nanoclusters of lead.

We have used ab initio methods to study the possible transition between icosahedral (ico) and cuboctahedral (fcc) structures in lead nanoclusters of sizes up to 309 atoms. Spontaneous fcc-to-ico transition in Pb(13) was observed in the ab initio molecular dynamics (MD) simulations at various temperatures. The transition path can be described predominantly by an angular variable s, which can, generally be applied to the similar transitions in clusters of larger sizes and was observed to follow the Mackay model. We have calculated the two-dimensional energy surface that describes the transition in Pb(13) and found a barrierless fcc-to-ico transition path, which is consistent with the observed spontaneous transition in the ab initio MD simulations. The atomic displacements in the transition were identified as one of the vibrational eigenmodes of these two Pb(13) clusters. For clusters of larger sizes (Pb(n), where n = 55, 147, and 309), the possible transitions following similar paths were determined not to be barrierless and the sizes of the barriers were determined by the ab initio elastic band method.

Journal Article↗