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Glycogen synthase kinase-3β (GSK-3β) is an important serine/threonine kinase that implicates in multiple cellular processes and links with the neurodegenerative diseases including Alzheimer's disease (AD). In this study, structure-based virtual screening was performed to search database for compounds targeting GSK-3β from Enamine's screening collection. Of the top-ranked compounds, 7 primary hits underwent a luminescent kinase assay and a cell assay using human neuroblastoma SH-SY5Y cells expressing Tau repeat domain (Tau

Supplementary Materials, Figures 1-7, Table 1 from A Novel Sialyltransferase Inhibitor Suppresses FAK/Paxillin Signaling and Cancer Angiogenesis and Metastasis Pathways

Nowadays identifying a high-performance catalyst for converting methane to methanol is crucial because methanol serves as an excellent energy source and has wide chemical applications. In the present study, we used DFT, a computational chemistry method, to investigate the reaction mechanism of methanol production by conversion of methane on Pt5 nanoparticles supported on graphene oxide (GO) substrates. Computational results predicted that the Pt5/GO system exhibits excellent catalysis efficiency, compared with those of the previously examined Pt2/GO and Pt2O2/GO systems. Energetics of examined molecular species and the reaction mechanism showed that the Pt5/GO system exhibits high stability in this catalysis reaction and catalyzes the reaction efficiently. Moreover, between the two investigated surfaces GO and UGO, GO performed better and should be a promising catalyst support to convert methane into methanol.

Decreased BDNF and impaired TRKB signaling contribute to neurodegeneration in Alzheimer's disease (AD). We have shown previously that coumarin derivative LM-031 enhanced CREB/BDNF/BCL2 pathway. In this study we explored if LM-031 analogs LMDS-1 to -4 may act as TRKB agonists to protect SH-SY5Y cells against Aβ toxicity. By docking computation for binding with TRKB using 7,8-DHF as a control, all four LMDS compounds displayed potential of binding to domain d5 of TRKB. In addition, all four LMDS compounds exhibited anti-aggregation and neuroprotective efficacy on SH-SY5Y cells with induced Aβ-GFP expression. Knock-down of TRKB significantly attenuated TRKB downstream signaling and the neurite outgrowth-promoting effects of these LMDS compounds. Among them, LMDS-1 and -2 were further examined for TRKB signaling. Treatment of ERK inhibitor U0126 or PI3K inhibitor wortmannin decreased p-CREB, BDNF and BCL2 in Aβ-GFP cells, implicating the neuroprotective effects are via activating TRKB downstream ERK, PI3K-AKT and CREB signaling. LMDS-1 and -2 are blood-brain barrier permeable as shown by parallel artificial membrane permeability assay. Our results demonstrate how LMDS-1 and -2 are likely to work as TRKB agonists to exert neuroprotection in Aβ cells, which may shed light on the potential application in therapeutics of AD.

Alzheimer’s disease (AD) is a common neurodegenerative disease presenting with progressive memory and cognitive impairments. One of the pathogenic mechanisms of AD is attributed to the aggregation of misfolded amyloid β (Aβ), which induces neurotoxicity by reducing the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase B (TRKB) and increasing oxidative stress, caspase-1, and acetylcholinesterase (AChE) activities. Here, we have found the potential of two novel synthetic coumarin derivatives, ZN014 and ZN015, for the inhibition of Aβ and neuroprotection in SH-SY5Y neuroblastoma cell models for AD. In SH-SY5Y cells expressing the GFP-tagged Aβ-folding reporter, both ZN compounds reduced Aβ aggregation, oxidative stress, activities of caspase-1 and AChE, as well as increased neurite outgrowth. By activating TRKB-mediated extracellular signal-regulated kinase (ERK) and AKT serine/threonine kinase 1 (AKT) signaling, these two ZN compounds also upregulated the cAMP-response-element binding protein (CREB) and its downstream BDNF and anti-apoptotic B-cell lymphoma 2 (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of ZN014 and ZN015. A parallel artificial membrane permeability assay showed that ZN014 and ZN015 could be characterized as blood–brain barrier permeable. Our results suggest ZN014 and ZN015 as novel therapeutic candidates for AD and demonstrate that ZN014 and ZN015 reduce Aβ neurotoxicity via pleiotropic mechanisms.

The pathogenesis of Alzheimer's disease (AD) is involved in the aggregation of misfolded amyloid β (Aβ), which upregulates the activity of acetylcholinesterase (AChE), increases the production of reactive oxygen species (ROS), enhances neuroinflammation, and eventually leads to neuronal death. Therefore, compounds targeting these mechanisms may be candidates for multitarget drugs in AD treatment. We found that two quinoline derivatives, VB-030 and VB-037, markedly reduced Aβ aggregation and ROS levels in the thioflavin T biochemical assay and Tet-On Aβ-green fluorescent protein (GFP) 293 AD cell model. These compounds further improved neurite outgrowth, reduced AChE activity and upregulated the molecular chaperone heat shock protein family B [small] member 1 (HSP27), whereas knockdown of HSP27 counteracted the compounds' neuroprotective effects on the Tet-On Aβ-GFP SH-SY5Y AD neuronal model. Furthermore, VB-037 attenuated lipopolysaccharide (LPS)/interferon (IFN)-γ-induced activation of BV-2 microglial cells. In addition, VB-037 demonstrated its potential to diminish LPS/IFN-γ-induced upregulation of caspase 1 activity, expression of interleukin (IL)-1β, and active phosphorylation of mitogen-activated protein kinase 14 (P38), mitogen-activated protein kinase 8 (JNK), and Jun proto-oncogene, AP-1 transcription factor subunit (JUN) signalings, as well as improve cell viability in the Tet-On Aβ-GFP SH-SY5Y AD neuronal model. Our findings strongly indicate the potential of VB-037 for modifying AD progression by targeting multiple mechanisms, thereby offering a new drug development avenue for AD treatment.

Abnormal accumulations of misfolded Aβ and tau proteins are major components of the hallmark plaques and neurofibrillary tangles in the brains of Alzheimer’s disease (AD) patients. These abnormal protein deposits cause neurodegeneration through a number of proposed mechanisms, including downregulation of the cAMP-response-element (CRE) binding protein 1 (CREB) signaling pathway. Using CRE-GFP reporter cells, we investigated the effects of three coumarin-chalcone derivatives synthesized in our lab on CREB-mediated gene expression. Aβ-GFP- and ΔK280 tauRD-DsRed-expressing SH-SY5Y cells were used to evaluate these agents for possible antiaggregative, antioxidative, and neuroprotective effects. Blood-brain barrier (BBB) penetration was assessed by pharmacokinetic studies in mice. Of the three tested compounds, (E)-3-(3-(4-(dimethylamino)phenyl)acryloyl)-4-hydroxy-2H-chromen-2-one (LM-021) was observed to increase CREB-mediated gene expression through protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and extracellular signal-regulated kinase (ERK) in CRE-GFP reporter cells. LM-021 exhibited antiaggregative, antioxidative, and neuroprotective effects mediated by the upregulation of CREB phosphorylation and its downstream brain-derived neurotrophic factor and BCL2 apoptosis regulator genes in Aβ-GFP- and ΔK280 tauRD-DsRed-expressing SH-SY5Y cells. Blockage of the PKA, CaMKII, or ERK pathway counteracted the beneficial effects of LM-021. LM-021 also exhibited good BBB penetration ability, with brain to plasma ratio of 5.3%, in in vivo pharmacokinetic assessment. Our results indicate that LM-021 works as a CREB enhancer to reduce Aβ and tau aggregation and provide neuroprotection. These findings suggest the therapeutic potential of LM-021 in treating AD.

The signaling pathways of tropomyosin-related kinase B (TrkB) receptor play a pivotal role in axonal sprouting, proliferation of dendritic arbor, synaptic plasticity, and neuronal differentiation. The levels of BDNF and TrkB receptor were reduced in patients with Alzheimer’s disease (AD). The activation of TrkB signaling pathways is a potential strategy for AD therapies. We intended to identify potential TrkB agonists to activate the neuroprotective signaling to alleviate the pathological features of AD mice. Both of the Aβ-deteriorated hippocampal primary neurons and mouse models were generated and showed AD characteristics. We first investigated 12 potential TrkB agonists with primary hippocampal neurons of mice. Both 7,8-DHF and LMDS-1 were identified to have better effect than the other compounds on dendritic arborization of the neurons and were further applied to the Aβ-injected mouse model. The short-term cognitive behavior and pathology in the mice were improved by LMDS-1. Further investigation indicated that LMDS-1 activated the TrkB through phosphorylation at Y516 rather than Y816. In addition, the ERK but not CaMKII or Akt was activated in the mouse hippocampus with LMDS-1 administration. LMDS-1 treatment also upregulated CREB and BDNF while downregulated the GSK3β active form and tau phosphorylation. This study suggests that LMDS-1 upregulates the expression of BDNF and ameliorates the early-phase phenotypes of the AD-like mice through the pTrkB (Y516)-ERK-CREB pathway. In addition, LMDS-1 has better effect than 7,8-DHF in ameliorating the behavioral and pathological features of AD-like mice.

Nowadays identifying a high-performance catalyst for converting methane to methanol is crucial because methanol serves as an excellent energy source and has wide chemical applications. In the present study, we used DFT, a computational chemistry method, to investigate the reaction mechanism of methanol production by conversion of methane on Pt

Hyperglycemia accelerates the progression of Alzheimer’s disease (AD), and GSK3β plays a potential link between AD and hyperglycemia. Therefore, a direct or indirect GSK3β inhibition may have potential to delay the progression of AD. Our previous biochemical assay identified AM404 as a GSK3β inhibitor at high dose (IC50 = 5.353 μM); however, other study suggests that AM404 impaired synaptic plasticity of hippocampus at high dose (10 mg/kg; i.p.). Therefore, the dose and duration of treatment are crucial for the effects of AM404. The effects and molecular mechanisms of AM404 at low dose were evaluated from in vitro to in vivo models. AM404 (0.1–0.5 μM) was tested on tau hyperphosphorylated mouse hippocampal primary cultures treated with Wortmannin (WT) and GF109203X (GFX). Hyperglycemic triple transgenic AD (3×Tg-AD) mice at 6 months old were intraperitoneally injected with AM404 (0.25 mg/kg) for 4 weeks. The spatial learning and memory of mice were measured using the Morris water maze. Mouse brain and serum samples were collected for pathological analyses. AM404 (0.5 μM) exhibited significantly augmented neuroprotection toward tau hyperphosphorylation in primary cultures. The chronic systemic administration of AM404 (0.25 mg/kg) attenuated cognitive deficits in hyperglycemic 3×Tg-AD mice. Moreover, chronic low dose of AM404 significantly attenuated Aβ production, tau protein phosphorylation, and inflammation associated with an increase of pS473Akt and pS9-GSK3β. Therefore, AM404 at low dose, not only increased neuroprotection, but also ameliorated cognitive deficit, could be partly by regulating the Akt/GSK3β signaling, which may contribute to downregulation of Aβ, tau hyperphosphorylation, and inflammation in hyperglycemic 3×Tg-AD mice. These results highlight that chronic administration of AM404 at low dose may be through the Akt/GSK3β pathway to ameliorate the impairment in hyperglycemic 3×Tg-AD mice.

GSK3β kinase is a noteworthy target for discovery of the drugs that will be used to treat several diseases. In the effort to identify a new inhibitor lead compound, we utilized thermodynamic integration (TI)-molecular dynamics (MD) simulation and kinase assay to investigate the bindings between GSK3β kinase and five compounds that were analogous to a known inhibitor with an available crystal structure. TI-MD simulations of the first two compounds (analogs 1 and 2) were used for calibration. The computed binding affinities of analogs 1 and 2 agreed well with the experimental results. The rest three compounds (analogs 3-5) were newly obtained from a database search, and their affinity data were newly measured in our labs. TI-MD simulations predicted the binding modes and the computed ΔΔG values have a reasonably good correlation with the experimental affinity data. These newly identified inhibitors appear to be new leads according to our survey of GSK3β inhibitors listed in recent review articles. The predicted binding modes of these compounds should aid in designing new derivatives of these compounds in the future.

Thermodynamic integration molecular dynamics simulation was used to investigate how TI-MD simulation preforms in reproducing relative protein-ligand binding free energy of a pair of analogous GSK3β kinase inhibitors of available experimental data (see Fig. 1), and to predict the affinity for other analogs. The computation for the pair gave a ΔΔG of 1.0 kcal/mol, which was in reasonably good agreement with the experimental value of -0.1 kcal/mol. The error bar was estimated at 0.5 kcal/mol. Subsequently, we employed the same protocol to proceed with simulations to find analogous inhibitors with a stronger affinity. Four analogs with a substitution at one site inside the binding pocket were the first to be tried, but no significant enhancement in affinity was found. Subsequent simulations for another 7 analogs was focused on substitutions at the benzene ring of another site, which gave two analogs (analogs 9 and 10) with ΔΔG values of -0.6 and -0.8 kcal/mol, respectively. Both analogs had a OH group at the meta position and another OH group at the ortho position at the other side of the benzene ring, as shown in Table 3. To explore further, another 4 analogs with this characteristic were investigated. Three analogs with ΔΔG values of -2.2, -1.7 and -1.2 kcal/mol, respectively, were found. Hydrogen bond analysis suggested that the additional hydrogen bonds of the added OH groups with Gln185 and/or Asn64, which did not appear in the reference inhibitor or as an analog with one substitution only in the examined cases, were the main contributors to an enhanced affinity. A prediction for better inhibitors should interest experimentalists of enzyme and/or cell assays. Analysis of the interactions between GSK3β kinase and the investigated analogs will be useful in the design of GSK3β kinase inhibitors for compounds of this class.

In the present study, we carried out thermodynamic integration molecular dynamics simulation for a pair of analogous inhibitors binding with Erk kinase to investigate how computation performs in reproducing the relative binding free energy. The computation with BCC-AM1 charges for ligands gave -1.1 kcal/mol, deviated from experimental value of -2.3 kcal/mol by 1.2 kcal/mol, in good agreement with experimental result. The error of computed value was estimated to be 0.5 kcal/mol. To obtain convergence, switching vdw interaction on and off required approximately 10 times more CPU time than switching charges. Residue-based contributions and hydrogen bonding were analyzed and discussed. Furthermore, subsequent simulation using RESP charge for ligand gave ΔΔG of -1.6 kcal/mol. The computed results are better than the result of -5.6 kcal/mol estimated using PBSA method in a previous study. Based on these results, we further carried out computations to predict ΔΔG for five new analogs, focusing on placing polar and nonpolar functional groups at the meta site of benzene ring shown in the Fig. 1, to see if these ligands have better binding affinity than the above ligands. The computations resulted that a ligand with polar -OH group has better binding affinity than the previous examined ligand by ~2.0 kcal/mol and two other ligands have better affinity by ~1.0 kcal/mol. The predicted better inhibitors of this kind should be of interest to experimentalist for future experimental enzyme and/or cell assays.

GSK3β plays an important role in many physiological functions; dysregulated GSK3β is involved in human diseases such as diabetes, cancer, and Alzheimer's disease. This study uses MD simulations to determine the interaction between GSK3β and a peptide derived from GSKIP, a novel GSK3β interacting protein. Results show that GSKIPtide is inlaid in a binding pocket consisting of an α-helix and an extended loop near the carboxy-terminal end. This binding pocket is hydrophobic, and is responsible for the protein-protein interaction of two other GSK3β interacting proteins: FRAT and Axin. The GSKIPtide binding mode is closer to that of AxinGID (in the Axin-GSK3-interacting domain). The single-point mutations of V267G and Y288F in GSK3β differentiate the binding modes between GSK3 and GSKIPtide, AxinGID, and FRATide. The V2677G mutation of GSK3β reduces the GSKIPtide binding affinity by 70% and abolishes the binding affinity with AxinGID, but has no effect on FRATide. However, GSK3β Y288F completely abolishes the FRATide binding without affecting GSKIPtide or AxinGID binding. An analysis of the GSK3β-GSKIPtide complex structure and the X-ray crystal structures of GSK3β-FRATide and GSK3β-AxinGID complexes suggests that the hydroxyl group of Y288 is crucial to maintaining a hydrogen bond network in GSK3β-FRATide. The hydrophobic side chain of V267 maintains the integrity of helix-helix ridge-groove hydrophobic interaction for GSK3β-GSKIPtide and GSK3β-AxinGID. This study simulates these two mutant systems to provide atomic-level evidence of the aforementioned experimental results and validate the wild-type complex structure prediction.

Increased sialyltransferase (ST) activity promotes cancer cell metastasis, and overexpression of cell surface sialic acid correlates with poor prognosis in cancer patients. To seek therapies targeting metastasis for cancer treatment, we developed a novel ST inhibitor, Lith-O-Asp, and investigated its antimetastatic and antiangiogenic effects and mechanisms. We found that cells treated with Lith-O-Asp showed a reduction of activity on various ST enzymes by in vitro and cell-based activity analyses. Lith-O-Asp inhibited migration and invasion abilities in various cancer cell lines and showed inhibitory effect on the angiogenic activity of human umbilical vein endothelial cells. Indeed, Lith-O-Asp treatment consequently delayed cancer cell metastasis in experimental and spontaneous metastasis assays in animal models. Importantly, Lith-O-Asp decreased the sialic acid modification of integrin-β1 and inhibited the expression of phospho-FAK, phospho-paxillin, and the matrix metalloprotease (MMP) 2 and MMP9. Lith-O-Asp attenuated the Rho GTPase activity leading to actin dynamic impairment. In addition, 2DE-MS/MS and immunoblotting analyses showed that Lith-O-Asp altered the protein expression level and phosphorylation status of various proteins involved in crucial metastasis and angiogenesis pathways such as vimentin and ribonuclease/angiogenin inhibitor RNH1. Furthermore, Lith-O-Asp treatment significantly inhibited the invasive ability exerted by ectopic overexpression of various ST enzymes catalyzing α-2,6- or α-2,3-sialylation. Our results provide compelling evidence that the potential pan-ST inhibitor, Lith-O-Asp, suppressed cancer cell metastasis likely by inhibiting FAK/paxillin signaling and expressing antiangiogenesis factors. Lith-O-Asp is worthy for further testing as a novel antimetastasis drug for cancer treatment. Cancer Res; 71(2); 473–83. ©2011 AACR.

A 3D-QSAR study using comparative molecular field analysis (CoMFA) was carried out on anti-tubulin agents with indole as a nucleus core. The structures of the compounds were obtained using docking calculations, and were then subjected to alignment procedures. CoMFA calculations for the 42 ligands that were examined as the training set gave a q2 value of 0.623 in correlation with experimental IC50 values for the inhibition of MKN-45 gastric cancer cells. Calculation for the test set of 17 ligands resulted in an r2 value of 0.714. The calculated results suggest that the R3 functional group site (see structure in Fig. 1) favored bulky groups while R1, R2, and R4 sites favored the opposite. At the R5 and R6 sites, parts of the region favored bulky groups while other parts favored the opposite. As for the electrostatic aspect, the R3 site was found to favor groups with a negative partial charge. At the R2 site, part of the region favored the group with a negative partial charge while other regions favored groups with a positive partial charge. The R4 and R5 sites favored groups with negative and positive partial charges, respectively, with a less favorable magnitude when compared with the R2 and R3 sites. The R1 and R6 sites did not exhibit significant electrostatic favor. Correlation of the results with IC50 values of ligands were analyzed and discussed.

Summary Taking advantage of the reversible association–dissociation between glutathione (GSH) and glutathione S-transferase (GST), we have developed a novel method by surface-functionalizing GSH on silicon nanowire field-effect transistors (SiNW-FET) and then anchoring a particular GST-fused protein for the studies of protein–protein interactions. The reversible surface functionalization method has been proven by analytical techniques, fluorescence imaging, atomic force microscopic imaging, and electrical measurements. The reversible GSH–GST functionality on the SiNW-FET has made this sensorial device consecutively reusable and calibratable, allowing for quantitative analysis. In this work, we have demonstrated that the biologically modified SiNW-FET can be used as a screening sensor for the future studies of biomolecular associations, such as protein–protein interactions, protein–DNA interactions, protein–carbohydrate interactions, etc.

A 3D-QSAR study of celebrex-based compounds of PDK1 inhibitors using comparative molecular field analysis (CoMFA) was carried out. The structures of the compounds were obtained using quantum chemistry calculation. CoMFA calculations for a number of grouped subsets of compounds gave q 2 values of correlation in the range from 0 to 0.8. The low q 2 values should be mainly due to the narrow span of biological activity. Calculations for several subsets of 11-13 compounds gave high q 2 values, with 0.5-0.8. Factors affecting the results of the calculations are discussed. Calculated results with high q 2 values suggest that further chemical modifications of the compounds could lead to enhanced activity and could be an aid in the design of celebrex-based cancer drugs.

We propose a coarse-grained (CG) model to study the native structure and physical properties of helical membrane proteins (HMPs) using off-lattice computer simulations. Instead of considering sequence heterogeneity explicitly, we model its effect on the packing of helices by employing a mean packing parameter r(0), which is calculated from an all-atom (AA) model. Specifically, this CG model is applied to investigate the packing of helices in bacteriorhodopsin (BR), and predicts the seven helix bundle structure of BR with a root mean square deviation (RMSD) in coordinates of helix backbone atoms (N, C, C(alpha)) of 3.99 A from its crystal structure. This predicted structure is further refined in an AA model by Amber and the refined structure has a RMSD (in coordinates of helix backbone atoms) of 2.64 A. The predicted packing position, tilting angle, and orientation angle of each helix in the refined structure are consistent with experimental data and their physical origins can be well understood in our model. Our results show that a reasonably good structure of BR can be predicted by using such a dual-scale approach, provided that its secondary structure is known. Starting from a random initial configuration, the folded structure can be obtained in days using a regular desktop computer. Various thermodynamic properties of helix packing of BR are also investigated in this CG model.

A molecular dynamics simulation of the folding of a short helical toxin peptide was carried out. The simulation gave a folding time of ~10 ns, which is longer than typical time of ~1 ns for the formation of 1–2 helical turns. The simulation demonstrates that a helical peptide with disulfide bonds, which may encounter extra steric hindrance compared with the peptide without disulfide bonds, can fold in nanosecond timescale. An analysis shows that this folding time should correspond to the folding time in weak denaturation condition in experiment. Interactions and factors affecting folding pathways are analyzed and discussed.

Glycogen synthase kinase 3β (GSK-3β) is widely known as a critical target protein for treating Alzheimer's disease (AD). We utilized virtual screening to search databases for compounds with the potential to be used in drugs targeting GSK-3β kinase, and kinase as well as cell assays to investigate top-scored, selected compounds. Virtual screening of >1.1 million compounds in the ZINC and in-house databases was conducted using an optimized computational protocol in the docking program GOLD. Of the top-ranked compounds, 16 underwent a luminescent kinase assay and a cell assay using HEK293 cells expressing DsRed-tagged ΔK280 in the repeat domain of tau (tauRD). The compounds VB-003 (a potent GSK-3β inhibitor) and VB-008 (AM404, an anandamide transport inhibitor), with determined IC50 values of 0.25 and 5.4μM, respectively, were identified as reducing tau aggregation. Both compounds increased expression of phospho-GSK-3β (Ser9) and reduced endogenous tau phosphorylation at the sites of Ser202, Thr231, and Ser396. In the ∆K280 tauRD-DsRed SH-SY5Y cells, VB-008, but not VB-003, enhanced HSPB1 and GRP78 expression, increased ∆K280 tauRD-DsRed solubility, and promoted neurite outgrowth. Thus VB-008 performed best to the end of the present study. The identified compound VB-008 may guide the identification and synthesis of potential inhibitors analogous to this compound.

Thermodynamic integration (TI) molecular dynamics (MD) simulations for the binding of a pair of a reference ("ref") ligand and an analogous ("analog") ligand to either tagged (with six extra residues at the N-terminus) or untagged p38 kinase proteins were carried out in order to probe how the binding affinity is influenced by the presence or absence of the peptide tag in p38 kinase. This possible effect of protein length on the binding affinity of a ligand-which is seldom addressed in the literature-is important because, even when two labs claim to have performed experiments with the same protein, they may actually have studied variants of the same protein with different lengths because they applied different protein expression conditions/procedures. Thus, if we wanted to compare ligand binding affinities measured in the two labs, it would be necessary to account for any variation in ligand binding affinity with protein length. The pair of ligand-p38 kinase complexes examined in this work (pdb codes: 3d7z and 3lhj, respectively) were ideal for investigating this effect. The experimentally determined binding energy for the ref ligand with the untagged p38 kinase was -10.9 kcal mol(-1), while that for the analog ligand with the tagged p38 kinase was -11.9 kcal mol(-1). The present TI-MD simulation of the mutation of the ref ligand into the analog ligand while the ligand is bound to the untagged p38 kinase predicted that the binding affinity of the analog ligand is 2.0 kcal mol(-1) greater than that of the ref ligand. A similar simulation also indicated that the same was true for ligand binding to the tagged protein, but in this case the binding affinity for the analog ligand is 2.5 kcal mol(-1) larger than that for the ref ligand. These results therefore suggest that the presence of the peptide tag on p38 kinase increased the difference in the binding energies of the ligands by a small amount of 0.5 kcal mol(-1). This result supports the assumption that the presence of a peptide tag has only a minor effect on ΔG values. The error bars in the computed ΔG values were then estimated via confidence interval analysis and a time autocorrelation function for the quantity dV/dλ. The estimated correlation time was ~0.5 ps and the error bar in the ΔG values estimated using nanosecond-scale simulations was ±0.3 kcal mol(-1) at a confidence level of 95%. These predicted results can be verified in future experiments and should prove useful in subsequent similar studies. Graphical Abstract Thermodynamic cycles for binding of two analogous ligands with untagged and tagged p38 kinases and associated Gibbs free energy.

This article reports the results of a computational and experimental study on the reaction of hydrazoic acid, HN3, adsorbed on 15-20 nm TiO2 particle films. Experimentally, FTIR spectra of HN3(a) have been measured by varying HN3 dosage, UV irradiation time and surface annealing temperature. Three sharp peaks, related to v(a)(NNN) of HN3(a) and N3(a) with different configurations in the 2000-2200 cm(-1) region, and a broad band absorption, related to associated and isolated HN(a) and HO(a) adsorptions in the 3000-3800 cm(-1) region, have been detected. Computationally, molecular structures, vibrational frequencies and adsorption energies of possible adsorbates including HN3 and its derivatives, N3, N2, NH, and H, have been predicted by first-principles calculations based on the density functional theory (DFT) and the pseudopotential method. On the basis of the experimental and computational results, the peak appeared at 2075 cm(-1), which increases at a faster rate with HN3 exposure time, is attributed to a stable adsorbate, N3-Ti(a), with the predicted adsorption energy, E(ads) = 13 kcal/mol. The peak at 2118 cm(-1), which survives at the highest surface temperature in the heating experiment, is attributable to the most stable adsorbate, Ti-N2N(H)-O(a) with E(ads) = 36 kcal/mol. The peak at 2170 cm(-1), which vanishes most readily in all of the aforementioned experiments, is related to less stable molecular adsorbates, end-on HN3-Ti(a) with E(ads) = 5 kcal/mol and side-on HN(N2)-Ti(a) with E(ads) = 8 kcal/mol. A potential energy diagram for the formation of various absorbates with their transition states has been established for the HN3/TiO2 system. On the basis of the predicted desorption energies, the four most stable products of the HN3 reaction on TiO2 are H-O(a), 118 kcal/mol; HN-O(a), 85 kcal/mol; Ti-N2N(H)-O(a), 36 kcal/mol; and N3-O(a), 19 kcal/mol.

The O(1D) + C2H6 reaction has been studied using a combined quantum chemistry and RRKM calculation to find the rate constants for the elementary reaction channels. The calculations of the relative branching ratios for various products formed through the insertion mechanism have been carried out. The calculations gave 60, 8, 4, 1, and 27% for the CH3, OH, H, H2, and H2O formation channels, respectively. These calculated results for the first four species are in good agreement with the available experimental results of 70, 25, 3, and 2%, while water molecules were not detected in the experiments. It is noted that the calculations underestimated the branching ratio for OH formation channel and predicted that a large quantity of water molecules would be formed. In addition to the calculation for the insertion mechanism, the abstraction mechanism pathway via a weak O−C2H6 complex has been examined as well. The calculation gave a low energy barrier of 2.2 kcal/mol for this mechanism, supporting the conclusion t...

Face selectivity for the reactions of 5-substituted (X)-2-dicyanomethyleneadamantanes with a Grignard reagent was examined using ab initio calculation for the substituents (X=F, Cl, Br, OH, NH 2 , and CH 3 ). The calculatedsyn/anti product ratio based on the results of transition state energies for the halide substituents are in good agreement with the available experimental results. In addition, the results of the natural bond orbital calculation suggest that the through-bond Cieplak hyperconjugation effect, instead of the through-space interaction suggested by the experimental results in a prior study, is the main factor in determining face selectivity for the halide substituents in the present study, while for (X=OH, NH 2 , and CH 3 ) substituents, other interactions may have unnegligible effects as well.

Molecular dynamics simulation for hydrogen-covered Si(1 0 0):H-2×1 silicon surface was carried out to calculate the vibrational energy relaxation rates of Si–H stretches based on the Bloch–Redfield theory. The calculation gave a lifetime of 0.35 ns at 300 K, about three times shorter than the experimental result of 1.2 ns. With a reduction of force constants for the first layer reconstructed silicon dimer Si–Si stretches and Si–Si–Si bends by multiplying with 0.9 in this molecular mechanics force field, the calculation gave a lifetime of 0.51 ns, closer to the experimental result than the calculated result above. This suggests that the vibrational frequencies of first layer silicon dimers should be lower than the bulk modes. In addition, it is noted that the Si–Si–H bending frequency of 625 cm −1 on this Si(1 0 0):H-2×1 surface is lower than the 640 cm −1 on the Si(1 1 1):H-1×1 surface but the lifetime of Si–H stretches on (1 0 0) surface is shorter than (1 1 1) surface. This is in contrast to a result in a previous study for (1 1 1) surface in which the higher Si–Si–H bending frequency should result in a shorter lifetime. These results indicate that the couplings between Si–H stretches and Si–Si–H bends on the Si(1 0 0):H-2×1 surface differ significantly from the Si(1 1 1):H-1×1 surface. Besides discussion of this coupling, the isotope and thermal effects in the calculated lifetimes are reported and discussed as well.

The energetics of adsorption of non-hydrocarbon radical species on H/C(1 1 1) diamond surface and the abstraction energies of these species abstracted by hydrogen atoms, which are in excess in gas phase in the diamond thin film growth using the chemical vapor deposition (CVD) method, were examined using ab initio calculation method. Based on the calculated results for the examined species, which include H, F, OH, NH 2 , Cl, CH m X n (X=F or Cl) radicals, the tendency of incorporation of F, O, N, H and Cl atoms in the diamond thin film is discussed. The high adsorption energy and the high abstraction energy abstracted by excess gas-phase H atoms for F radicals suggest that F atom has the highest tendency to stay in the diamond thin film among the examined non-carbon atoms. In contrast, the comparable adsorption energy of Cl atom with other examined radicals except F radical, and its low abstraction energy, indicate that Cl atom possesses the least tendency to be incorporated in the diamond thin film. For O, N and H atoms, their calculated abstraction energy values suggest that the overall order of tendency of incorporation in diamond thin film is F>O>N>H>Cl. In addition, the energetically comparable adsorption energy for the CH 2 Cl radical, compared with the other examined CH m X n species, and the low abstraction energy of Cl atom support that CH 2 Cl is a good growth species in diamond CVD thin film growth.

In the present study, the energetics of H-abstraction reaction on the hydrogen-covered diamond H/C(1 1 1) surface abstracted by hydrogen atom (H), carbon (CH3, C2H), nitrogen (NH2, CN), oxygen (O, OH), and halogen-containing radicals (F, Cl, Br, CF3, CCl3) in gas phase in the diamond chemical vapor deposition process were examined using ab initio calculation. The calculations for O, F, Cl, and Br radicals gave results consistent with available experimental results. These calculated results show that F, Cl, O, OH, CN, and C2H are much stronger abstractors while NH2, CH3, CF3, and CCl3 radicals are weaker abstractors, compared with this abstraction reaction abstracted by H atoms, which is in excess in gas phase. Finally, the energy barrier heights of these examined radicals are generally correlated well with an index of electrophilicity, suggesting that this index serves as a good index to account for the ability of these examined radicals to abstract the adsorbed H atoms on H/C(1 1 1) diamond surface.

In the pres ent study, we re port the cal cu lated life times of the first hy dro gen stretch ing ex cited state on a hy dro gen-covered H/Ge(111) ger ma nium sur face us ing mo lec u lar dy nam ics sim u la tion based on the Bloch-Redfield the ory. The life time was found to be 20 mi cro sec onds at room tem per a ture, four or ders lon ger than the hy dro gen stretches on a H/Si(111) sil i con sur face. In ad di tion, the cal cu la tions for the Ge-D and Ge-T stretches gave life times in the time scale of hun dreds and tens of nano sec onds, re spec tively, at room tem per a ture. The ther mal ef fect and an ef fect of the Ge-Ge-H bend ing fre quency in the cal cu lated life times are dis cussed.

Molecular dynamics simulations of hydrogen isotope-covered silicon(111) and (110) surfaces based on the Bloch–Redfield theory were carried out to calculate the lifetimes of hydrogen isotope stretching modes on these two silicon surfaces at high temperatures. The computations gave lifetimes of 1700 and 500 ps for the Si–H stretches on H/Si(111) surface at 300 and 460 K, in good agreement with the experimental results of 950 and 550 ps, respectively. The calculations for the isotope Si–D,T stretches gave lifetimes on the time-scale of tens of picosecond at room temperature. Thermal effect and the precision of calculated lifetimes are discussed.

Molecular dynamics simulations were carried out to determine the vibrational energy relaxation rates for C–H,D,T stretches on hydrogen-, deuterium-, and tritium-terminated H,D,T/C(111) and H,D,T/C(110) diamond surfaces at high temperatures based on the Bloch–Redfield theory and the calculated power spectra of fluctuating force along C–H,D,T stretches. The lifetime of C–H stretches on H/(110) surfaces at room temperature was found to be 0.8 ps, which is much shorter than the calculated lifetime of 30 ps on a H/C(111) surface attributed to 1:3 resonance. This is due to the blueshift of the 1:2 resonance domain in the force power spectra for a H/C(110) surface. The lifetimes of C–H stretches on a H/C(110) surface and C–D,T stretches on both D,T/C(111) and D,T/C(110) surfaces, which all undergo 1:2 resonance energy relaxation, are all on the time scale of tenths of a picosecond at room temperature and are approximately inversely proportional to the square of the temperature at high temperatures. For C–H stret...

The vibrational energy relaxation rates of excited C−H,D,T stretching modes on hydrogen, deuterium, and tritium-terminated H,D,T/C(111)1×1 diamond surfaces, respectively, are calculated using the B...

Free energy calculations were carried out to determine the relative unfolding free energy of the Ile96 wild type and Ala96 mutant barnases. The total calculated free energies suggest that substitution of Ile96 with Ala destabilizes barnase by 3.9 kcal/mol, which is in good agreement with the independently determined experimental values of 4.0 and 3.3 kcal/mol and a previous simulation. However, a decomposition of the free energy finds the dominant contributions to this free energy arising from the noncovalent interactions between the perturbed group and distant residues of barnase in the sequence and water molecules and only a very small contribution from covalent interactions. This is in contrast to the previous simulation, using the dual topology methodology, which produced a decomposition with an approximately 60% free energy contribution from changes in covalent interactions. The use of the single topology employed in the present calculations and the dual topology employed in the previous study are analyzed in order to understand the contrast between the present results and the results of the previous study.

The vibrational energy relaxation rates of excited SiH stretching modes on the monohydride steps of miscut H/Si(111) 1×1 surfaces are calculated using Bloch-Redfield theory combined with classical molecular dynamics (MD) simulation. The structure and vibrational frequencies of the surface are first investigated using the Car-Parrinello ab initio MD method. The calculated SiSiH bending frequencies and relaxed structures are then used to refine the empirical potential for the classical MD simulations. The lifetime of the excited SiH stretching mode at the step is found to be shorter than the modes on the terrace. Both the magnitude and the trend of the calculated results agree well with the experimental measurement on the 9° monohydride stepped surface. The vibrational relaxation rate of the SiH stretching modes on the 15° monohydride stepped surface are also calculated and predicted to have a slightly shorter lifetime than for the 9° surface.

The vibrational energy relaxation rate of an excited C–H stretching mode on the hydrogen‐terminated H/C(111)1×1 surface is calculated using Bloch–Redfield theory combined with classical molecular dynamics. The lifetime of an excited state is determined by the strength of the power spectrum of the force on the stretching mode at the resonance frequency. The lifetime of the first excited state is found to be 60 ps at 300 K which is shorter than the Si–H stretching mode lifetime on the H/Si(111)1×1 surface. The lifetime of the v=2 first overtone state is found to be 200 times shorter (0.30 ps). Analysis of the power spectrum of the fluctuating force along the C–H bond suggests that the mechanism of the energy relaxation for the v=1 stretching state on the H/C(111)1×1 surface is due to lower‐order interactions than on the H/Si(111)1×1 surface. The predicted fast relaxation of the overtone state may cast some doubt on the observability of that state.

Path integral quantum transition state theory is implemented to calculate the diffusion constant for atomic hydrogen on metal surfaces at low coverage. The path integral theory provides a unified computational methodology to study the influence on the diffusion constant from multidimensional tunneling, vibrational mode quantization, surface distortion, and phonon thermal fluctuations. An approximate technique has also been employed to incorporate the dissipative effect from the electron–hole pair excitations of the metal. The hydrogen diffusion rates on two model metal surfaces are calculated. These surface models are (1) a simple rigid model of the Cu(100) surface allowing a comparison with previous theoretical results, and (2) a more realistic moving model of the Cu(100) surface to examine the effects of surface atom motion. The quantum diffusion constant for hydrogen is calculated over a temperature range of 100–300 K. The largest effect from the moving lattice atoms is found to be the surface distortion effect, leading to a 5% modification of the activation free energy for site‐to‐site hopping. The phonon thermal fluctuations are not found to significantly enhance or dissipate the tunneling at low temperatures. The electron–hole pair dissipation is, however, estimated to have an effect on the tunneling behavior at the lowest temperature studied (100 K).