Top PDF Molecular determinants of epidermal growth factor binding: a molecular dynamics study.

Molecular determinants of epidermal growth factor binding: a molecular dynamics study.

Molecular determinants of epidermal growth factor binding: a molecular dynamics study.

provide a quantitative analysis of the binding mode of a ligand to a protein. Molecular mechanics Poison-Boltzmann Surface Area (MM-PBSA) calculations are a computationally efficient method to compute relative binding affinities [24]. Enthalpy terms are computed from the molecular mechanics energies recorded during the simulation and the solvation of the receptor and ligand using continuum solvent models coupled with salt models to account for ionic solvent effects. Entropy is calculated using normal mode analysis and can be is computationally expensive. It has been shown that relative free energies omitting the entropy terms can be used to calculated relative affinities and accurate ranking of ligands [25]. MM-GBSA methods are more frequently used to predict absolute binding energies because MM-PBSA depends more heavily on the internal dielectric constant of the solute, which can vary greatly depending on the system and the number of internal ionizable groups [26]. Since the errors are dependent on sequence content, ligands with homologous sequences would be expected to have similar errors. This dielectric estimation error would not affect PBSA when predicting accurate rankings, but could fail on absolute binding energy predictions. Given the size of each EGFR dimer-ligand complex, we chose to compute only relative binding energies to see if MM-PBSA/GBSA could rank the EGFR ligands based on the high and low affinity states. MM-PBSA results (Table 2) ranked the ligands in the following order: EGF.HB- EGF.TGF-a.BTC.EPR.EPG.AR. MMGBSA produced different ranking results: EGF.TGF-a.HB-EGF.BTC.E- PR.AR .EPG. (Table S1). Nonpolar solvation energies contrib- uted favorably in all cases, as did electrostatic and van der Waals forces. The polar contributions to EGFR binding, however, were significantly unfavorable to binding in all complexes. This suggests that the overall driving forces for EGFR ligand binding are favorable van der Waals and electrostatic interactions, with little contribution from nonpolar solvation energies.
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Identification of potent EGFR inhibitors from TCM Database@Taiwan.

Identification of potent EGFR inhibitors from TCM Database@Taiwan.

Overexpression of epidermal growth factor receptor (EGFR) has been associated with cancer. Targeted inhibition of the EGFR pathway has been shown to limit proliferation of cancerous cells. Hence, we employed Traditional Chinese Medicine Database (TCM Database@Taiwan ) (http://tcm.cmu.edu.tw) to identify potential EGFR inhibitor. Multiple Linear Regression (MLR), Support Vector Machine (SVM), Comparative Molecular Field Analysis (CoMFA), and Comparative Molecular Similarities Indices Analysis (CoMSIA) models were generated using a training set of EGFR ligands of known inhibitory activities. The top four TCM candidates based on DockScore were 2-O-caffeoyl tartaric acid, Emitine, Rosmaricine, and 2-O- feruloyl tartaric acid, and all had higher binding affinities than the control Iressa H. The TCM candidates had interactions with Asp855, Lys716, and Lys728, all which are residues of the protein kinase binding site. Validated MLR (r 2 = 0.7858) and SVM
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Exploring PHD fingers and H3K4me0 interactions with molecular dynamics simulations and binding free energy calculations: AIRE-PHD1, a comparative study.

Exploring PHD fingers and H3K4me0 interactions with molecular dynamics simulations and binding free energy calculations: AIRE-PHD1, a comparative study.

PHD fingers represent one of the largest families of epigenetic readers capable of decoding post-translationally modified or unmodified histone H3 tails. Because of their direct involvement in human pathologies they are increasingly considered as a potential therapeutic target. Several PHD/histone-peptide structures have been determined, however relatively little information is available on their dynamics. Studies aiming to characterize the dynamic and energetic determinants driving histone peptide recognition by epigenetic readers would strongly benefit from computational studies. Herein we focus on the dynamic and energetic characterization of the PHD finger subclass specialized in the recognition of histone H3 peptides unmodified in position K4 (H3K4me0). As a case study we focused on the first PHD finger of autoimmune regulator protein (AIRE-PHD1) in complex with H3K4me0. PCA analysis of the covariance matrix of free AIRE-PHD1 highlights the presence of a ‘‘flapping’’ movement, which is blocked in an open conformation upon binding to H3K4me0. Moreover, binding free energy calculations obtained through Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) methodology are in good qualitative agreement with experiments and allow dissection of the energetic terms associated with native and alanine mutants of AIRE-PHD1/H3K4me0 complexes. MM/PBSA calculations have also been applied to the energetic analysis of other PHD fingers recognizing H3K4me0. In this case we observe excellent correlation between computed and experimental binding free energies. Overall calculations show that H3K4me0 recognition by PHD fingers relies on compensation of the electrostatic and polar solvation energy terms and is stabilized by non-polar interactions.
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Coarse-grained molecular simulation of epidermal growth factor receptor protein tyrosine kinase multi-site self-phosphorylation.

Coarse-grained molecular simulation of epidermal growth factor receptor protein tyrosine kinase multi-site self-phosphorylation.

there was overall a statistically significant increased propensity for cis versus trans phosphorylation, there was no significant difference when P-site-992 binding events were excluded from the analysis. Thus, while it is generally assumed that self-phosphorylation of the EGFR and other receptor PTKs occurs in trans, a belief promulgated by the observation that EGFR dimerization is required for PTK activation (e.g. [38]) and direct demonstrations of the phosphory- lation of kinase-deficient PTK mutants by their wild-type counter- parts (e.g. [39], see also [40]), our results indicate that cis and trans phosphorylation, at least in the case of the EGFR, should occur with a similar efficiency. This issue is particularly relevant in the context of the larger HER/ErbB family of receptors, in which the kinase- impaired HER3 receptor functions only upon its heterodimerization with the kinase-active EGFR, HER2 or HER4 receptor. Thus, while HER3 must in an EGFR/HER3 or HER2/HER3 hetero- dimer be phosphorylated primarily in trans [41], its partner EGFR or HER2 might still be phosphorylated in cis in such heterodimers, adding to the diversity of their downstream signaling. It should be noted that although HER2 is known to be phosphorylated in the Figure 10. Second P-site binding event following an initial binding of P-site-992A. Repeated simulations were initiated with structures representing the dimeric EGFR with P-site-992A of the receiver monomer bound in the catalytic site (see Fig. 8B), and with the nascent phosphorylation of P-site-992A mimicked by the introduction of a negative charge and the removal of its P-site/active site interaction potentials in the simulation model (see text). Shown here are the frequencies with which individual P-sites underwent a subsequent P-site binding event over a course of 192 total simulations. A notable bias in favor of cis (Receiver, n = 138) versus trans (Activator, n = 54) binding events was seen, with the sites closest in sequence to P-site-992 of the receiver molecule binding most frequently.
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Licenciado Molecular Determinants of Ligand Specificity in Carbohydrate-Binding Modules: an NMR and X-ray crystallography integrated study

Licenciado Molecular Determinants of Ligand Specificity in Carbohydrate-Binding Modules: an NMR and X-ray crystallography integrated study

ligand recognition. Using saturation transfer difference NMR (STD-NMR) and line broadening studies I have shown that CtCBM11 does not interact (or has a very low affinity) with cellobiose and displays very low affinity (most likely unspecific) for laminarihexaose. Moreover, experiments with cellotetraose and cellohexaose show that the protein interacts more strongly with the central glucose-units, mainly through interactions with positions 2 and 6 of the sugar units. In order to identify the residues of the proteins responsible for recognition and binding, I titrated the protein with several ligands and followed the variations in the amide chemical shifts by NMR. This allowed pinpointing the residues involved in ligand recognition and identifying key features in ligand recognition. This information was complemented with docking and molecular dynamics studies that gave localized structural information on the pocket site of CtCBM11. Furthermore, I have also studied the influence of temperature and binding in the structure of the protein by analyzing the backbone dynamics of CtCBM11 and amide exchange rates in the presence and absence of ligand and at 25 and 50ºC. 15 N longitudinal
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Molecular Dynamics Simulation Studies of dTTP Binding and Catalysis Mediated by YhdE Dimerization.

Molecular Dynamics Simulation Studies of dTTP Binding and Catalysis Mediated by YhdE Dimerization.

To further analyze cooperative effect, we also performed correlation factor study using the closed state of YhdE dimer with one dTTP bound. In this model, one of the active sites is filled with one dTTP molecule from the docking results. Results suggest that multiple hydrogen bonds between two β6 strands in two YhdE molecules stabilize the entire β-sheet of β3-β4-β5- β6, which acts as the foundation of binding pocket and controls its accessible area/volume. It also shows that correlation between β6 in two YhdE molecules is reduced with the dTTP bind- ing in Model 5 but not in Model 7, indicating that dTTP could regulate allosteric communica- tions in the YhdE open state dimer, but not in the closed state dimer. The pocket analysis suggests that in the apo-form, the active site is closer than that in dTTP-bound side. Length between Cα of A5 and Cα of E140 in apo-form side is larger than that in dTTP-bound side. This indicates that YhdE shows cooperative effect in dTTP catalytic reaction with a conforma- tional change. Hydrogen bonding analysis suggests that strength of intermolecular Hydrogen bond is as large as those among β-strand network, indicating that the cooperative effect involves a possible transmission pathway leading to conformational changes through the β- strand network.
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Conformational changes in acetylcholine binding protein investigated by temperature accelerated molecular dynamics.

Conformational changes in acetylcholine binding protein investigated by temperature accelerated molecular dynamics.

Despite the large number of studies available on nicotinic acetylcholine receptors, a complete account of the mechanistic aspects of their gating transition in response to ligand binding still remains elusive. As a first step toward dissecting the transition mechanism by accelerated sampling techniques, we study the ligand-induced conformational changes of the acetylcholine binding protein (AChBP), a widely accepted model for the full receptor extracellular domain. Using unbiased Molecular Dynamics (MD) and Temperature Accelerated Molecular Dynamics (TAMD) simulations we investigate the AChBP transition between the apo and the agonist-bound state. In long standard MD simulations, both conformations of the native protein are stable, while the agonist-bound structure evolves toward the apo one if the orientation of few key sidechains in the orthosteric cavity is modified. Conversely, TAMD simulations initiated from the native conformations are able to produce the spontaneous transition. With respect to the modified conformations, TAMD accelerates the transition by at least a factor 10. The analysis of some specific residue-residue interactions points out that the transition mechanism is based on the disruption/formation of few key hydrogen bonds. Finally, while early events of ligand dissociation are observed already in standard MD, TAMD accelerates the ligand detachment and, at the highest TAMD effective temperature, it is able to produce a complete dissociation path in one AChBP subunit.
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The Study on the Nanocutting by Rigid Body Tool and Elastic Body Tool Using Molecular Dynamics Simulations

The Study on the Nanocutting by Rigid Body Tool and Elastic Body Tool Using Molecular Dynamics Simulations

Figures 5 and 6 show the results of a completely sharp rigid body tool and a rigid body tool with nose cutting at a depth of 0.25 nm and a speed of 200 m/s. Figure 5 reveals that a completely sharp rigid body tool already produced a pile of chips during the early cutting stage and possessed a clear shear plane. Figure 6 indicates that when a rigid body tool with nose is used, the copper workpiece by the compression effect of the nose during the early stages of cutting. Additionally, once the tool has cut to the 5000th step, its shear zone is larger and distributed around the nose. Both figures 5 and 6 reveal that the types of chip piles created by nanocutting with a nosed tool and a completely sharp tool are entirely different.
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Estudo morfofisiométrico de ovários e maturação ovocitária in vitro em bubalinos e bovinos nas diferentes fases da atividade reprodutiva

Estudo morfofisiométrico de ovários e maturação ovocitária in vitro em bubalinos e bovinos nas diferentes fases da atividade reprodutiva

Influence of epidermal growth factor and insulin-like growth factor 1 on nuclear maturation and fertilization of buffalo cumulus oocyte complexes in serum free media and their subseq[r]

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Active synthesis of epidermal growth factor in human mammary glands

Active synthesis of epidermal growth factor in human mammary glands

Wst p. Ludzkie mleko zawiera znacz ącą liczbę czynników wzrostowych, w tym nabłon- kowy czynnik wzrostu (epidermal growth factor – EGF) oraz insulinopodobny czynnik wzrostu (insulin-like growth factor-1 – IGF-1). Dotychczas nie porównano poziomów EGF i IGF-1 w surowicy i mleku karmi ących kobiet. Dlatego te celem badania była oce- na potencjalnego zwi ązku pomiędzy stę eniami tych czynników wzrostowych.

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Transgenic Soybean Production of Bioactive Human Epidermal Growth Factor (EGF).

Transgenic Soybean Production of Bioactive Human Epidermal Growth Factor (EGF).

Synthesis of hEGF does not affect overt soybean seed composition In developing a food-based delivery platform for biopharma it is important to address the question of whether there are significant collateral consequences in seed composition resulting from the genetic modification. Ideally a consumption plant biotechnology platform, such as soymilk, should be fully equivalent to the standard type other than the intended modification. Seeds in general, including soybeans, possess an inventory of bioactive proteins and small mol- ecules that will affect the metabolism of consumers in both advantageous and disadvantageous manner. For soybeans some of the relevant molecules are allergens, anti-metabolite proteins, and small molecules especially isoflavones. To test for potential collateral composition in the hEGF-producing soybeans, the ShEGF transgenic and nontransgenic control soybeans were analyzed by non-targeted proteomics and metabolomics. Among the significant proteins iden- tified include various well-documented allergens and anti-metabolite proteins. A comparison of standard soybeans with hEGF-producing soybean lines showed that there was no significant difference (p = .01) between nontransgenic control and ShEGF transgenic soybeans aside from the targeted production of hEGF for any other proteins of concern. This data is available in PRIDE partner repository with the dataset identifier PXD003326 and 10.6019/PXD003326. Non-targeted small molecule metabolomics was used to conduct a parallel analysis of the nontransgenic and hEGF soybeans. Again there were insignificant differences between non- transgenic soybean seeds and the ShEGF transgenic seeds (Fig 6) with one notable exception. Soybean highly regulates sulfur availability and its allocation into protein. From a nutritional perspective soybean is considered a somewhat sulfur deficient crop. There have been a number of biotechnology experiments to increase sulfur content be either modifying assimilation and
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Clonagem, superexpressão, purificação e caracterização da proteína recombinante humana fator estimulador de colônias de granulócitos

Clonagem, superexpressão, purificação e caracterização da proteína recombinante humana fator estimulador de colônias de granulócitos

Synthesis of G/CSF coding DNA sequence was carried out by a method developed in our laboratory, to which a patent has been filed [20]. We used the native sequence of hG/CSF, without making any modification such as replacement of GC rich regions with AT rich regions or replacement of rare codons, as have been reported by others [16, 21, 22]. A PCR amplification fragment consistent with that expected for hG/CSF (522 bp) was detected on agarose gel (Fig. 1), and its DNA sequence confirmed by automatic sequencing. Recombinant hG/CSF protein was expressed in insoluble form in BL21(DE3) host cells. The best conditions for expression of the rhG/CSF protein in the BL21(DE3) strain were reached at 24 hours in the absence of IPTG induction. In the pET system, target genes are positioned downstream of bacteriophage T7 late promoter. Typically, production hosts contain a prophage (λDE3) encoding the highly processive T7 RNA polymerase under control of the IPTG/inducible UV5 promoter that would ensure tight control of recombinant gene basal expression [23]. In agreement with the results presented here, high levels of protein
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Operating mechanism and molecular dynamics of pheromone-binding protein ASP1 as influenced by pH.

Operating mechanism and molecular dynamics of pheromone-binding protein ASP1 as influenced by pH.

Earlier structural biology investigations [7,13–17] have mainly focused on the functionality of the C-ter loop and key residues such as Asp35 in response to mutation and pH changes. However, they neglected the detailed and complete dynamics pathways on how OBP protein binds and unbinds its odorants, particularly at different conditions of pH. Recently, a few molecular modellings attempted to tackle the OBP- odorant dynamics and interactions [22–27]. These works encourage further investigation due to the still missing mechanisms, the lack of dynamics details and considerable uncertainty about the structure-function rationale. In this work, we chose honeybee Apis mellifera ASP1 as a model system and undertook long-time all-atom molecular simulations in order to elucidate the molecular mechanism and dynamics interaction of OBPs and its odorant ligands. ASP1, in significant contrast to many other OBPs, was reported to bind its ligands at lower pH condition while releasing them at neutral or high pH [7]. At the same time, ASP1 is structurally and genetically aligned well with many other OBPs (Fig. 1a & 1b). In our work, we focus on how pH affects the interation of OBP with its ligands and the mechanisms of OBP releasing ligand at a favorable pH condition. Through quantitative analysis of the global, local conformational changes and other dynamic properties of apo- and holo-ASP1s at pH 4.5 or pH 7.0, we try to illustrate a complete dynamics picture of molecular process how pH affects odorant release. We examined the dynamics contribution, not only of C-ter but also
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GH/IGF e neoplasia: o que há de novo nesta associação .

GH/IGF e neoplasia: o que há de novo nesta associação .

Estudos in vitro e em animais sugerem que os membros do sistema insulin-like growth factors (IGFs), incluindo IGF-I, IGF-II, receptores de IGF- I e IGF-II (IGF-IR e IGF-IIR), e as IGF-binding proteins (IGFBPs) podem ter um importante envolvimento no desenvolvimento e na progressão de neoplasias. Mais especificamente, as IGFs promovem a progressão do ciclo celular e inibem a apoptose tanto por ação direta com outros fatores de crescimento como por ação indireta interagindo com outros sistemas moleculares intracelulares envolvidos na promoção e/ou pro- gressão do câncer. Além disso, inúmeros estudos epidemiológicos têm sugerido que concentrações elevadas das IGFs, independente das alterações nas IGFBPs, podem estar associadas a um aumento no risco de desenvolver determinadas neoplasias. Esta revisão tem como obje- tivo apresentar o envolvimento do sistema IGF na regulação tumoral, os principais estudos epidemiológicos realizados e o risco de desenvolvi- mento de neoplasia em pacientes (com ou sem história pessoal de neoplasia prévia) que receberam hormônio de crescimento (rhGH). É importante salientar que o uso clínico de rhGH, nas indicações aprovadas internacionalmente, é seguro e não existem evidências, até o momento, da associação com o desenvolvimento de neoplasias. (Arq Bras Endocrinol Metab 2005;49/5:833-842)
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Molecular dynamic simulation reveals damaging impact of RAC1 F28L mutation in the switch I region.

Molecular dynamic simulation reveals damaging impact of RAC1 F28L mutation in the switch I region.

Position restraint simulation for 20 ns was implemented to allow solvent molecules to enter the cavity region of structure. It also helps in restraining the atoms at a fixed reference position. Finally, systems were subjected to MD simulation for 300 ns. We computed the comparative analysis of structural deviations in native and mutant RAC1 structure. g_rms compares two structures by computing the root mean square deviation (RMSD), the size-independent ’rho’ similarity parameter (rho) or the scaled rho (rhosc) and the g_rmsf computes the root mean square fluctuation. g_rms, g_rmsf, g_covar and g_anaeig gromacs inbuilt tools were used for protein trajectories and atomic interaction analysis. Number of distinct hydrogen bonds formed by specific residues to other amino acids within the protein during the simulation (NHbond) was calculated using g_hbond. The program g_hbond analyses the hydrogen bonds (H-bonds) between all possible donors D and acceptors A. To determine if an H-bond exists, a geometrical criterion is used, r ≤ rHB = 0.35 nm and α ≤ αHB = 30°. The value of rHB = 0.35 nm corresponds to the first minimum of the radial distribution function of SPC water. NHbond determined on the basis of donor–acceptor distance smaller than 0.35 nm and of donor–hydrogen-acceptor. Graphs were plotted using Grace GUI toolkit 5.1.22 version.
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Molecular determinants of the response to malaria therapeutics

Molecular determinants of the response to malaria therapeutics

The pharmacogenetic characterization of the population of Zanzibar concerning other important proteins in the metabolism of antimalarials was performed in a parallel study not included in this thesis (Ferreira et al., submitted, Other Publications). In this study the DNA from the children previously analysed for CYP2C8 was studied for the main functionally relevant SNPs present in genes potentially involved in the elimination of other central antimalarial drugs in current use in Zanzibar. The genes included in this study were the cytochrome P450s CYP3A4, CYP3A5, CYP2B6, the MDR1 transporter and the nuclear receptor PXR. From all the variants analysed, CYP3A4*1B allele was the more frequent being present in 49.5% of the patients in the homozygous form. The other alleles analysed coding for low activity proteins were found in the homozygous form in frequencies ranging from 2.9% in MDR1 to 14.6% in CYP3A5. An important result in the analysis was the fact that ten subjects were found to be predicted low metabolizers simultaneously for CYP3A4 and CYP3A5, which can be a major problem in the case of antimalarial drugs where the metabolism is mainly performed by these enzymes (e.g. quinine, mefloquine and LUM). In this study, regions of MDR1 and CYP3A4 promoters associated to the transcriptional control of these genes were sequenced. In PXR the sequencing was performed in the exons 2 and 5, coding part of the functionally important DNA binding domain (DBD) and Ligand Binding Domain (LBD) (Lamba et al., 2005). From this analysis only one SNP, previously described (Zhang et al., 2001), was observed (79 C>T, P27S) in a frequency of 11.2%, showing that these two exons are highly conserved. In MDR1 a new SNP was found, –158 T>C (tagtcatgT/Cactcaaaa) with a prevalence of 7.3%.
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Bioinformatics Analyses of the Role of Vascular Endothelial Growth Factor in Patients with Non-Small Cell Lung Cancer.

Bioinformatics Analyses of the Role of Vascular Endothelial Growth Factor in Patients with Non-Small Cell Lung Cancer.

Furthermore, the down-regulated DEG of PCNA was identified in the PPI network and sub- network. In normal cells, the proliferation and apoptosis are under the control of cell cycle reg- ulatory systems. The uncontrolled cell proliferation is considered to be the hallmark of cancer cells, thus, the proliferative potential of cancer cells may be an important prognostic factor [38]. Some antibodies including PCNA have been used to investigate the cell proliferation [39]. Zienolddiny et al. [40] has reported that PCNA is a marker for the evaluation of cell prolifer- ative activity in lung cancer. Therefore, PCNA may participate in the regulation network of VEGFA to play an important role in NSCLC tumorigenesis and serve as a potential molecular marker associated with NSCLC.
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Systems biology modeling reveals a possible mechanism of the tumor cell death upon oncogene inactivation in EGFR addicted cancers.

Systems biology modeling reveals a possible mechanism of the tumor cell death upon oncogene inactivation in EGFR addicted cancers.

In the normal condition, the network signaling is initiated by binding of epidermal growth factor (EGF) to EGFR, followed by the dimerization and subsequent mutual trans-phosphorylation on several tyrosine residues of EGFR; although EGFR family has other three members including ErbB2, ErbB3, and ErbB4 in addition to EGFR (ErbB1) which can form different dimmers (either homo- or hetero-dimers) [30,35], just EGFR and EGFR- EGFR homo-dimers are considered in this model for simplifica- tion. These phospho-tyrosine residues act as docking sites that enable receptors to recruit adaptor proteins Shc and Grb2 [36], which can then recruit the guanosine nucleotide exchange factor SOS. SOS promotes the replacement of GDP by GTP in Ras, thereby activating Ras [37]. The activated Ras subsequently results in the activation of protein kinase Raf [38]; since the direct activator of Raf kinase is not known yet, we assume that Raf phosphorylation is caused directly by a Ras-GTP molecule in this model. The activated Raf finally activates the mitogen-activated protein kinase kinase1/2 (MEK) and ERK in a cascade way [39]. The activated ERK can phosphorylate the upstream protein SOS, hence causing the dissociation of Grb2-SOS from the receptor complex, which forms a negative feedback loop [40]. In addition, Grb2 in cytomembrane can also recruit Gab1, which causes the phosphorylation of Gab1 and the consequent recruitment of PI3K [41]. In cytomembrane, PI3K transforms phosphatidylinositol 4,5- bisphosphate (PIP2) into phosphatidylinositol (3,4,5)-trisphosphate (PIP3) that induces the activation of AKT through cooperating with 3-phosphoinositide dependent protein kinase-1 (PDK1) [42]. In this process, phosphatase and tensin homolog (PTEN) and protein phosphatase 2A (PP2A) can specifically dephosphorylate PIP3 and AKT respectively [43]. Phosphorylated Raf, MEK and ERK can be dephosphorylated by their specific phosphatases [30]. P38 that is thought as an important pro-apoptotic effector can
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Alloy by Molecular Dynamics Simulation

Alloy by Molecular Dynamics Simulation

During the cooling-down, the volume of the system decreases continuously as a function of temperature due to the high undercooling condition of liquid, avoiding the nucleation and growth of crystals. At glass transition temperature, the material becomes rigid and behaves like a solid, while preserving the amorphous atomic arrangement. The glass transition temperature, in this case, was determined as the intersection of two straight lines, with different slopes in the TE-T curve (Figure 2). This fact is similar to the second order thermodynamics phase transition. However, since T g is dependent on the cooling rates, the kinetic is also affected. Therefore, the higher cooling rate leads to higher T g value because the atoms have less time to relax, as shown in Figure 2. Cooling curves with the higher T g temperature occur at cooling rates higher than 50 K/ps, for the present alloy. Also, the curves obtained at the cooling rates of 5 and 0.5 K/ps present only a small variation, indicating similar behavior at different cooling rates. Nevertheless, some differences still exist, such as in the T g value that is related
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Colocalization of coregulated genes: a steered molecular dynamics study of human chromosome 19.

Colocalization of coregulated genes: a steered molecular dynamics study of human chromosome 19.

This standing question was addressed here numerically by carrying out molecular dynamics simulations of a knowledge-based coarse-grained model of human chromosome 19. The model consisted of a coarse-grained representation (30nm resolution) of the chromatin fiber complemented by the knowledge-based information of the loci corresponding to (&1500) coregulated gene pairs. These pairs were identified from the analysis of extensive sets of publicly-available gene expression profiles. To mimic the crowded nuclear environment, we considered a system where several copies of the model chromosome 19 were packed at typical Figure 5. Summary of the structural properties of the native system (Fig. 1B) and its three variants (Fig. 4). (First column) Distribution of the spatial distances between steered loci. The distribution of the random-walk-like is broader than the native case one. The randomized position and randomized pairs cases have instead a similar distribution with respect to the native case. (Second column) Distribution of the genomic distances between steered loci. (Third column) Clustering coefficients (see Materials and Methods) of the corresponding networks of pairings between steered loci. Dashed lines correspond to the median values. The results are cumulated over all 6 chromosome copies in the simulation box.
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