Investigation of Structural Dynamics of Enzymes and Protonation States of Substrates Using Computational Tools.

This review discusses the use of molecular modeling tools, together with existing experimental findings, to provide a complete atomic-level description of enzyme dynamics and function. We focus on functionally relevant conformational dynamics of enzymes and the protonation states of substrates. The conformational fluctuations of enzymes usually play a crucial role in substrate recognition and catalysis. Protein dynamics can be altered by a tiny change in a molecular system such as different protonation states of various intermediates or by a significant perturbation such as a ligand association. Here we review recent advances in applying atomistic molecular dynamics (MD) simulations to investigate allosteric and network regulation of tryptophan synthase (TRPS) and protonation states of its intermediates and catalysis. In addition, we review studies using quantum mechanics/molecular mechanics (QM/MM) methods to investigate the protonation states of catalytic residues of β-Ketoacyl ACP synthase I (KasA). We also discuss modeling of large-scale protein motions for HIV-1 protease with coarse-grained Brownian dynamics (BD) simulations

Mechanism of PhosphoThreonine/Serine Recognition and Specificity for Modular Domains from All-atom Molecular Dynamics

<p>Abstract</p> <p>Background</p> <p>Phosphopeptide-binding domains mediate many vital cellular processes such as signal transduction and protein recognition. We studied three well-known domains important for signal transduction: BRCT repeats, WW domain and forkhead-associated (FHA) domain. The first two recognize both phosphothreonine (pThr) and phosphoserine (pSer) residues, but FHA has high specificity for pThr residues. Here we used molecular dynamics (MD) simulations to reveal how FHA exclusively chooses pThr and how BRCT and WW recognize both pThr/pSer. The work also investigated the energies and thermodynamic information of intermolecular interactions.</p> <p>Results</p> <p>Simulations carried out included wide-type and mutated systems. Through analysis of MD simulations, we found that the conserved His residue defines dual loops feature of the FHA domain, which creates a small cavity reserved for only the methyl group of pThr. These well-organized loop interactions directly response to the pThr binding selectivity, while single loop (the 2nd phosphobinding site of FHA) or in combination with α-helix (BRCT repeats) or β-sheet (WW domain) fail to differentiate pThr/pSer.</p> <p>Conclusions</p> <p>Understanding the domain pre-organizations constructed by conserved residues and the driving force of domain-phosphopeptide recognition provides structural insight into pThr specific binding, which also helps in engineering proteins and designing peptide inhibitors.</p

EVALUATION THE EXPRESSION OF THREE GENES TO EPITHELIAL OVARIAN CANCER RISK IN CHINESE POPULATION

Background: Ovarian cancer is associated with poor survival, because patients are diagnosed at an advanced stage of the disease, and in addition, tumors develop chemoresistance, which carries a poor prognosis for the patient. Material and methods: We hypothesize that high expression of SDF-1, survivin and smac is associated with ovarian cancers development and could be used as a biomarker to identify this disease. The expressions of SDF-1, survivin and smac in normal ovarian (NO) tissue, benign tumor (BT) tissue and epithelial ovarian cancer (EOC) tissue were immunohistochemically analysed. Results: Positive expressions of SDF-1, survivin and smac were significantly higher in EOC tissue than those in NO and BT tissues. SDF-1 expressions were significantly more weaker in advanced ovarian carcinomas (FIGO stage III–IV), and in high-grade carcinomas. There was a positive correlation between EOC patients with lymph node metastasis and with ascites and SDF-1 positivity (P < 0.05). Survivin expressions were significantly more stronger in advanced ovarian carcinomas (FIGO stage III–IV), and in high-grade carcinomas. There was a positive correlation between EOC patients with lymph node metastasis and with ascites and surviving positivity (P < 0.05). Smac expressions were significantly more stronger in advanced ovarian carcinomas (FIGO stage III–IV), and in high-grade carcinomas. There was a positive correlation between EOC patients with lymph node metastasis and with ascites and smac positivity (P < 0.05)

GRB 120729A: External Shock Origin for Both the Prompt Gamma-Ray Emission and Afterglow

Gamma-ray burst (GRB) 120729A was detected by Swift/BAT and Fermi/GBM, and then rapidly observed by Swift/XRT, Swift/UVOT, and ground-based telescopes. It had a single long and smooth \gamma-ray emission pulse, which extends continuously to the X-rays. We report Lick/KAIT observations of the source, and make temporal and spectral joint fits of the multiwavelength light curves of GRB 120729A. It exhibits achromatic light-curve behavior, consistent with the predictions of the external shock model. The light curves are decomposed into four typical phases: onset bump (Phase I), normal decay (Phase II), shallow decay (Phase III), and post-jet break (Phase IV). The spectral energy distribution (SED) evolves from prompt \gamma-ray emission to the afterglow with photon index from Γγ=1.36 to Γ≈1.75. There is no obvious evolution of the SED during the afterglow. ...(Please see article full tet for complete abstract.

Insights from Free-Energy Calculations: Protein Conformational Equilibrium, Driving Forces, and Ligand-Binding Modes

AbstractAccurate free-energy calculations provide mechanistic insights into molecular recognition and conformational equilibrium. In this work, we performed free-energy calculations to study the thermodynamic properties of different states of molecular systems in their equilibrium basin, and obtained accurate absolute binding free-energy calculations for protein-ligand binding using a newly developed M2 algorithm. We used a range of Asp-Phe-Gly (DFG)-in/out p38α mitogen-activated protein kinase inhibitors as our test cases. We also focused on the flexible DFG motif, which is closely connected to kinase activation and inhibitor binding. Our calculations explain the coexistence of DFG-in and DFG-out states of the loop and reveal different components (e.g., configurational entropy and enthalpy) that stabilize the apo p38α conformations. To study novel ligand-binding modes and the key driving forces behind them, we computed the absolute binding free energies of 30 p38α inhibitors, including analogs with unavailable experimental structures. The calculations revealed multiple stable, complex conformations and changes in p38α and inhibitor conformations, as well as balance in several energetic terms and configurational entropy loss. The results provide relevant physics that can aid in designing inhibitors and understanding protein conformational equilibrium. Our approach is fast for use with proteins that contain flexible regions for structure-based drug design

Atypical Adams-Oliver syndrome with typical ocular signs of familial exudative vitreoretinopathy

AIM: To report an atypical Adams-Oliver syndrome (AOS) family with typical ocular signs of familial exudative vitreoretinopathy (FEVR). METHODS: A patient with visible avascular area and obvious non-perfusion zone in the peripheral retina with systemic signs of AOS was reported. Familial and personal characteristics were collected for the patient and his sister. Gene sequencing and ophthalmic examinations including fluorescein angiography were all performed for the whole family. RESULTS: Two novel mutations of DOCK6 (c.1396C>T and c.4796G>A) were identified in the proband and his family, and two compound heterozygous mutations were revealed in the proband and his sister. The patient and his sister showed physical deformities and mental abnormalities while FEVR mimicking retinal disorder can also be defined. No remarkable ocular or systemic abnormality can be observed for their parents. Peripheral retinal non-perfusion area, obvious abnormal vascularization or even retinal fold were observed in the proband and his sister, while only small avascular zone was identified for their parents. CONCLUSION: This is the first genetic authenticated AOS case mimicked as FEVR with genetic sequencing of a family. For the patients with ocular phenotype of FEVR, further examination should be performed if the systemic or mental abnormalities exist

An Opacity-Free Method of Testing the Cosmic Distance Duality Relation Using Strongly Lensed Gravitational Wave Signals

The cosmic distance duality relation (CDDR), expressed as DL(z) = (1 + z)2DA(z), plays an important role in modern cosmology. In this paper, we propose a new method of testing CDDR using strongly lensed gravitational wave (SLGW) signals. Under the geometric optics approximation, we calculate the gravitational lens effects of two lens models, the point mass and singular isothermal sphere. We use functions of {\eta}1(z) = 1 + {\eta}0z and {\eta}2(z) = 1 + {\eta}0z=(1 + z) to parameterize the deviation of CDDR. By reparameterizing the SLGW waveform with CDDR and the distance-redshift relation, we include the deviation parameters {\eta}0 of CDDR as waveform parameters. We evaluate the ability of this method by calculating the parameter estimation of simulated SLGW signals from massive binary black holes. We apply the Fisher information matrix and Markov Chain Monte Carlo methods to calculate parameter estimation. We find that with only one SLGW signal, the measurement precision of {\eta}0 can reach a considerable level of 0.5-1.3% for {\eta}1(z) and 1.1-2.6% for {\eta}2(z), depending on the lens model and parameters.Comment: 15 pages, 7 figure

Measuring the Hubble Constant Using Strongly Lensed Gravitational Wave Signals

The measurement of the Hubble constant $H_0$ plays an important role in the study of cosmology. In this letter, we propose a new method to constrain the Hubble constant using the strongly lensed gravitational wave (GW) signals. By reparameterizing the waveform, we find that the lensed waveform is sensitive to the $H_0$. Assuming the scenario that no electromagnetic counterpart of the GW source can be identified, our method can still give meaningful constraints on the $H_0$ with the information of the lens redshift. We then apply Fisher information matrix and Markov Chain Monte Carlo to evaluate the potential of this method. For the space-based GW detector, TianQin, the $H_0$ can be constrained within a relative error of $\sim$ 0.3-2\%, using a single strongly lensed GW event. Precision varies according to different levels of electromagnetic information.Comment: 8 pages, 4 figure