Aggregation Prediction in Therapeutic Protein Formulations for Excipient Design

Computational Infrastructure & Informatics Poster SessionA major concern in the development therapeutic protein formulations is protein aggregation. Proteins can interact to form bound groups of protein molecules or aggregates. Aggregates in protein formulations reduce effectiveness and can lead to severe immune responses in patients. Excipients are additive molecules that are not therapeutically active, but can increase the stability of protein formulations. An ideal excipient binds with aggregation prone regions on the protein to limit interaction of that region with another protein molecule. The goal of this project is to predict aggregation prone regions and design excipients to interact with these regions. Several tools exist to predict which regions on a protein will be most likely to initiate aggregation. Aggrescan (http://bioinf.uab.es/aggrescan/) and SAP (Spatial Aggregation Potential) were used to predict aggregation prone regions on proteins and the results were compared. Aggrescan uses experimental data to assign each amino acid an aggregation propensity score. An aggregation prone region is identified by a sequence of amino acids with high propensities. The three-dimensional structure is not used in the aggregation prediction. SAP uses molecular simulation to determine regions that are hydrophobic and solvent accessible. Each residue is scored and the results are mapped to the three-dimensional protein structure. A successful prediction tool must use parameters that correlate with aggregation potential for a folded protein. The aggregation prone regions predicted by Aggrescan and SAP were compared to experimental data on protein aggregation. Proteins with a high number of predicted regions or large predicted regions were found to have higher experimental percent aggregation. With the regions identified, molecular simulations were performed for protein-excipient systems. A protein and small molecule docking algorithm was used to determine which regions of the protein certain excipients interacted with. Trehalose, poly(vinylpyrrolidone), and guanadine hydrochloride were used. For an excipient to successfully stabilize a protein and prevent aggregation, the excipient should interact with the aggregation prone regions predicted by Aggrescan and SAP. The predicted regions were compared to the regions where the excipient docks in the molecular simulation. The simulation results were compared to experimental data on the percent aggregation observed in several protein-excipient formulations. The excipients that were found to interact with the predicted aggregation prone regions in simulations should also experimentally prohibit aggregation, leading to lower percent aggregation. Hydrogen-deuterium swapping along with FTIR analysis will be performed experimentally to determine exposed regions on the protein. Proteins with a high number of exposed regions are less stable. The exposed regions will be compared to the aggregation prone regions predicted by Aggrescan and SAP

Statistical properties of power-law random banded unitary matrices in the delocalization-localization transition regime

Power-law random banded unitary matrices (PRBUM), whose matrix elements decay in a power-law fashion, were recently proposed to model the critical statistics of the Floquet eigenstates of periodically driven quantum systems. In this work, we numerically study in detail the statistical properties of PRBUM ensembles in the delocalization-localization transition regime. In particular, implications of the delocalization-localization transition for the fractal dimension of the eigenvectors, for the distribution function of the eigenvector components, and for the nearest neighbor spacing statistics of the eigenphases are examined. On the one hand, our results further indicate that a PRBUM ensemble can serve as a unitary analog of the power-law random Hermitian matrix model for Anderson transition. On the other hand, some statistical features unseen before are found from PRBUM. For example, the dependence of the fractal dimension of the eigenvectors of PRBUM upon one ensemble parameter displays features that are quite different from that for the power-law random Hermitian matrix model. Furthermore, in the time-reversal symmetric case the nearest neighbor spacing distribution of PRBUM eigenphases is found to obey a semi-Poisson distribution for a broad range, but display an anomalous level repulsion in the absence of time-reversal symmetry.Comment: 10 pages + 13 fig

Variation of electric shielding on virtual Frisch-grid detectors

Because of the low mobility of holes, CdZnTe (CZT) detectors operate as electron-transport-only type devices whose particular geometrical parameters and contacts configurations are specially chosen to minimize the contribution of uncollected holes into the output signal amplitudes (induction effect). Several detector configurations have been proposed to address this problem. One of them employs a large geometrical aspect ratio, parallelepiped-shaped crystal with two planar contacts on the top and bottom surfaces (anode and cathode) and an additional shielding electrode placed on a crystal\u27s side to create the virtual Frisch-grid effect. We studied the effect of the shielding electrode length, as well as its location, on the responses of 6 x 6 x 15 mm(3) virtual Frisch-grid detectors. We found that the length of the shielding electrode placed next to the anode can be reduced to 5 mm with no adverse effects on the device performance. Meanwhile, this allows for charge loss correction by reading the cathode signal

Search for Neutral Higgs Bosons in Events with Multiple Bottom Quarks at the Tevatron

The combination of searches performed by the CDF and D0 collaborations at the Fermilab Tevatron Collider for neutral Higgs bosons produced in association with b quarks is reported. The data, corresponding to 2.6 fb-1 of integrated luminosity at CDF and 5.2 fb-1 at D0, have been collected in final states containing three or more b jets. Upper limits are set on the cross section multiplied by the branching ratio varying between 44 pb and 0.7 pb in the Higgs boson mass range 90 to 300 GeV, assuming production of a narrow scalar boson. Significant enhancements to the production of Higgs bosons can be found in theories beyond the standard model, for example in supersymmetry. The results are interpreted as upper limits in the parameter space of the minimal supersymmetric standard model in a benchmark scenario favoring this decay mode.Comment: 10 pages, 2 figure

Precise measurement of the W-boson mass with the CDF II detector

We have measured the W-boson mass MW using data corresponding to 2.2/fb of integrated luminosity collected in proton-antiproton collisions at 1.96 TeV with the CDF II detector at the Fermilab Tevatron collider. Samples consisting of 470126 W->enu candidates and 624708 W->munu candidates yield the measurement MW = 80387 +- 12 (stat) +- 15 (syst) = 80387 +- 19 MeV. This is the most precise measurement of the W-boson mass to date and significantly exceeds the precision of all previous measurements combined

QCD analysis of W- and Z-boson production at Tevatron

Recent measurements of the W-boson charge asymmetry and of the Z-boson production cross sections, performed at the Tevatron collider in Run II by the D0 and CDF collaborations, are studied using the HERAFitter framework to assess their impact on the proton parton distribution functions (PDFs). The Tevatron measurements, together with deep-inelastic scattering data from HERA, are included in a QCD analysis performed at next-to-leading order, and compared to the predictions obtained using other PDF sets from different groups. Good agreement between measurements and theoretical predictions is observed. The Tevatron data provide significant constraints on the d-valence quark distribution

A search for resonant production of ttˉt\bar{t} pairs in $4.8\ \rm{fb}^{-1}ofintegratedluminosityof of integrated luminosity of p\bar{p}collisionsat collisions at \sqrt{s}=1.96\ \rm{TeV}$

We search for resonant production of tt pairs in 4.8 fb^{-1} integrated luminosity of ppbar collision data at sqrt{s}=1.96 TeV in the lepton+jets decay channel, where one top quark decays leptonically and the other hadronically. A matrix element reconstruction technique is used; for each event a probability density function (pdf) of the ttbar candidate invariant mass is sampled. These pdfs are used to construct a likelihood function, whereby the cross section for resonant ttbar production is estimated, given a hypothetical resonance mass and width. The data indicate no evidence of resonant production of ttbar pairs. A benchmark model of leptophobic Z \rightarrow ttbar is excluded with m_{Z'} < 900 GeV at 95% confidence level.Comment: accepted for publication in Physical Review D Sep 21, 201

Search for the standard model Higgs boson decaying to a bb pair in events with one charged lepton and large missing transverse energy using the full CDF data set

We present a search for the standard model Higgs boson produced in association with a W boson in sqrt(s) = 1.96 TeV p-pbar collision data collected with the CDF II detector at the Tevatron corresponding to an integrated luminosity of 9.45 fb-1. In events consistent with the decay of the Higgs boson to a bottom-quark pair and the W boson to an electron or muon and a neutrino, we set 95% credibility level upper limits on the WH production cross section times the H->bb branching ratio as a function of Higgs boson mass. At a Higgs boson mass of 125 GeV/c2 we observe (expect) a limit of 4.9 (2.8) times the standard model value.Comment: Submitted to Phys. Rev. Lett (v2 contains clarifications suggested by PRL

Search for the standard model Higgs boson decaying to a bbˉb\bar{b} pair in events with no charged leptons and large missing transverse energy using the full CDF data set

We report on a search for the standard model Higgs boson produced in association with a vector boson in the full data set of proton-antiproton collisions at $\sqrt{s} = 1.96$ TeV recorded by the CDF II detector at the Tevatron, corresponding to an integrated luminosity of 9.45 fb$^{-1}$. We consider events having no identified charged lepton, a transverse energy imbalance, and two or three jets, of which at least one is consistent with originating from the decay of a $b$ quark. We place 95% credibility level upper limits on the production cross section times standard model branching fraction for several mass hypotheses between 90 and $150 \mathrm{GeV}/c^2$. For a Higgs boson mass of $125 \mathrm{GeV}/c^2$, the observed (expected) limit is 6.7 (3.6) times the standard model prediction.Comment: Accepted by Phys. Rev. Let