Surveying determinants of protein structure designability across different energy models and amino-acid alphabets: A consensus

A variety of analytical and computational models have been proposed to answer the question of why some protein structures are more “designable” (i.e., have more sequences folding into them) than others. One class of analytical and statistical-mechanical models has approached the designability problem from a thermodynamic viewpoint. These models highlighted specific structural features important for increased designability. Furthermore, designability was shown to be inherently related to thermodynamically relevant energetic measures of protein folding, such as the foldability F and energy gap Δ10.Δ10. However, many of these models have been done within a very narrow focus: Namely, pair–contact interactions and two-letter amino-acid alphabets. Recently, two-letter amino-acid alphabets for pair–contact models have been shown to contain designability artifacts which disappear for larger-letter amino-acid alphabets. In addition, a solvation model was demonstrated to give identical designability results to previous two-letter amino-acid alphabet pair–contact models. In light of these discordant results, this report synthesizes a broad consensus regarding the relationship between specific structural features, foldability F, energy gap Δ10,Δ10, and structure designability for different energy models (pair–contact vs solvation) across a wide range of amino-acid alphabets. We also propose a novel measure ZdkZdk which is shown to be well correlated to designability. Finally, we conclusively demonstrate that two-letter amino-acid alphabets for pair–contact models appear to be solvation models in disguise. © 2000 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/69591/2/JCPSA6-112-5-2533-1.pd

Universal correlation between energy gap and foldability for the random energy model and lattice proteins

The random energy model, originally used to analyze the physics of spin glasses, has been employed to explore what makes a protein a good folder versus a bad folder. In earlier work, the ratio of the folding temperature over the glass–transition temperature was related to a statistical measure of protein energy landscapes denoted as the foldability F. It was posited and subsequently established by simulation that good folders had larger foldabilities, on average, than bad folders. An alternative hypothesis, equally verified by protein folding simulations, was that it is the energy gap Δ between the native state and the next highest energy that distinguishes good folders from bad folders. This duality of measures has led to some controversy and confusion with little done to reconcile the two. In this paper, we revisit the random energy model to derive the statistical distributions of the various energy gaps and foldability. The resulting joint distribution allows us to explicitly demonstrate the positive correlation between foldability and energy gap. In addition, we compare the results of this analytical theory with a variety of lattice models. Our simulations indicate that both the individual distributions and the joint distribution of foldability and energy gap agree qualitatively well with the random energy model. It is argued that the universal distribution of and the positive correlation between foldability and energy gap, both in lattice proteins and the random energy model, is simply a stochastic consequence of the “thermodynamic hypothesis.” © 1999 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/70084/2/JCPSA6-111-14-6599-1.pd

Experimental investigation of continuous variable quantum teleportation

We report the experimental demonstration of quantum teleportation of the quadrature amplitudes of a light field. Our experiment was stably locked for long periods, and was analyzed in terms of fidelity, F; and with signal transfer, T_{q}=T^{+}+T^{-}, and noise correlation, V_{q}=V_{in|out}^{+} V_{in|out}^{-}. We observed an optimum fidelity of 0.64 +/- 0.02, T_{q}= 1.06 +/- 0.02 and V_{q} =0.96 +/- 0.10. We discuss the significance of both T_{q}>1 and V_{q}<1 and their relation to the teleportation no-cloning limit.Comment: 4 pages, 4 figure

Double-blind, placebo-controlled first in human study to investigate an oral vaccine aimed to elicit an immune reaction against the VEGF-Receptor 2 in patients with stage IV and locally advanced pancreatic cancer

BACKGROUND: The investigational oral DNA vaccine VXM01 targets the vascular endothelial growth factor receptor 2 (VEGFR-2) and uses Salmonella typhi Ty21a as a vector. The immune reaction elicited by VXM01 is expected to disrupt the tumor neovasculature and, consequently, inhibit tumor growth. VXM01 potentially combines the advantages of anti-angiogenic therapy and active immunotherapy. METHODS/DESIGN: This phase I trial examines the safety, tolerability, and immunological and clinical responses to VXM01. The randomized, placebo-controlled, double blind dose-escalation study includes up to 45 patients with locally advanced and stage IV pancreatic cancer. The patients will receive four doses of VXM01 or placebo in addition to gemcitabine as standard of care. Doses from 10(6) cfu up to 10(10) cfu of VXM01 will be evaluated in the study. An independent data safety monitoring board (DSMB) will be involved in the dose-escalation decisions. In addition to safety as primary endpoint, the VXM01-specific immune reaction, as well as clinical response parameters will be evaluated. DISCUSSION: The results of this study shall provide the first data regarding the safety and immunogenicity of the oral anti-VEGFR-2 vaccine VXM01 in cancer patients. They will also define the recommended dose for phase II and provide the basis for further clinical evaluation, which may also include additional cancer indications. TRIAL REGISTRATION: EudraCT No.: 2011-000222-29, NCT01486329, ISRCTN6880927

JOURNAL OF MAGNETIC RESONANCE 125, 34–42 (1997) ARTICLE NO. MN971106 Protein Heteronuclear NMR Assignments Using Mean-Field Simulated Annealing

A computational method for the assignment of the NMR spec- number of source NMR spectra. For a variety of reasons, tra of larger (21 kDa) proteins using a set of six of the most even modest increases in protein size greatly complicate the sensitive heteronuclear multidimensional nuclear magnetic resonance experiments is described. Connectivity data obtained from HNCa, HN(CO)Ca, HN(Ca)Ha, andHa(CaCO)NH and spin-system identification data obtained from CP-(H)CCH–TOCSY and CP-(H)C(CaCO)NH–TOCSY were used to perform sequence-specific assignments using a mean-field formalism and simulated annealing. This mean-field method reports the reso-nance assignments in a probabilistic fashion, displaying the cer-assignment process. First, the larger number of more poorly resolved resonances results in greater problems with spectral overlap. This situation is exacerbated by increased relaxation rates, which limit the source data to only those obtainable by the most sensitive experiments. Because of these limita-tions, any practical automated assignment method for proteins above 15 kDa must be able to work with data that are tainty of assignments in an unambiguous and quantitative man-limited, probabilistic, ambiguous, and sometimes missing or ner. This technique was applied to the NMR data of the 172- inaccurate. A further problem is the existence of an exponenresidue peptide-binding domain of the E. coli heat-shock protein, tially large number of ways of assigning N spin systems to DnaK. The method is demonstrated to be robust to significant amounts of missing, spurious, noisy, extraneous, and erroneous data. � 1997 Academic Press N residues in the protein, which eliminates any hope of performing an exhaustive search over all possible assign-ments, even using the fastest computers. In order to deal with this problem, many automated methods rely on som