Predicting Peptide Structures in Native Proteins from Physical Simulations of Fragments

It has long been proposed that much of the information encoding how a protein folds is contained locally in the peptide chain. Here we present a large-scale simulation study designed to examine the extent to which conformations of peptide fragments in water predict native conformations in proteins. We perform replica exchange molecular dynamics (REMD) simulations of 872 8-mer, 12-mer, and 16-mer peptide fragments from 13 proteins using the AMBER 96 force field and the OBC implicit solvent model. To analyze the simulations, we compute various contact-based metrics, such as contact probability, and then apply Bayesian classifier methods to infer which metastable contacts are likely to be native vs. non-native. We find that a simple measure, the observed contact probability, is largely more predictive of a peptide's native structure in the protein than combinations of metrics or multi-body components. Our best classification model is a logistic regression model that can achieve up to 63% correct classifications for 8-mers, 71% for 12-mers, and 76% for 16-mers. We validate these results on fragments of a protein outside our training set. We conclude that local structure provides information to solve some but not all of the conformational search problem. These results help improve our understanding of folding mechanisms, and have implications for improving physics-based conformational sampling and structure prediction using all-atom molecular simulations

Association Control in Wireless Mesh Networks

Ph.DDOCTOR OF PHILOSOPH

Structure and dynamics of biomacromolecules in solution: recent developments and future perspectives in SANS/SAXS and neutron spectroscopy

This French University Habilitation (“mémoire” to obtain the “Diplôme d’Habilitation à Diriger des Recherches”, DHDR) is divided into two parts: the first one deals with the results that I have obtained after my PhD thesis in 2003, the second one discusses open questions related to theseresults as well as mid- and long-term perspectives.Three different topics are presented in the result chapters: 1) a combination of small angle scattering (SAS) and nuclear magnetic resonance (NMR) for rigid-body modeling of biomacromolecular complexes, 2) the combined use of small angle X-ray (SAXS) and neutron (SANS) scattering for the study of unfolded proteins and 3) the study of biomacromolecular and solvent dynamics by neutron spectroscopy combining several instruments.Points 1) and 3) are discussed in great detail, both in the results and perspective sections, since they represent the most advanced projects of my research. Point 2) is dealt with more briefly in the results section, since few results are available so far. However, perspectives are discussed. Aspecial perspective chapter deals with applications on membrane proteins. Key publications for the different chapters are:Chapter 1: Gabel et al. (2006) A target function for quaternary structural refinement from small angle scattering and NMR orientational restraints. Eur. Biophys. J. 35(4), 313-327. Gabel et al. (2008) A structure refinement protocol combining NMR residual dipolar couplings and small angle scattering restraints. J. Biomol. NMR 41(4), 199-208.Chapter 2: Gabel et al. (2009) Quantitative Modelfree Analysis of Urea Binding to Unfolded Ubiquitin Using a Combination of Small Angle X-ray and Neutron Scattering. J. Am. Chem. Soc. 131(25), 8769-8771.Chapter 3: Gabel (2005) Protein dynamics in solution and powder measured by incoherent elastic neutron scattering: the influence of Q-range and energy resolution. Eur. Biophys. J. 31(1), 1-12. Gabel & Bellissent-Funel (2007) C-Phycocyanin Hydration Water Dynamics in the Presence of Trehalose: An Incoherent Elastic Neutron Scattering Study at Different Energy Resolutions. Biophys. J. 92(11), 4054-4063.The habilitation thesis is focused on methodological aspects and developments of small angle scattering and neutron spectroscopy. It is obvious that the approaches discussed here and their sophisticated levels of data analysis rely fundamentally on the quality of the sample, and inparticular on monodispersity (for SAS) and amount of material for spectroscopy. The paramount importance of good biochemistry and the use of complementary techniques for the characterization of samples can hardly be overestimated. They include, amongst others, gelfiltration, analytical ultracentrifugation, static and dynamic light scattering, NMR, etc. They are quite simply indispensable for doing good and accurate science with SAS, in particular in more complex systems (macromolecular complexes, membrane proteins …). If they are not presentedin more detail in this thesis, it is not out of ignorance of this fact but due to the lack of space

Efficient Spectrum Management for Mobile Ad Hoc Networks

The successful deployment of advanced wireless network applications for defense, homeland security, and public safety depends on the availability of relatively interference-free spectrum. Setup and maintenance of mobile networks for military and civilian first-response units often requires temporary allocation of spectrum resources for operations of finite, but uncertain, duration. As currently practiced, this is a very labor-intensive process with direct parallels to project management. Given the wide range of real-time local variation in propagation conditions, spatial distribution of nodes, and evolving technical and mission priorities current human-in-the loop conflict resolution approaches seem untenable. If the conventional radio regulatory structure is strictly adhered to, demand for spectrum will soon exceed supply. Software defined radio is one technology with potential to exploit local inefficiencies in spectrum usage, but questions regarding the management of such network have persisted for years. This dissertation examines a real-time spectrum distribution approach that is based on principles of economic utility and equilibrium among multiple competitors for limited goods in a free market. The spectrum distribution problem may be viewed as a special case of multi-objective optimization of a constrained resource. A computer simulation was developed to create hundreds of cases of local spectrum crowding, to which simultaneous perturbation simulated annealing (SPSA) was applied as a nominal optimization algorithm. Two control architectures were modeled for comparison, one requiring a local monitoring infrastructure and coordination ("top down") the other more market based ("bottom up"). The analysis described herein indicates that in both cases "hands-off" local spectrum management by trusted algorithms is not only feasible, but that conditions of entry for new networks may be determined a priori, with a degree of confidence described by relatively simple algebraic formulas

ISIPTA'07: Proceedings of the Fifth International Symposium on Imprecise Probability: Theories and Applications

B

LABORATORY ANALOGUE INVESTIGATION OF COGNITIVE DEFUSION AND COGNITIVE REAPPRAISAL STRATEGIES IN THE CONTEXT OF SYMBOLICALLY GENERALIZED AVOIDANCE

The present study used a basic behavioral paradigm derived from Relational Frame Theory (RFT), a contemporary behavioral account of language and cognition, to validate principle-based definitions of the cognitive interventions of defusion and reappraisal. Ninety-one participants first underwent an RFT learning paradigm that established symbolically generalized avoidance. Participants were then randomized to a defusion, reappraisal, or control condition. The main outcomes were equivalence responding—indicative of the trained relational network and analogous to the content of cognition—and avoidance—analogous to the behavioral impact of cognition. Defusion and reappraisal significantly reduced avoidance responding, providing support for the hypothesis that these interventions target the behavior of relational framing. Mediation analyses, conducted on an exploratory basis, revealed differences between the mechanisms of defusion and reappraisal and provided preliminary support for the classification of these interventions as a functional context intervention and a relational context intervention, respectively