5 resultados para The Folding Wife

em Boston University Digital Common


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Memorial Sermon

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Similarly to protein folding, the association of two proteins is driven by a free energy funnel, determined by favorable interactions in some neighborhood of the native state. We describe a docking method based on stochastic global minimization of funnel-shaped energy functions in the space of rigid body motions (SE(3)) while accounting for flexibility of the interface side chains. The method, called semi-definite programming-based underestimation (SDU), employs a general quadratic function to underestimate a set of local energy minima and uses the resulting underestimator to bias further sampling. While SDU effectively minimizes functions with funnel-shaped basins, its application to docking in the rotational and translational space SE(3) is not straightforward due to the geometry of that space. We introduce a strategy that uses separate independent variables for side-chain optimization, center-to-center distance of the two proteins, and five angular descriptors of the relative orientations of the molecules. The removal of the center-to-center distance turns out to vastly improve the efficiency of the search, because the five-dimensional space now exhibits a well-behaved energy surface suitable for underestimation. This algorithm explores the free energy surface spanned by encounter complexes that correspond to local free energy minima and shows similarity to the model of macromolecular association that proceeds through a series of collisions. Results for standard protein docking benchmarks establish that in this space the free energy landscape is a funnel in a reasonably broad neighborhood of the native state and that the SDU strategy can generate docking predictions with less than 5 � ligand interface Ca root-mean-square deviation while achieving an approximately 20-fold efficiency gain compared to Monte Carlo methods.

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A foundational issue underlying many overlay network applications ranging from routing to P2P file sharing is that of connectivity management, i.e., folding new arrivals into the existing mesh and re-wiring to cope with changing network conditions. Previous work has considered the problem from two perspectives: devising practical heuristics for specific applications designed to work well in real deployments, and providing abstractions for the underlying problem that are tractable to address via theoretical analyses, especially game-theoretic analysis. Our work unifies these two thrusts first by distilling insights gleaned from clean theoretical models, notably that under natural resource constraints, selfish players can select neighbors so as to efficiently reach near-equilibria that also provide high global performance. Using Egoist, a prototype overlay routing system we implemented on PlanetLab, we demonstrate that our neighbor selection primitives significantly outperform existing heuristics on a variety of performance metrics; that Egoist is competitive with an optimal, but unscalable full-mesh approach; and that it remains highly effective under significant churn. We also describe variants of Egoist's current design that would enable it to scale to overlays of much larger scale and allow it to cater effectively to applications, such as P2P file sharing in unstructured overlays, based on the use of primitives such as scoped-flooding rather than routing.

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A foundational issue underlying many overlay network applications ranging from routing to peer-to-peer file sharing is that of connectivity management, i.e., folding new arrivals into an existing overlay, and rewiring to cope with changing network conditions. Previous work has considered the problem from two perspectives: devising practical heuristics for specific applications designed to work well in real deployments, and providing abstractions for the underlying problem that are analytically tractable, especially via game-theoretic analysis. In this paper, we unify these two thrusts by using insights gleaned from novel, realistic theoretic models in the design of Egoist – a distributed overlay routing system that we implemented, deployed, and evaluated on PlanetLab. Using extensive measurements of paths between nodes, we demonstrate that Egoist’s neighbor selection primitives significantly outperform existing heuristics on a variety of performance metrics, including delay, available bandwidth, and node utilization. Moreover, we demonstrate that Egoist is competitive with an optimal, but unscalable full-mesh approach, remains highly effective under significant churn, is robust to cheating, and incurs minimal overhead. Finally, we use a multiplayer peer-to-peer game to demonstrate the value of Egoist to end-user applications. This technical report supersedes BUCS-TR-2007-013.