Protein Docking by the Underestimation of Free Energy Funnels in the Space of Encounter Complexes

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.

On the Efficiency and Fairness of Transmission Control Loops: A Case for Exogenous Losses

We postulate that exogenous losses-which are typically regarded as introducing undesirable "noise" that needs to be filtered out or hidden from end points-can be surprisingly beneficial. In this paper we evaluate the effects of exogenous losses on transmission control loops, focusing primarily on efficiency and convergence to fairness properties. By analytically capturing the effects of exogenous losses, we are able to characterize the transient behavior of TCP. Our numerical results suggest that "noise" resulting from exogenous losses should not be filtered out blindly, and that a careful examination of the parameter space leads to better strategies regarding the treatment of exogenous losses inside the network. Specifically, we show that while low levels of exogenous losses do help connections converge to their fair share, higher levels of losses lead to inefficient network utilization. We draw the line between these two cases by determining whether or not it is advantageous to hide, or more interestingly introduce, exogenous losses. Our proposed approach is based on classifying the effects of exogenous losses into long-term and short-term effects. Such classification informs the extent to which we control exogenous losses, so as to operate in an efficient and fair region. We validate our results through simulations.

Parameter Sensitive Detectors

Object detection can be challenging when the object class exhibits large variations. One commonly-used strategy is to first partition the space of possible object variations and then train separate classifiers for each portion. However, with continuous spaces the partitions tend to be arbitrary since there are no natural boundaries (for example, consider the continuous range of human body poses). In this paper, a new formulation is proposed, where the detectors themselves are associated with continuous parameters, and reside in a parameterized function space. There are two advantages of this strategy. First, a-priori partitioning of the parameter space is not needed; the detectors themselves are in a parameterized space. Second, the underlying parameters for object variations can be learned from training data in an unsupervised manner. In profile face detection experiments, at a fixed false alarm number of 90, our method attains a detection rate of 75% vs. 70% for the method of Viola-Jones. In hand shape detection, at a false positive rate of 0.1%, our method achieves a detection rate of 99.5% vs. 98% for partition based methods. In pedestrian detection, our method reduces the miss detection rate by a factor of three at a false positive rate of 1%, compared with the method of Dalal-Triggs.

Learning Euclidean Embeddings for Indexing and Classification

BoostMap is a recently proposed method for efficient approximate nearest neighbor retrieval in arbitrary non-Euclidean spaces with computationally expensive and possibly non-metric distance measures. Database and query objects are embedded into a Euclidean space, in which similarities can be rapidly measured using a weighted Manhattan distance. The key idea is formulating embedding construction as a machine learning task, where AdaBoost is used to combine simple, 1D embeddings into a multidimensional embedding that preserves a large amount of the proximity structure of the original space. This paper demonstrates that, using the machine learning formulation of BoostMap, we can optimize embeddings for indexing and classification, in ways that are not possible with existing alternatives for constructive embeddings, and without additional costs in retrieval time. First, we show how to construct embeddings that are query-sensitive, in the sense that they yield a different distance measure for different queries, so as to improve nearest neighbor retrieval accuracy for each query. Second, we show how to optimize embeddings for nearest neighbor classification tasks, by tuning them to approximate a parameter space distance measure, instead of the original feature-based distance measure.

A Gestalt Bubble Model of Visuosptial Perception

A neural network model is presented to account for the three dimensional perception of visual space by way of an analog Gestalt-like perceptual mechanism.

Dynamic Programming for Optimal Control of Set-Up Scheduling with Neural Network Modifications

This paper demonstrates an optimal control solution to change of machine set-up scheduling based on dynamic programming average cost per stage value iteration as set forth by Cararnanis et. al. [2] for the 2D case. The difficulty with the optimal approach lies in the explosive computational growth of the resulting solution. A method of reducing the computational complexity is developed using ideas from biology and neural networks. A real time controller is described that uses a linear-log representation of state space with neural networks employed to fit cost surfaces.