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.

Building Responsive Systems from Physically-correct Specifications

Predictability - the ability to foretell that an implementation will not violate a set of specified reliability and timeliness requirements - is a crucial, highly desirable property of responsive embedded systems. This paper overviews a development methodology for responsive systems, which enhances predictability by eliminating potential hazards resulting from physically-unsound specifications. The backbone of our methodology is the Time-constrained Reactive Automaton (TRA) formalism, which adopts a fundamental notion of space and time that restricts expressiveness in a way that allows the specification of only reactive, spontaneous, and causal computation. Using the TRA model, unrealistic systems - possessing properties such as clairvoyance, caprice, in finite capacity, or perfect timing - cannot even be specified. We argue that this "ounce of prevention" at the specification level is likely to spare a lot of time and energy in the development cycle of responsive systems - not to mention the elimination of potential hazards that would have gone, otherwise, unnoticed. The TRA model is presented to system developers through the CLEOPATRA programming language. CLEOPATRA features a C-like imperative syntax for the description of computation, which makes it easier to incorporate in applications already using C. It is event-driven, and thus appropriate for embedded process control applications. It is object-oriented and compositional, thus advocating modularity and reusability. CLEOPATRA is semantically sound; its objects can be transformed, mechanically and unambiguously, into formal TRA automata for verification purposes, which can be pursued using model-checking or theorem proving techniques. Since 1989, an ancestor of CLEOPATRA has been in use as a specification and simulation language for embedded time-critical robotic processes.

OS Support for Portable Bulk Synchronous Parallel Programs

Predictability -- the ability to foretell that an implementation will not violate a set of specified reliability and timeliness requirements -- is a crucial, highly desirable property of responsive embedded systems. This paper overviews a development methodology for responsive systems, which enhances predictability by eliminating potential hazards resulting from physically-unsound specifications. The backbone of our methodology is the Time-constrained Reactive Automaton (TRA) formalism, which adopts a fundamental notion of space and time that restricts expressiveness in a way that allows the specification of only reactive, spontaneous, and causal computation. Using the TRA model, unrealistic systems – possessing properties such as clairvoyance, caprice, infinite capacity, or perfect timing -- cannot even be specified. We argue that this "ounce of prevention" at the specification level is likely to spare a lot of time and energy in the development cycle of responsive systems -- not to mention the elimination of potential hazards that would have gone, otherwise, unnoticed. The TRA model is presented to system developers through the Cleopatra programming language. Cleopatra features a C-like imperative syntax for the description of computation, which makes it easier to incorporate in applications already using C. It is event-driven, and thus appropriate for embedded process control applications. It is object-oriented and compositional, thus advocating modularity and reusability. Cleopatra is semantically sound; its objects can be transformed, mechanically and unambiguously, into formal TRA automata for verification purposes, which can be pursued using model-checking or theorem proving techniques. Since 1989, an ancestor of Cleopatra has been in use as a specification and simulation language for embedded time-critical robotic processes.

Contour Generator Points for Threshold Selection and a Novel Photo-Consistency Measure for Space Carving

Space carving has emerged as a powerful method for multiview scene reconstruction. Although a wide variety of methods have been proposed, the quality of the reconstruction remains highly-dependent on the photometric consistency measure, and the threshold used to carve away voxels. In this paper, we present a novel photo-consistency measure that is motivated by a multiset variant of the chamfer distance. The new measure is robust to high amounts of within-view color variance and also takes into account the projection angles of back-projected pixels. Another critical issue in space carving is the selection of the photo-consistency threshold used to determine what surface voxels are kept or carved away. In this paper, a reliable threshold selection technique is proposed that examines the photo-consistency values at contour generator points. Contour generators are points that lie on both the surface of the object and the visual hull. To determine the threshold, a percentile ranking of the photo-consistency values of these generator points is used. This improved technique is applicable to a wide variety of photo-consistency measures, including the new measure presented in this paper. Also presented in this paper is a method to choose between photo-consistency measures, and voxel array resolutions prior to carving using receiver operating characteristic (ROC) curves.

Periodic Motion Detection and Estimation via Space-Time Sampling

A novel technique to detect and localize periodic movements in video is presented. The distinctive feature of the technique is that it requires neither feature tracking nor object segmentation. Intensity patterns along linear sample paths in space-time are used in estimation of period of object motion in a given sequence of frames. Sample paths are obtained by connecting (in space-time) sample points from regions of high motion magnitude in the first and last frames. Oscillations in intensity values are induced at time instants when an object intersects the sample path. The locations of peaks in intensity are determined by parameters of both cyclic object motion and orientation of the sample path with respect to object motion. The information about peaks is used in a least squares framework to obtain an initial estimate of these parameters. The estimate is further refined using the full intensity profile. The best estimate for the period of cyclic object motion is obtained by looking for consensus among estimates from many sample paths. The proposed technique is evaluated with synthetic videos where ground-truth is known, and with American Sign Language videos where the goal is to detect periodic hand motions.

A Type System For Safe SN Resource Allocation

snBench is a platform on which novice users compose and deploy distributed Sense and Respond programs for simultaneous execution on a shared, distributed infrastructure. It is a natural imperative that we have the ability to (1) verify the safety/correctness of newly submitted tasks and (2) derive the resource requirements for these tasks such that correct allocation may occur. To achieve these goals we have established a multi-dimensional sized type system for our functional-style Domain Specific Language (DSL) called Sensor Task Execution Plan (STEP). In such a type system data types are annotated with a vector of size attributes (e.g., upper and lower size bounds). Tracking multiple size aspects proves essential in a system in which Images are manipulated as a first class data type, as image manipulation functions may have specific minimum and/or maximum resolution restrictions on the input they can correctly process. Through static analysis of STEP instances we not only verify basic type safety and establish upper computational resource bounds (i.e., time and space), but we also derive and solve data and resource sizing constraints (e.g., Image resolution, camera capabilities) from the implicit constraints embedded in program instances. In fact, the static methods presented here have benefit beyond their application to Image data, and may be extended to other data types that require tracking multiple dimensions (e.g., image "quality", video frame-rate or aspect ratio, audio sampling rate). In this paper we present the syntax and semantics of our functional language, our type system that builds costs and resource/data constraints, and (through both formalism and specific details of our implementation) provide concrete examples of how the constraints and sizing information are used in practice.

Search Space Reduction in QoS Routing

To provide real-time service or engineer constrained-based paths, networks require the underlying routing algorithm to be able to find low-cost paths that satisfy given Quality-of-Service (QoS) constraints. However, the problem of constrained shortest (least-cost) path routing is known to be NP-hard, and some heuristics have been proposed to find a near-optimal solution. However, these heuristics either impose relationships among the link metrics to reduce the complexity of the problem which may limit the general applicability of the heuristic, or are too costly in terms of execution time to be applicable to large networks. In this paper, we focus on solving the delay-constrained minimum-cost path problem, and present a fast algorithm to find a near-optimal solution. This algorithm, called DCCR (for Delay-Cost-Constrained Routing), is a variant of the k-shortest path algorithm. DCCR uses a new adaptive path weight function together with an additional constraint imposed on the path cost, to restrict the search space. Thus, DCCR can return a near-optimal solution in a very short time. Furthermore, we use the method proposed by Blokh and Gutin to further reduce the search space by using a tighter bound on path cost. This makes our algorithm more accurate and even faster. We call this improved algorithm SSR+DCCR (for Search Space Reduction+DCCR). Through extensive simulations, we confirm that SSR+DCCR performs very well compared to the optimal but very expensive solution.

Articulated Pose Estimation in a Learned Smooth Space of Feasible Solutions

A learning based framework is proposed for estimating human body pose from a single image. Given a differentiable function that maps from pose space to image feature space, the goal is to invert the process: estimate the pose given only image features. The inversion is an ill-posed problem as the inverse mapping is a one to many process. Hence multiple solutions exist, and it is desirable to restrict the solution space to a smaller subset of feasible solutions. For example, not all human body poses are feasible due to anthropometric constraints. Since the space of feasible solutions may not admit a closed form description, the proposed framework seeks to exploit machine learning techniques to learn an approximation that is smoothly parameterized over such a space. One such technique is Gaussian Process Latent Variable Modelling. Scaled conjugate gradient is then used find the best matching pose in the space of feasible solutions when given an input image. The formulation allows easy incorporation of various constraints, e.g. temporal consistency and anthropometric constraints. The performance of the proposed approach is evaluated in the task of upper-body pose estimation from silhouettes and compared with the Specialized Mapping Architecture. The estimation accuracy of the Specialized Mapping Architecture is at least one standard deviation worse than the proposed approach in the experiments with synthetic data. In experiments with real video of humans performing gestures, the proposed approach produces qualitatively better estimation results.

Tracking Human Body Pose on a Learned Smooth Space

Particle filtering is a popular method used in systems for tracking human body pose in video. One key difficulty in using particle filtering is caused by the curse of dimensionality: generally a very large number of particles is required to adequately approximate the underlying pose distribution in a high-dimensional state space. Although the number of degrees of freedom in the human body is quite large, in reality, the subset of allowable configurations in state space is generally restricted by human biomechanics, and the trajectories in this allowable subspace tend to be smooth. Therefore, a framework is proposed to learn a low-dimensional representation of the high-dimensional human poses state space. This mapping can be learned using a Gaussian Process Latent Variable Model (GPLVM) framework. One important advantage of the GPLVM framework is that both the mapping to, and mapping from the embedded space are smooth; this facilitates sampling in the low-dimensional space, and samples generated in the low-dimensional embedded space are easily mapped back into the original highdimensional space. Moreover, human body poses that are similar in the original space tend to be mapped close to each other in the embedded space; this property can be exploited when sampling in the embedded space. The proposed framework is tested in tracking 2D human body pose using a Scaled Prismatic Model. Experiments on real life video sequences demonstrate the strength of the approach. In comparison with the Multiple Hypothesis Tracking and the standard Condensation algorithm, the proposed algorithm is able to maintain tracking reliably throughout the long test sequences. It also handles singularity and self occlusion robustly.

Hippocampal Modulation of Recognition, Conditioning, Timing, and Space: Why So Many Functions?

Advanced Research Projects Agency (ONR N00014-92-J-4015); National Science Foundation (IRI-90-24877); Office of Naval Research (N00014-91-J-1309)

Space, Time and Learning in the Hippocampus: How Fine Spatial and Temporal Scales Are Expanded into Population Codes for Behavioral Control

The hippocampus participates in multiple functions, including spatial navigation, adaptive timing, and declarative (notably, episodic) memory. How does it carry out these particular functions? The present article proposes that hippocampal spatial and temporal processing are carried out by parallel circuits within entorhinal cortex, dentate gyrus, and CA3 that are variations of the same circuit design. In particular, interactions between these brain regions transform fine spatial and temporal scales into population codes that are capable of representing the much larger spatial and temporal scales that are needed to control adaptive behaviors. Previous models of adaptively timed learning propose how a spectrum of cells tuned to brief but different delays are combined and modulated by learning to create a population code for controlling goal-oriented behaviors that span hundreds of milliseconds or even seconds. Here it is proposed how projections from entorhinal grid cells can undergo a similar learning process to create hippocampal place cells that can cover a space of many meters that are needed to control navigational behaviors. The suggested homology between spatial and temporal processing may clarify how spatial and temporal information may be integrated into an episodic memory.