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.

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.

A Lower-Bound Result on the Power of a Genetic Algorithm

This paper presents a lower-bound result on the computational power of a genetic algorithm in the context of combinatorial optimization. We describe a new genetic algorithm, the merged genetic algorithm, and prove that for the class of monotonic functions, the algorithm finds the optimal solution, and does so with an exponential convergence rate. The analysis pertains to the ideal behavior of the algorithm where the main task reduces to showing convergence of probability distributions over the search space of combinatorial structures to the optimal one. We take exponential convergence to be indicative of efficient solvability for the sample-bounded algorithm, although a sampling theory is needed to better relate the limit behavior to actual behavior. The paper concludes with a discussion of some immediate problems that lie ahead.

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.