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.

A General Theory of Semi-Unification

Various restrictions on the terms allowed for substitution give rise to different cases of semi-unification. Semi-unification on finite and regular terms has already been considered in the literature. We introduce a general case of semi-unification where substitutions are allowed on non-regular terms, and we prove the equivalence of this general case to a well-known undecidable data base dependency problem, thus establishing the undecidability of general semi-unification. We present a unified way of looking at the various problems of semi-unification. We give some properties that are common to all the cases of semi-unification. We also the principality property and the solution set for those problems. We prove that semi-unification on general terms has the principality property. Finally, we present a recursive inseparability result between semi-unification on regular terms and semi-unification on general terms.

Physically-Based Combinations of Views: Representing Rigid and Nonrigid Motion

Nonrigid motion can be described as morphing or blending between extremal shapes, e.g., heart motion can be described as transitioning between the systole and diastole states. Using physically-based modeling techniques, shape similarity can be measured in terms of forces and strain. This provides a physically-based coordinate system in which motion is characterized in terms of physical similarity to a set of extremal shapes. Having such a low-dimensional characterization of nonrigid motion allows for the recognition and the comparison of different types of nonrigid motion.

Non-Rigid Shape from Image Streams

We present a framework for estimating 3D relative structure (shape) and motion given objects undergoing nonrigid deformation as observed from a fixed camera, under perspective projection. Deforming surfaces are approximated as piece-wise planar, and piece-wise rigid. Robust registration methods allow tracking of corresponding image patches from view to view and recovery of 3D shape despite occlusions, discontinuities, and varying illumination conditions. Many relatively small planar/rigid image patch trackers are scattered throughout the image; resulting estimates of structure and motion at each patch are combined over local neighborhoods via an oriented particle systems formulation. Preliminary experiments have been conducted on real image sequences of deforming objects and on synthetic sequences where ground truth is known.