7582792
Relative contributions of desolvation, inter- and intramolecular interactions to binding affinity in protein kinase systems
In several previous studies, we performed sensitivity analysis to gauge the relative importance of different atomic partial charges in determining protein-ligand binding. In this work, we gain further insights by decomposing these results into three contributions: desolvation, intramolecular interactions, and intermolecular interactions, again based on a Poisson continuum electrostatics model. Three protein kinase-inhibitor systems have been analyzed: CDK2-deschloroflavopiridol, PKA-PKI, and LCK-PP2. Although our results point out the importance of specific intermolecular interactions to the binding affinity, they also reveal the remarkable contributions from the solvent-mediated intramolecular interactions in some cases. Thus, it is necessary to look beyond analyzing protein-ligand interactions to understand protein-ligand recognition or to gain insights into designing ligands and proteins. In analyzing the contributions of the three components to the overall binding free energy, the PKA-PKI system with a much larger ligand was found to behave differently from the other two systems with smaller ligands. In the former case, the intermolecular interactions are very favorable, and together with the favorable solvent-mediated intramolecular interactions, they overcome the large desolvation penalties to give a favorable electrostatics contribution to the overall binding affinity. On the other hand, the other two systems with smaller ligands only present modest intermolecular interactions and they are not or are only barely sufficient to overcome the desolvation penalty even with the aid of the favorable intramolecular contributions. As a result, the binding affinity of these two systems do not or only barely benefit from electrostatics contributions.
1861595
Charge optimization of the interface between protein kinases and their ligands
Examining the potential for electrostatic complementarity between a ligand and a receptor is a useful technique for rational drug design, and can demonstrate how a system prioritizes interactions when allowed to optimize its charge distribution. In this computational study, we implemented the previously developed, continuum solvent-based charge optimization theory with a simple, quadratic programming algorithm and the UHBD Poisson-Boltzmann solver. This method allows one to compute the best set of point charges for a ligand or ligand region based on the ligand and receptor shape, and the receptor partial charges, by optimizing the binding free energy obtained from a continuum-solvent model. We applied charge optimization to a fragment of the heat-stable protein kinase inhibitor (PKI) of protein kinase A (PKA), to three flavopiridol inhibitors of CDK2, and to cyclin A which interacts with CDK2 to regulate the cell cycle. We found that a combination of global (involving every charge) and local (involving only charges in a local region) optimization can give useful hints for designing better inhibitors. Although some parts of an inhibitor may already contribute significantly to binding, we found that they could still be the most important targets for modifications to obtain stronger binders. In studying the binding of flavopiridol inhibitors to CDK2, comparable binding affinity could be obtained regardless of whether the net charges of the inhibitors were constrained to -2, -1, 0, 1, or 2 during the optimization. This provides flexibility in inhibitor design when a certain net charge of the inhibitor is desired in addition to strong binding affinity. For the study of the PKA-PKI and CDK2-cyclin A interfaces, we identified residues whose charge distributions are already close to optimal and those whose charge distributions could be refined to further improve binding.
31592050
Analysis of a General Mass Storage System
A model of a general mass storage system is presented and its performance analyzed. The system is composed of a square two-dimensional grid of storage cells over which a single read/write head moves freely. The head can contain at most some fixed number b of cell contents. Algorithms for realizing an arbitrary permutation of the memory contents are presented for all ranges of b, particularly the important case $b = 1$; in each case the algorithms’ performances are explicitly characterized. Open problems, especially regarding the development of good heuristics, are then discussed.
8828112
Real-Time Rate Control Via Variable Frame Rate and Quantization Parameters
Most of existing rate control schemes in the literature focus on the bit allocation under the assumption of constant frame rate. As a result, the distortion of consecutive frames varies in a great extent, which may result in low temporal quality (e.g. flickering effect). In this work, we design rate control with two control parameters (i.e. quantization factor and frame rate) to achieve better tradeoff between spatial quality and temporal quality in low complexity. Our optimization gives two suggested quantization step sizes. One is used to change the frame rate in order to allocate how many bits used in the current frame. Another one is used to change the quantization factor in order to quantize MBs to achieve target bit rates. The experimental results suggest that our scheme can achieve more consistent quality while keeping high spatial quality.
37608950
Efficient Heuristics for Orientation Metric and Euclidean Steiner Tree Problems
AbstractWe consider Steiner minimum trees (SMT) in the plane, where only orientations with angle
$${\sigma }$$
 , 0 ≤ i ≤ σ − 1 and σ an integer, are allowed. The orientations define a metric, called the orientation metric, λσ, in a natural way. In particular, λ2 metric is the rectilinear metric and the Euclidean metric can beregarded as λ∞ metric. In this paper, we provide a method to find an optimal λσ SMT for 3 or 4 points by analyzing the topology of λσ SMT's in great details. Utilizing these results and based on the idea of loop detection first proposed in Chao and Hsu, IEEE Trans. CAD, vol. 13, no. 3, pp. 303–309, 1994, we further develop an O(n2) time heuristic for the general λσ SMT problem, including the Euclidean metric. Experiments performed on publicly available benchmark data for 12 different metrics, plus the Euclidean metric, demonstrate the efficiency of our algorithms and the quality of our results.
15615911
Time-varying shortest path problems with constraints
The shortest path problem is considered with yet another extension. The transit times b(x,y,u) and the arc costs c(x,y,u) on arc (x,y) vary as a function of the departure time u at the beginning vertex of the arc. The problem considered is to find the shortest path between a pair of nodes such that the total traverse time is lesser than some specified value T. Waiting times at nodes are considered as decision variables in this paper as well. Three variations of the problem are analyzed in which the waiting times are allowed to be arbitrary, the waiting times are zero and the waiting time has an upper bound at each vertex. Algorithms are also discussed to solve the problem. Some of the applications of the problem are encountered in communication networks and freight delivery problems. Suppose that some freight is to be sent from one city to another in a network before a deadline T. Different types of freight services with different costs and transit times are available between the two cities. An optimal solution would have to specify the route as well as the waiting times of the freight at each city so that the overall cost is minimum. A dynamic programming approach is used to compute the shortest path from the origin node to the destination node. Three cases are considered for the waiting times and an algorithm is suggested for each of those cases. This problem is obviously an NP-Complete problem as it is more difficult to solve than a problem with constant transit times and arc costs such as the previous problem which is NP-Complete. Some definitions: Waiting time w(x i) at a vertex x i is a nonnegative integer with an upper bound U x >= 0. Let P be a path from vertex x 1 to x r. The departure time T(x i) at a vertex x i can be expressed as below: T(x 1) = w(x 1) The departure time for all other vertices on the path can be expressed recursively as : The time of path P is defined as T(x r) where x r is the final node on the path..
654791
An image signature for any kind of image
We describe an algorithm for computing an image signature, suitable for first-stage screening for duplicate images. Our signature relies on the relative brightness of image regions, and is generally applicable to photographs, text documents, and line art. We give experimental results on the sensitivity and robustness of signatures for actual image collections, and also results on the robustness of signatures under transformations such as resizing, rescanning, and compression.