New Approaches to Protein Structure Prediction

Protein structure prediction is concerned with the prediction of a protein's three dimensional structure from its amino acid sequence. Such predictions are commonly performed by searching the possible structures and evaluating each structure by using some scoring function. If it is assumed that the target protein structure resembles the structure of a known protein, the search space can be significantly reduced. Such an approach is referred to as comparative structure prediction. When such an assumption is not made, the approach is known as ab initio structure prediction. There are several difficulties in devising efficient searches or in computing the scoring function. Many of these problems have ready solutions from known mathematical methods. However, the problems that are yet unsolved have hindered structure prediction methods from more ideal predictions. The objective of this study is to present a complete framework for ab initio protein structure prediction. To achieve this, a new search strategy is proposed, and better techniques are devised for computing the known scoring functions. Some of the remaining problems in protein structure prediction are revisited. Several of them are shown to be intractable. In many of these cases, approximation methods are suggested as alternative solutions. The primary issues addressed in this thesis are concerned with local structures prediction, structure assembly or sampling, side chain packing, model comparison, and structural alignment. For brevity, we do not elaborate on these problems here; a concise introduction is given in the first section of this thesis. Results from these studies prompted the development of several programs, forming a utility suite for ab initio protein structure prediction. Due to the general usefulness of these programs, some of them are released with open source licenses to benefit the community

Methods for Inference in Graphical Models

Graphical models provide a flexible, powerful and compact way to model relationships between random variables, and have been applied with great success in many domains. Combining prior beliefs with observed evidence to form a prediction is called inference. Problems of great interest include finding a configuration with highest probability (MAP inference) or solving for the distribution over a subset of variables (marginal inference). Further, these methods are often critical subroutines for learning the relationships. However, inference is computationally intractable in general. Hence, much effort has focused on two themes: finding subdomains where exact inference is solvable efficiently, or identifying approximate methods that work well. We explore both these themes, restricting attention to undirected graphical models with discrete variables. First we address exact MAP inference by advancing the recent method of reducing the problem to finding a maximum weight stable set (MWSS) on a derived graph, which, if perfect, admits polynomial time inference. We derive new results for this approach, including a general decomposition theorem for models of any order and number of labels, extensions of results for binary pairwise models with submodular cost functions to higher order, and a characterization of which binary pairwise models can be efficiently solved with this method. This clarifies the power of the approach on this class of models, improves our toolbox and provides insight into the range of tractable models. Next we consider methods of approximate inference, with particular emphasis on the Bethe approximation, which is in widespread use and has proved remarkably effective, yet is still far from being completely understood. We derive new formulations and properties of the derivatives of the Bethe free energy, then use these to establish an algorithm to compute log of the optimum Bethe partition function to arbitrary epsilon-accuracy. Further, if the model is attractive, we demonstrate a fully polynomial-time approximation scheme (FPTAS), which is an important theoretical result, and demonstrate its practical applications. Next we explore ways to tease apart the two aspects of the Bethe approximation, i.e. the polytope relaxation and the entropy approximation. We derive analytic results, show how optimization may be explored over various polytopes in practice, even for large models, and remark on the observed performance compared to the true distribution and the tree-reweighted (TRW) approximation. This reveals important novel observations and helps guide inference in practice. Finally, we present results related to clamping a selection of variables in a model. We derive novel lower bounds on an array of approximate partition functions based only on the model's topology. Further, we show that in an attractive binary pairwise model, clamping any variable and summing over the approximate sub-partition functions can only increase (hence improve) the Bethe approximation, then use this to provide a new, short proof that the Bethe partition function lower bounds the true value for this class of models. The bulk of this work focuses on the class of binary, pairwise models, but several results apply more generally

Quantum Hamiltonian Complexity

Constraint satisfaction problems are a central pillar of modern computational complexity theory. This survey provides an introduction to the rapidly growing field of Quantum Hamiltonian Complexity, which includes the study of quantum constraint satisfaction problems. Over the past decade and a half, this field has witnessed fundamental breakthroughs, ranging from the establishment of a "Quantum Cook-Levin Theorem" to deep insights into the structure of 1D low-temperature quantum systems via so-called area laws. Our aim here is to provide a computer science-oriented introduction to the subject in order to help bridge the language barrier between computer scientists and physicists in the field. As such, we include the following in this survey: (1) The motivations and history of the field, (2) a glossary of condensed matter physics terms explained in computer-science friendly language, (3) overviews of central ideas from condensed matter physics, such as indistinguishable particles, mean field theory, tensor networks, and area laws, and (4) brief expositions of selected computer science-based results in the area. For example, as part of the latter, we provide a novel information theoretic presentation of Bravyi's polynomial time algorithm for Quantum 2-SAT.Comment: v4: published version, 127 pages, introduction expanded to include brief introduction to quantum information, brief list of some recent developments added, minor changes throughou

Approximability of Combinatorial Optimization Problems on Power Law Networks

One of the central parts in the study of combinatorial optimization is to classify the NP-hard optimization problems in terms of their approximability. In this thesis we study the Minimum Vertex Cover (Min-VC) problem and the Minimum Dominating Set (Min-DS) problem in the context of so called power law graphs. This family of graphs is motivated by recent findings on the degree distribution of existing real-world networks such as the Internet, the World-Wide Web, biological networks and social networks. In a power law graph the number of nodes yi of a given degree i is proportional to i-ß, that is, the distribution of node degrees follows a power law. The parameter ß > 0 is the so called power law exponent. With the aim of classifying the above combinatorial optimization problems, we are pursuing two basic approaches in this thesis. One is concerned with complexity theory and the other with the theory of algorithms. As a result, our main contributions to the classification of the problems Min-VC and Min-DS in the context of power law graphs are twofold: - Firstly, we give substantial improvements on the previously known approximation lower bounds for Min-VC and Min-DS in combinatorial power law graphs. More precisely, we are going to show the APX-hardness of Min-VC and Min-DS in connected power law graphs and give constant factor lower bounds for Min-VC and the first logarithmic lower bounds for Min-DS in this setting. The results are based on new approximation-preserving embedding reductions that embed certain instances of Min-VC and Min-DS into connected power law graphs. - Secondly, we design a new approximation algorithm for the Min-VC problem in random power law graphs with an expected approximation ratio strictly less than 2. The main tool is a deterministic rounding procedure that acts on a half-integral solution for Min-VC and produces a good approximation on the subset of low degree vertices. Moreover, for the case of Min-DS, we improve on the previously best upper bounds that rely on a greedy algorithm. The improvements are based on our new techniques for determining upper and lower bounds on the size and the volume of node intervals in power law graphs

Department of Computer Science Activity 1998-2004

This report summarizes much of the research and teaching activity of the Department of Computer Science at Dartmouth College between late 1998 and late 2004. The material for this report was collected as part of the final report for NSF Institutional Infrastructure award EIA-9802068, which funded equipment and technical staff during that six-year period. This equipment and staff supported essentially all of the department\u27s research activity during that period