The prediction of energetically favorable side-chain conformations is a fundamental element in homology modeling of proteins and the design of novel protein sequences. The space of side-chain conformations can be approximated by a discrete space of probabilistically representative side-chain conformations (called rotamers). The problem is, then, to find a rotamer selection for each amino acid that minimizes a potential energy function. This is called the Global Minimum Energy Conformation (GMEC) problem. This problem is an NP-hard optimization problem. The Dead-End Elimination theorem together with the A* algorithm (DEE/A*) has been successfully applied to this problem. However, DEE fails to converge for some complex instances. In this paper, we explore two alternatives to DEE/A* in solving the GMEC problem. We use a probabilistic inference method, the max-product (MP) belief-propagation algorithm, to estimate (often exactly) the GMEC. We also investigate integer programming formulations to obtain the exact solution. There are known ILP formulations that can be directly applied to the GMEC problem. We review these formulations and compare their effectiveness using CPLEX optimizers. We also present preliminary work towards applying the branch-and-price approach to the GMEC problem. The preliminary results suggest that the max-product algorithm is very effective for the GMEC problem. Though the max-product algorithm is an approximate method, its speed and accuracy are comparable to those of DEE/A* in large side-chain placement problems and may be superior in sequence design. / Singapore-MIT Alliance (SMA)

We propose a novel branch-and-price (B&P) approach to solve the maximum weighted independent set problem (MWISP). Our approach uses clones of vertices to create edge-disjoint partitions from vertex-disjoint partitions. We solve the MWISP on sub-problems based on these edge-disjoint partitions using a B&P framework, which coordinates sub-problem solutions by involving an equivalence relationship between a vertex and each of its clones. We present test results for standard instances and randomly generated graphs for comparison. We show analytically and computationally that our approach gives tight bounds and it solves both dense and sparse graphs quite quickly.

We consider combinatorial t-design problems as discrete optimization problems. Our motivation is that only a few studies have been done on the use of exact optimization techniques in designs, and that classical methods in design theory have still left many open existence questions. Roughly defined, t-designs are pairs of discrete sets that are related following some strict properties of size, balance, and replication. These highly structured relationships provide optimal solutions to a variety of problems in computer science like error-correcting codes, secure communications, network interconnection, design of hardware; and are applicable to other areas like statistics, scheduling, games, among others. We give a new approach to combinatorial t-designs that is useful in constructing t-designs by polyhedral methods. The first contribution of our work is a new result of equivalence of t-design problems with a graph theory problem. This equivalence leads to a novel integer programming formulation for t-designs, which we call GDP. We analyze the polyhedral properties of GDP and conclude, among other results, the associated polyhedron dimension. We generate new classes of valid inequalities to aim at approximating this integer program by a linear program that has the same optimal solution. Some new classes of valid inequalities are generated as Chv´atal-Gomory cuts, other classes are generated by graph complements and combinatorial arguments, and others are generated by the use of incidence substructures in a t-design. In particular, we found a class of valid inequalities that we call stable-set class that represents an alternative graph equivalence for the problem of finding a t-design. We analyze and give results on the strength of these new classes of valid inequalities. We propose a separation problem and give its integer programming formulation as a maximum (or minimum) edge-weight biclique subgraph problem. We implement a pure cutting-plane algorithm using one of the stronger classes of valid inequalities derived. Several instances of t-designs were solved efficiently by this algorithm at the root node of the search tree. Also, we implement a branch-and-cut algorithm and solve several instances of 2-designs trying different base formulations. Computational results are included.

Consider the problem of maximizing the revenue generated by tolls set on a subset of arcs of a transportation network, where origin-destination flows (commodities) are assigned to shortest paths with respect to the sum of tolls and initial costs. This thesis is concerned with a particular case of the above problem, in which all toll arcs are connected and constitute a path, as occurs on highways. Further, as toll levels are usually computed using the highway entry and exit points, a complete toll subgraph is considered, where each toll arc corresponds to a toll subpath. Two variants of the problem are studied, with or without specific constraints linking together the tolls on the arcs. The problem is modelled as a linear mixed integer program, and proved to be NP-hard. Next, several classes of valid inequalities are proposed, which strengthen important constraints of the initial model. Their efficiency is first shown theoretically, as these are facet defining for the restricted one and two commodity problems. Also, we prove that some of the valid inequalities proposed, together with several constraints of the linear program, provide a complete description of the convex hull of feasible solutions for a single commodity problem. Numerical tests have also been conducted, and highlight the real efficiency of the valid inequalities for the multi-commodity case. Finally, we point out the links between the problem studied in the thesis and a more classical design and pricing problem in economics. / Considérons le problème qui consiste à maximiser les profits issus de la tarification d’un sous-ensemble d’arcs d’un réseau de transport, où les flots origine-destination (produits) sont affectés aux plus courts chemins par rapport aux tarifs et aux coûts initiaux. Cette thèse porte sur une structure de réseau particulière du problème ci-dessus, dans laquelle tous les arcs tarifables sont connectés et forment un chemin, comme c’est le cas sur une autoroute. Étant donné que les tarifs sont habituellement déterminés selon les points d’entrée et de sortie sur l’autoroute, nous considérons un sous-graphe tarifable complet, où chaque arc correspond en réalité à un sous-chemin. Deux variantes de ce problème sont étudiées, avec ou sans contraintes spécifiques reliant les niveaux de tarifs sur les arcs. Ce problème peut être modélisé comme un programme linéaire mixte entier. Nous prouvons qu’il est NP-difficile. Plusieurs familles d’inégalités valides sont ensuite proposées, celles-ci renforçant certaines contraintes du modèle initial. Leur efficacité est d’abord démontrée de manière théorique, puisqu’il s’agit de facettes des problèmes restreints à un ou deux produits. Certaines des inégalités valides proposées, ainsi que plusieurs contraintes du modèle initial, permettent aussi de donner une description complète de l’enveloppe convexe des solutions réalisables d’un problème restreint à un seul produit. Des tests numériques ont également été menés, et mettent en évidence l’efficacité réelle des inégalités valides pour le problème général à plusieurs produits. Enfin, nous soulignons les liens entre le problème de tarification de réseau étudié dans cette thèse et un problème plus classique de tarification de produits en gestion.

In this thesis, we introduce the Partitioning-Hub Location-Routing problem (PHLRP), which can be classied as a variant of the hub location problem. PHLRP consists of partitioning a network into sub-networks, locating at least one hub in each subnetwork and routing the traffic within the network such that all inter-subnetwork traffic is routed through the hubs and all intra-subnetwork traffic stays within the sub-networks all the way from the source to the destination. Obviously, besides the hub location component, PHLRP also involves a graph partitioning component and a routing component. PHLRP finds applications in the strategic planning or deployment of the Intermediate System-Intermediate System (ISIS) Internet Protocol networks and the Less-than-truck load freight distribution systems. First, we introduce three IP formulations for solving PHLRP. The hub location component and the graph partitioning components of PHLRP are modeled in the same way in all three formulations. More precisely, the hub location component is represented by the p-median variables and constraints; and the graph partitioning component is represented by the size-constrained graph partitioning variables and constraints. The formulations differ from each other in the way the peculiar routing requirements of PHLRP are modeled. We then carry out analytical and empirical comparisons of the three IP formulations. Our thorough analysis reveals that one of the formulations is provably the tightest of the three formulations. We also show analytically that the LP relaxations of the other two formulations do not dominate each other. On the other hand, our empirical comparison in a standard branch-and-cut framework that is provided by CPLEX shows that not the tightest but the most compact of the three formulations yield the best performance in terms of solution time. From this point on, based on the insight gained from detailed analysis of the formulations, we focus our attention on a common sub-problem of the three formulations: the so-called size-constrained graph partitioning problem. We carry out a detailed polyhedral analysis of this problem. The main benet from this polyhedral analysis is that the facets we identify for the size-constrained graph partitioning problem constitute strong valid inequalities for PHLRP. And finally, we wrap up our efforts for solving PHLRP. Namely, we present the results of our computational experiments, in which we employ some facets of the size-constrained graph partitioning polytope in a branch-and-cut algorithm for solving PHLRP. Our experiments show that our approach brings signicant improvements to the solution time of PHLRP when compared with the default branch-and-cut solver of XPress. / Dans cette thèse, nous introduisons le problème Partitionnement-Location des Hubs et Acheminement (PLHA), une variante du problème de location de hubs. Le problème PLHA partitionne un réseau afin d'obtenir des sous-réseaux, localise au moins un hub dans chaque sous-réseau et achemine le traffic dans le réseau de la maniére suivante : le traffic entre deux sous-réseaux distincts doit être éxpedié au travers des hubs tandis que le traffic entre deux noeuds d'un même sous-réseau ne doit pas sortir de celui-ci. PLHA possède des applications dans le planning stratégique, ou déploiement, d'un certain protocole de communication utilisé dans l'Internet, Intermediate System - Intermediate System, ainsi que dans la distribution des frets. Premièrement, nous préesentons trois formulations linéaires en variables entières pour résoudre PLHA. Le partitionnement du graphe et la localisation des hubs sont modélisées de la même maniére dans les trois formulations. Ces formulations diffèrent les unes des autres dans la maniére dont l'acheminement du traffic est traité. Deuxièmement, nous présentons des comparaisons analytiques et empiriques des trois formulations. Notre comparaison analytique démontre que l'une des formulations est plus forte que les autres. Néanmoins, la comparaison empirique des formulations, via le solveur CPLEX, montre que la formulation la plus compacte (mais pas la plus forte) obtient les meilleures performances en termes de temps de résolution du problème. Ensuite, nous nous concentrons sur un sous-problème, à savoir, le partitionnement des graphes sous contrainte de taille. Nous étudions le polytope des solutions réalisables de ce sous-problème. Les facettes de ce polytope constituent des inégalités valides fortes pour PLHA et peuvent être utilisées dans un algorithme de branch-and-cut pour résoudre PLHA. Finalement, nous présentons les résultats d'un algorithme de branch-and-cut que nous avons développé pour résoudre PLHA. Les résultats démontrent que la performance de notre méthode est meilleure que celle de l'algorithme branch-and-cut d'Xpress.

This thesis consists of an introduction and sevenindependent, but closely related, papers which all deal withproblems in structural optimization. In particular, we considermodels and methods for global optimization of problems intopology design of discrete and continuum structures. In the first four papers of the thesis the nonconvex problemof minimizing the weight of a truss structure subject to stressconstraints is considered. First itis shown that a certainsubclass of these problems can equivalently be cast as linearprograms and thus efficiently solved to global optimality.Thereafter, the behavior of a certain well-known perturbationtechnique is studied. It is concluded that, in practice, thistechnique can not guarantee that a global minimizer is found.Finally, a convergent continuous branch-and-bound method forglobal optimization of minimum weight problems with stress,displacement, and local buckling constraints is developed.Using this method, several problems taken from the literatureare solved with a proof of global optimality for the firsttime. The last three papers of the thesis deal with topologyoptimization of discretized continuum structures. Theseproblems are usually modeled as mixed or pure nonlinear 0-1programs. First, the behavior of certain often usedpenalization methods for minimum compliance problems isstudied. It is concluded that these methods may fail to producea zero-one solution to the considered problem. To remedy this,a material interpolation scheme based on a rational functionsuch that compli- ance becomes a concave function is proposed.Finally, it is shown that a broad range of nonlinear 0-1topology optimization problems, including stress- anddisplacement-constrained minimum weight problems, canequivalently be modeled as linear mixed 0-1 programs. Thisresult implies that any of the standard methods available forgeneral linear integer programming can now be used on topologyoptimization problems. <b>Keywords:</b>topology optimization, global optimization,stress constraints, linear programming, mixed integerprogramming, branch-and-bound.

Influenza is a public health problem that causes serious illness and deaths all over the world. Vaccination has been shown to be the most effective mean to prevent infection. The primary component of influenza vaccine is the weakened strains. Vaccination triggers the immune system to develop antibodies against those strains whose viral surface glycoprotein hemagglutinin (HA) is similar to that of vaccine strains. However, influenza vaccine must be updated annually since the antigenic structure of HA is constantly mutation. Hemagglutination inhibition (HI) assay is a laboratory procedure frequently applied to evaluate the antigenic relationships of the influenza viruses. It enables the World Health Organization (WHO) to recommend appropriate updates on strains that will most likely be protective against the circulating influenza strains. However, HI assay is labour intensive and time-consuming since it requires several controls for standardization. We use two machine-learning methods, i.e. Artificial Neural Network (ANN) and Logistic Regression, and a Mixed-Integer Optimization Model to predict antigenic variety. The ANN generalizes the input data to patterns inherent in the data, and then uses these patterns to make predictions. The logistic regression model identifies and selects the amino acid positions, which contribute most significantly to antigenic difference. The output of the logistic regression model will be used to predict the antigenic variants based on the predicted probability. The Mixed-Integer Optimization Model is formulated to find hyperplanes that enable binary classification. The performances of our models are evaluated by cross validation.

Solution methodologies for mixed integer bilinear problems (MIBLP) are studied in this dissertation. This problem class is motivated using the pooling problem, a multicommodity network flow problem that typically arises in chemical engineering applications. Stronger than previously known results are provided to compare the strengths of polyhedral relaxations of the pooling problem. A novel single node flow relaxation, defined by a bilinear equality constraint and flow balance, is proposed for the pooling problem. Linear valid inequalities in the original space of variables are derived using a well-known technique called lifting. Mixed integer linear (MILP) formulations are proposed for generating feasible solutions to the pooling problem. Some of these MILP models arise from variable discretizations while others possess a network flow interpretation. The effectiveness of these MILP models is empirically validated on a library of medium and large-scale instances. General MIBLPs, not necessarily pooling problems, are solved using extended MILP reformulations. The reformulation is obtained by writing binary representation for each general integer variable. Facet-defining inequalities are provided for the reformulation of each bilinear term. New valid inequalities are also proposed for bilinear terms with a nontrivial upper bound. The proposed reformulation and cutting planes are compared against a global solver on five different classes of MIBLPs.

Runway systems at airports have been identified as a major source of delay in the aviation system and efficient runway operations are, therefore, important to maintain and/or increase the capacity of the entire aviation system. The goal of the airport runway scheduling problem is to schedule a set of aircraft and minimize a given objective while maintaining separation requirements and enforcing other operational constraints. Uncertain factors such as weather, surrounding traffic and pilot behavior affect when aircraft can be scheduled, and these factors need to be considered in planning models. In this thesis we propose two stochastic programs to address the stochastic airport runway scheduling problem and similarly structured machine scheduling problems. In the first part, we develop a two-stage stochastic integer programming model and analyze it by developing alternative formulations and solution methods. As part of our analysis, we first show that a restricted version of the stochastic runway scheduling problem is equivalent to a machine scheduling problem on a single machine with sequence dependent setup times and stochastic due dates. We then extend this restricted model by considering characteristics specific to the runway scheduling problem and present two different stochastic integer programming models. We derive some tight valid inequalities for these formulations, and we propose a solution methodology based on sample average approximation and Lagrangian based scenario decomposition. Realistic data sets are then used to perform a detailed computational study involving implementations and analyses of several different configurations of the models. The results from the computational tests indicate that practically implementable truncated versions of the proposed solution algorithm almost always produce very high quality solutions. In the second part, we propose a sampling based stochastic program for a general machine scheduling problem with similar characteristics as the airport runway scheduling problem. The sampling based approach allows us to capture more detailed aspects of the problem, such as taxiway operations crossing active runways. The model is based on the stochastic branch and bound algorithm with several enhancements to improve the computational performance. More specifically, we incorporate a method to dynamically update the sample sizes in various parts of the branching tree, effectively decreasing the runtime without worsening the solution quality. When applied to runway scheduling, the algorithm is able to produce schedules with makespans that are 5% to 7% shorter than those obtained by optimal deterministic methods. Additional contributions in this thesis include the development of a global cost function, capturing all relevant costs in airport runway scheduling and trading off different, sometimes conflicting, objectives. We also analyze the impact of including environmental factors in the scheduling process.

We consider the daily transportation problem in forestry which arises when transporting logs from forest sites to customers such as sawmills and pulp and paper mills. Each customer requires a specific amount of a certain assortment, and the deliveries to the customers can be made within time intervals, known as time windows. Further, there are a number of supply points, each with a certain assortment, and a number of vehicles of a given capacity, to be used for transport. The log truck scheduling problem consists of finding a set of minimal costs routes, one for each vehicle, such that the customers’ demands are satisfied without exceeding the supplies available at the supplies. Each route has to satisfy a number of constraints concerning time windows, truck capacity, timetable of the driver, lunch breaks, et cetera. The model used to describe the log truck scheduling problem is based on the route concept, and each variable, or column, represents one feasible route. Since the number of feasible routes is huge, we work only with restricted versions of this problem, which are similar to restricted master problems in a Dantzig-Wolfe decomposition scheme. We use three solution methods based on the column generation principle, together with a pool strategy which allows us to deal with the feasible routes outside the restricted master problem. The three methods proposed have a common structure; they use branch-andprice together with a column generator, followed by branch-and-bound. The column generators in the three methods differ. In the first method, the subproblem is based on a cluster-first-route-second strategy. The column generator in the second method involves solving a constrained shortest path problem, and finally, the third method builds on a repeated generation of clusters and routes. The three methods are tested on real cases from Swedish forestry companies, and the third method has been adapted to a computerised system that utilises the Swedish national road data base, for computing travelling distances. The results obtained show that the optimisation methods succeed in finding significantly better solutions than those obtained by manual planning, and in a reasonable computing time.