In this work, the random vibration of higher-order nonlinear beams and composite plates subjected to stochastic loading is studied. The fourth-order nonlinear beam equation is examined to study the effect of rotary inertia and shear deformation on the root mean square values of displacement response. A new linearly coupled equivalent linearization method is proposed and compared with the widely used traditional equivalent linearization method. The new method is proven to yield closer predictions to the numerical simulation results of the nonlinear beam vibration. A systematical investigation of the nonlinear random vibration of composite plates is conducted in which effects of nonlinearity, choices of different plate theories (the first order shear deformation plate theory and the classical plate theory), and temperature gradient on the plate statistical transverse response are addressed. Attention is paid to calculate the R.M.S. values of stress components since they directly affect the fatigue life of the structure. A statistical data reconstruction technique named ARMA modeling and its applications in random vibration data analysis are discussed. The model is applied to the simulation data of nonlinear beams. It is shown that good estimations of both the nonlinear frequencies and the power spectral densities are given by the technique. / Ph. D.

Molecular Biology has allowed the characterization and manipulation of the molecules of life in the wet lab. Also the structures of those macromolecules are being continuously elucidated. During the last decades of the past century, there was an increasing interest to study how the different genes are organized into different organisms (‘genomes’) and how those genes are expressed into proteins to achieve their functions. Currently the sequences for many genes over several genomes have been determined. In parallel, the efforts to have the structure of the proteins coded by those genes go on. However it is experimentally much harder to obtain the structure of a protein, rather than just its sequence. For this reason, the number of protein structures available in databases is an order of magnitude or so lower than protein sequences. Furthermore, in order to understand how living organisms work at molecular level we need the information about the interaction of those proteins. Elucidating the structure of protein macromolecular assemblies is still more difficult. To that end, the use of computers to predict the structure of these complexes has gained interest over the last decades. The main subject of this thesis is the evaluation of current available computational methods to predict protein – protein interactions and build an atomic model of the complex. The core of the thesis is the evaluation protocol I have developed at Service de Conformation des Macromolécules Biologiques et de Bioinformatique, Université Libre de Bruxelles, and its computer implementation. This method has been massively used to evaluate the results on blind protein – protein interaction prediction in the context of the world-wide experiment CAPRI, which have been thoroughly reviewed in several publications [1-3]. In this experiment the structure of a protein complex (‘the target’) had to be modeled starting from the coordinates of the isolated molecules, prior to the release of the structure of the complex (this is commonly referred as ‘docking’). The assessment protocol let us compute some parameters to rank docking models according to their quality, into 3 main categories: ‘Highly Accurate’, ‘Medium Accurate’, ‘Acceptable’ and ‘Incorrect’. The efficiency of our evaluation and ranking is clearly shown, even for borderline cases between categories. The correlation of the ranking parameters is analyzed further. In the same section where the evaluation protocol is presented, the ranking participants give to their predictions is also studied, since often, good solutions are not easily recognized among the pool of computer generated decoys. An overview of the CAPRI results made per target structure and per participant regarding the computational method they used and the difficulty of the complex. Also in CAPRI there is a new ongoing experiment about scoring previously and anonymously generated models by other participants (the ‘Scoring’ experiment). Its promising results are also analyzed, in respect of the original CAPRI experiment. The Scoring experiment was a step towards the use of combine methods to predict the structure of protein – protein complexes. We discuss here its possible application to predict the structure of protein complexes, from a clustering study on the different results. In the last chapter of the thesis, I present the preliminary results of an ongoing study on the conformational changes in protein structures upon complexation, as those rearrangements pose serious limitations to current computational methods predicting the structure protein complexes. Protein structures are classified according to the magnitude of its conformational re-arrangement and the involvement of interfaces and particular secondary structure elements is discussed. At the end of the chapter, some guidelines and future work is proposed to complete the survey.

No description available.

There is a need for objective methods for wrist angular velocity measurements for accurate risk assessments because there is a high frequency of musculoskeletal disorder in workers. The goal of this project was to validate the accuracy of inertial measurement unit sensors to measure the angular velocity. More specifically, the purpose of this master thesis project was to apply an alternative algorithm to compute the markers velocity, other than the one from the optical system that Jenny Wingqvist, and Josephine Lantz used. The project used an experimental data of 10 participants from the previous project done by Jenny Wingqvist and Josephine Lantz. To validate the accuracy, the data of angular velocity of the sensors was compared with the data of angular velocity of markers. The lowest mean value of the root mean square differences value was 23.5 degrees/s during flexion and deviation standard movements at 40 BPM (Beats Per Minute) and the maximum value was 110.5 degrees/s at 140 BPM. The mean value of the correlation coefficients between markers and sensors angular velocities in standard movements of flexion and deviation were 0.85, 0.88, and 0.89 at 40 BPM, 90 BPM, and 140 BPM, respectively. The smallest and the largest mean value of the absolute difference in 50th percentile was found in 40 BPM (19.4±11.3), and 140 BPM (51.2±28.5) respectively. The decorrelation coefficient between the subjects 50th percentile of the angular velocity was 0.91 for the standard movements. The upper limit of agreement for the standard movements was 78.36 degrees/s, while the lower limit of agreement was -13.76 degrees/s.  The results show that the error was too large, so there is a need of further research to measure the wrist angular velocity using IMU sensors.

Made available in DSpace on 2015-03-26T13:32:05Z (GMT). No. of bitstreams: 1 texto completo.pdf: 688077 bytes, checksum: 369ec0145d58b4c3f2d93ab69403df95 (MD5) Previous issue date: 2009-01-19 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Many times, the interpretation of the results in cluster analysis is done subjectively, that is, through inspection on dendograms, since there are no objective criteria to identify the formed clusters. In face of such a problem, the present study aimed to: (1) find out an objective way to achieve the cut-point (optimal number of clusters) in a dendogram in order to help on taking the right decision; (2) work out index concepts such as Root Mean Square Standard Deviation (RMSSTD) and R Squared (RS), explaining the contribution of each one of them in determining the optimal number of cluster; (3) method application, aiming to identify divergent accessions that will be used on improvement programs. An alternative solution for this problem is to use the RMSSTD and RS which are calculated according to the number of variables among and within the clusters formed, characterizing an objective way to determine the optimal number. Another solution is achieved by using the RS. Some morphological characteristics of the forty nine accessions of the species Capsicum chinense Jacq. from the Germplasm Bank of Vegetables of the Federal University of Viçosa (Banco de Germoplasma de Hortaliças da Universidade Federal de Viçosa, Minas Gerais Brazil) were analyzed by means of cluster analysis. The accessions were clustered based on the proposed techniques and an optimal number of clusters was achieved. The 49 accessions analyzed were classified into only seven clusters according to the graph of the RMSSTD versus the number of clusters and the graph of the RS versus the number of clusters. / Muitas vezes, a interpretação dos resultados em análise de agrupamentos é feita de forma subjetiva, isto é, através da inspeção de dendrogramas. Isto se deve ao fato de haver dificuldade em se encontrar na literatura um critério objetivo de fácil aplicação para identificar o número ideal de grupos formados. Diante deste problema, o presente trabalho teve por objetivos: 1) Avaliar a aplicabilidade de critério objetivo de se obter o ponto de corte (número ótimo de clusters) num dendrograma para a tomada de decisão; 2) trabalhar os conceitos de índices como RMSSTD (root mean square standard deviation) e RS (R-Squared), discutindo a contribuição de cada um destes na obtenção do número ótimo de clusters em acessos de Capsicum chinense; 3) aplicação do método, visando a identificar acessos divergentes de Capsicum chinense para serem utilizados em programas de melhoramento. Os índices RMSSTD e RS são calculados de acordo com as variáveis entre e dentro dos grupos formados, caracterizando uma forma objetiva para determinar o número ótimo. Para se obter o ponto de máxima curvatura da trajetória dos índices RMSSTD e RS em função do aumento do número de grupos (X), utilizou-se o Método da Máxima Curvatura Modificado. Foram analisadas, por meio da análise de agrupamentos, algumas características morfológicas de quarenta e nove acessos da espécie Capsicum chinense Jacq. do Banco de Germoplasma de Hortaliças da Universidade Federal de Viçosa. A partir das técnicas propostas agrupou-se os acessos, obtendo um número ótimo de grupos. Os resultados classificam os 49 acessos avaliados em apenas sete grupos de acordo com o gráfico do RMSSTD versus o número de grupos e o gráfico do RS versus o número de grupos.

Today, Sport Utility Vehicles are marketed as both on-road and off-road vehicles. This results in a compromise when designing the suspension of the vehicle. If the suspension characteristics are fixed, the vehicle cannot have good handling capabilities on highways and good ride comfort over rough terrain. The rollover propensity of this type of vehicle compared to normal cars is high because it has a combination of a high centre of gravity and a softer suspension. The 4 State Semi-active Suspension System (4S4) that can switch between two discrete spring characteristics as well as two discrete damper characteristics, has been proven to overcome this compromise. The soft suspension setting (soft spring and low damping) is used for ride comfort, while the hard suspension setting (stiff spring and high damping) is used for handling. The following question arises: when is which setting most appropriate? The two main contributing factors are the terrain profile and the driver’s actions. Ride comfort is primarily dependant on the terrain that the vehicle is travelling over. If the terrain can be identified, certain driving styles can be expected for that specific environment. The terrains range from rough and uncomfortable to smooth with high speed manoeuvring. Terrain classification methods are proposed and tested with measured data from the test vehicle on known terrain types. Good results were obtained from the terrain classification methods. Five terrain types were accurately identified from over an hour’s worth of vehicle testing. Handling manoeuvres happen unexpectedly, often to avoid an accident. To improve the handling and therefore safety of the vehicle, the 4S4 can be switched to the hard suspension setting, which results in a reduced body roll angle. This decision should be made quickly with the occupants’ safety as the priority. Methods were investigated that will determine when to switch the suspension to the handling mode based on the kinematics of the vehicle. The switching strategies proposed in this study have the potential, with a little refinement, to make the ride versus handling decision correctly. Copyright 2007, University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. Please cite as follows: Bester, R 2007, The ride comfort versus handling decision for off-road vehicles, MEng dissertation, University of Pretoria, Pretoria, viewed yymmdd < http://upetd.up.ac.za/thesis/available/etd-10252007-111611 / > / Dissertation (MEng (Mechanical Engineering))--University of Pretoria, 2007. / Mechanical and Aeronautical Engineering / unrestricted

Belastningsskador hos arbetare är ett ökande problem hos olika företag och det har visat sig finnas en tydlig koppling mellan dessa skador och handledens vinkelhastigheten. Det är därför av stort intresse att kunna mäta dessa vinkelhastigheter på ett noggrant och smidigt sätt. Syftet med denna rapport är att utvärdera precisionen av IMU-sensorers förmåga att beräkna vinkelhastigheten av handleden. Detta görs genom att jämföra data från IMU-sensorer med data från ett optiskt spårningssystem (OTS), vilket klassas som en gold standard inom detta område. Ett experiment bestående av åtta övningar utfördes: tre standard rörelser (flexion och rotation i takterna 40, 90 och 140 slag per minut) och fyra simulerade arbeten (målning, pappersvikning, datorarbete och hårföning). Grad av överensstämmelse ges av 1,96 standardavvikelser (SD) för standardrörelserna (10 deltagare) vilka var -31,8 grader/s och 34,2 grader/s, medan för de simulerade arbetena var det -35,1 grader/s och 34,2 grader/s. Det lägsta medelvärdet av medelkvadratavvikelse (RMSD) var 15,7 grader/s och erhölls vid 40 BPM medan den högsta medelvärdet var 93,9 grader/s och erhölls vid målningsövningen. Medelvärdet av korrelationskoefficienten mellan IMU-sensorer och OTS varierade mellan 0,97 och 0,42 och korrelationskoefficienterna av deltagarnas 50:e percentiler av vinkelhastigheten var 0,95 för standardrörelserna och 0,96 för de simulerade arbetena. Medelvärdet av absoluta differensen mellan sensorer och OTS var givet i percentiler (10:e, 50:e och 90:e). Det största spannet för 50:e percentilen gavs vid 140 BPM (18,3 ± 24,6) och det minsta spannet vid 40 BPM (3,5 ± 4,7). Trots att det fanns mindre differenser mellan metodernas mätningar av vinkelhastighet, anser vi att IMU-sensorer har potential att användas för att mäta vinkelhastigheter hos handledens och med vidare utveckling kan den nuvarande differensen minimeras. / Musculoskeletal disorders (MSDs) are increasingly frequent amongst workers and there is a clear connection between work injuries and wrist angular velocities. One of the biggest issues therefore is the currently limited availability of means to measure these angular velocities. The aim of this study is to validate the usability of the IMU sensors to measure angular velocities. This is done by comparing the data from the IMU:s with the data obtained with the optical motion tracking system (OTS), which is considered gold standard within this field of studies. An experiment consisting of eight exercises was conducted: three standard movements (flexion and rotation in the pace 40, 90 and 140 repetitions per minute) and four simulated practical work tasks (painting, folding paper, computer exercise and using a hairdryer). The limits of agreement for the standard movements (10 subjects) were -31,8 degrees/s and 34,2 degrees/s, whereas for the simulated practical work tasks they were -35,1 degrees/s and 28,2 degrees/s. The lowest mean value of the root mean square deviation (RMSD) value was 15,7 degrees/s which represents the 40 BPM task whilst the highest mean value was 93,9 degrees/s which correspond to the painting task. The mean value of the correlation coefficients between the IMU:s and the OTS ranged between 0,97 and 0,42 and the correlation coefficient between the subjects 50:th percentiles of the angular velocity, was 0,95 for the standard movements whilst for the practical work tasks it was 0,96. The mean value of the absolute difference between the sensors and the OTS was given in percentiles (10th, 50th and 90th). The largest range within the 50th percentile occurred during the 140 BPM task (18,3 ± 24,6) and the smallest range during the 40 BPM task (3,5 ± 4,7). Although the measured angular velocities vary to a certain extent between the two methods, we conclude that the IMU sensors present the potential to work as measuring units for wrist angular velocities and with further development the current differences can be minimized. / Forte dnr: 2017-01209 "Enkel och tideffektiv metod att mät, analysera och presentera biomekaniskbelastning för hand-handled"

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-02-11T10:56:22Z No. of bitstreams: 1 juandavidvalenciapayan.pdf: 2769602 bytes, checksum: f450fbb83bbe8b4e5a8cdb7c9b4fa338 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-02-26T11:57:12Z (GMT) No. of bitstreams: 1 juandavidvalenciapayan.pdf: 2769602 bytes, checksum: f450fbb83bbe8b4e5a8cdb7c9b4fa338 (MD5) / Made available in DSpace on 2016-02-26T11:57:12Z (GMT). No. of bitstreams: 1 juandavidvalenciapayan.pdf: 2769602 bytes, checksum: f450fbb83bbe8b4e5a8cdb7c9b4fa338 (MD5) Previous issue date: 2014-03-27 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Esta contribuição descreve uma caracterização estatística da rede de baixa tensão Brasileira residencial como meio de comunicação. As discussões são baseadas em canais estimados obtidos em uma campanha de medição realizada em quatro apartamentos diferentes, com tamanhos que variam de 50 até 90 metros quadrados. Os parâmetros considerados para esta análise são o Root Mean Square Delay Spread, o ganho médio do canal e a capacidade do canal. Para efeitos de comparação com a rede de potencia dos Estados Unidos, a banda de frequência utilizada foi de 1:705 até 30 MHz. A análise relatada mostra que o Root Mean Square Delay Spread e o ganho médio do canal não podem ser modelados como variáveis log-normal. Os resultados obtidos geram dúvidas em relação aos atuais encontrados na literatura, em que se afirma que tanto o Root Mean Square Delay Spread quanto o ganho médio do canal seguem uma distribuição log-normal. Foram medidos também a impedância de acesso e o ruído do canal de comunicação via rede elétrica. Além disso, os conceitos de cooperação para melhorar o desempenho dos sistemas de comunicação via rede elétrica foram analisados, mais especificamente na rede de baixa tensão Brasileira residencial. Para isso, foram analisados a performance dos protocolos de Amplify-and-Forward e Decode-and-Forward, em conjunto com as técnicas de combinação Equal-Gain Combining, Selection-Combining e Maximal-Ratio Combining. A análise sobre os dados medidos cobriram uma faixa de frequência de 1:705 a 100 MHz. Os dados medidos abordam quatro cenários para possíveis localizações do nó Relay. Os resultados obtidos mostram que o Amplify-and- Forward é de aplicabilidade limitada no contexto de comunicação via rede elétrica e o oposto é válido para o protocolo de Decode-and-Forward, principalmente se a probabilidade de erro de detecção de símbolos no nó Relay tende a zero. / This thesis outlines a statistical characterization of the Brazilian In-Home Low-Voltage Electric Power Grid as a communication medium. The discussions are based on estimated channels obtained in a measurement campaign carried out in four different apartments with sizes ranging from 50 up to 90 square meters. The parameters considered for this analysis are the Root Mean Square Delay Spread, the average channel gain, and the channel capacity. For the sake of comparison with the Electric Power Grid in United States, the frequency band ranging from 1:705 up to 30 MHz was set. The reported analysis shows that the Root Mean Square Delay Spread and the average channel gain cannot be modeled as log-normal variables, this cast doubt the current results found in the literature, in which is stated that both the Root Mean Square Delay Spread and the average channel gain follow a log-normal distribution. This was followed by the Power Line Communication access impedance and noise measurements in the In-Home Low-Voltage Electric Power Grid. Additionally, the suitability of cooperation concepts for improving the performance of Power Line Communication systems was analyzed, more specifically in the Brazilian In-Home Low-Voltage Electric Power Grid. For this purpose, the performance of the Amplify-and-Forward and Decode-and- Forward protocols, together with the Equal-Gain Combining, Selection Combining, and Maximal-Ratio Combining techniques were analyzed. The analysis was carried out on the measured data covering a frequency band from 1:705 up to 100 MHz. The measured data addresses four scenarios for possible relay node locations. The attained results show that the Amplify-and-Forward is of limited applicability in the Power Line Communication context and the opposite is valid to the Decode-and-Forward protocol, mainly if the error probability of detecting symbols at the relay node is zero.

Le docking moléculaire est une méthode permettant de prédire l'orientation d'une molécule donnée relativement à une autre lorsque celles-ci forment un complexe. Le premier algorithme de docking moléculaire a vu jour en 1990 afin de trouver de nouveaux candidats face à la protéase du VIH-1. Depuis, l'utilisation de protocoles de docking est devenue une pratique standard dans le domaine de la conception de nouveaux médicaments. Typiquement, un protocole de docking comporte plusieurs phases. Il requiert l'échantillonnage exhaustif du site d'interaction où les éléments impliqués sont considérées rigides. Des algorithmes de clustering sont utilisés afin de regrouper les candidats à l'appariement similaires. Des méthodes d'affinage sont appliquées pour prendre en compte la flexibilité au sein complexe moléculaire et afin d'éliminer de possibles artefacts de docking. Enfin, des algorithmes d'évaluation sont utilisés pour sélectionner les meilleurs candidats pour le docking. Cette thèse présente de nouveaux algorithmes de protocoles de docking qui facilitent la prédiction des structures de complexes protéinaires, une des cibles les plus importantes parmi les cibles visées par les méthodes de conception de médicaments. Une première contribution concerne l‘algorithme Docktrina qui permet de prédire les conformations de trimères protéinaires triangulaires. Celui-ci prend en entrée des prédictions de contacts paire-à-paire à partir d'hypothèse de corps rigides. Ensuite toutes les combinaisons possibles de paires de monomères sont évalués à l'aide d'un test de distance RMSD efficace. Cette méthode à la fois rapide et efficace améliore l'état de l'art sur les protéines trimères. Deuxièmement, nous présentons RigidRMSD une librairie C++ qui évalue en temps constant les distances RMSD entre conformations moléculaires correspondant à des transformations rigides. Cette librairie est en pratique utile lors du clustering de positions de docking, conduisant à des temps de calcul améliorés d'un facteur dix, comparé aux temps de calcul des algorithmes standards. Une troisième contribution concerne KSENIA, une fonction d'évaluation à base de connaissance pour l'étude des interactions protéine-protéine. Le problème de la reconstruction de fonction d'évaluation est alors formulé et résolu comme un problème d'optimisation convexe. Quatrièmement, CARBON, un nouvel algorithme pour l'affinage des candidats au docking basés sur des modèles corps-rigides est proposé. Le problème d'optimisation de corps-rigides est vu comme le calcul de trajectoires quasi-statiques de corps rigides influencés par la fonction énergie. CARBON fonctionne aussi bien avec un champ de force classique qu'avec une fonction d'évaluation à base de connaissance. CARBON est aussi utile pour l'affinage de complexes moléculaires qui comportent des clashes stériques modérés à importants. Finalement, une nouvelle méthode permet d'estimer les capacités de prédiction des fonctions d'évaluation. Celle-ci permet d‘évaluer de façon rigoureuse la performance de la fonction d'évaluation concernée sur des benchmarks de complexes moléculaires. La méthode manipule la distribution des scores attribués et non pas directement les scores de conformations particulières, ce qui la rend avantageuse au regard des critères standard basés sur le score le plus élevé. Les méthodes décrites au sein de la thèse sont testées et validées sur différents benchmarks protéines-protéines. Les algorithmes implémentés ont été utilisés avec succès pour la compétition CAPRI concernant la prédiction de complexes protéine-protéine. La méthodologie développée peut facilement être adaptée pour de la reconnaissance d'autres types d'interactions moléculaires impliquant par exemple des ligands, de l'ARN… Les implémentations en C++ des différents algorithmes présentés seront mises à disposition comme SAMSON Elements de la plateforme logicielle SAMSON sur http://www.samson-connect.net ou sur http://nano-d.inrialpes.fr/software. / Molecular docking is a method that predicts orientation of one molecule with respect to another one when forming a complex. The first computational method of molecular docking was applied to find new candidates against HIV-1 protease in 1990. Since then, using of docking pipelines has become a standard practice in drug discovery. Typically, a docking protocol comprises different phases. The exhaustive sampling of the binding site upon rigid-body approximation of the docking subunits is required. Clustering algorithms are used to group similar binding candidates. Refinement methods are applied to take into account flexibility of the molecular complex and to eliminate possible docking artefacts. Finally, scoring algorithms are employed to select the best binding candidates. The current thesis presents novel algorithms of docking protocols that facilitate structure prediction of protein complexes, which belong to one of the most important target classes in the structure-based drug design. First, DockTrina - a new algorithm to predict conformations of triangular protein trimers (i.e. trimers with pair-wise contacts between all three pairs of proteins) is presented. The method takes as input pair-wise contact predictions from a rigid-body docking program. It then scans and scores all possible combinations of pairs of monomers using a very fast root mean square deviation (RMSD) test. Being fast and efficient, DockTrina outperforms state-of-the-art computational methods dedicated to predict structure of protein oligomers on the collected benchmark of protein trimers. Second, RigidRMSD - a C++ library that in constant time computes RMSDs between molecular poses corresponding to rigid-body transformations is presented. The library is practically useful for clustering docking poses, resulting in ten times speed up compared to standard RMSD-based clustering algorithms. Third, KSENIA - a novel knowledge-based scoring function for protein-protein interactions is developed. The problem of scoring function reconstruction is formulated and solved as a convex optimization problem. As a result, KSENIA is a smooth function and, thus, is suitable for the gradient-base refinement of molecular structures. Remarkably, it is shown that native interfaces of protein complexes provide sufficient information to reconstruct a well-discriminative scoring function. Fourth, CARBON - a new algorithm for the rigid-body refinement of docking candidates is proposed. The rigid-body optimization problem is viewed as the calculation of quasi-static trajectories of rigid bodies influenced by the energy function. To circumvent the typical problem of incorrect stepsizes for rotation and translation movements of molecular complexes, the concept of controlled advancement is introduced. CARBON works well both in combination with a classical force-field and a knowledge-based scoring function. CARBON is also suitable for refinement of molecular complexes with moderate and large steric clashes between its subunits. Finally, a novel method to evaluate prediction capability of scoring functions is introduced. It allows to rigorously assess the performance of the scoring function of interest on benchmarks of molecular complexes. The method manipulates with the score distributions rather than with scores of particular conformations, which makes it advantageous compared to the standard hit-rate criteria. The methods described in the thesis are tested and validated on various protein-protein benchmarks. The implemented algorithms are successfully used in the CAPRI contest for structure prediction of protein-protein complexes. The developed methodology can be easily adapted to the recognition of other types of molecular interactions, involving ligands, polysaccharides, RNAs, etc. The C++ versions of the presented algorithms will be made available as SAMSON Elements for the SAMSON software platform at http://www.samson-connect.net or at http://nano-d.inrialpes.fr/software.

Le docking moléculaire est une méthode permettant de prédire l'orientation d'une molécule donnée relativement à une autre lorsque celles-ci forment un complexe. Le premier algorithme de docking moléculaire a vu jour en 1990 afin de trouver de nouveaux candidats face à la protéase du VIH-1. Depuis, l'utilisation de protocoles de docking est devenue une pratique standard dans le domaine de la conception de nouveaux médicaments. Typiquement, un protocole de docking comporte plusieurs phases. Il requiert l'échantillonnage exhaustif du site d'interaction où les éléments impliqués sont considérées rigides. Des algorithmes de clustering sont utilisés afin de regrouper les candidats à l'appariement similaires. Des méthodes d'affinage sont appliquées pour prendre en compte la flexibilité au sein complexe moléculaire et afin d'éliminer de possibles artefacts de docking. Enfin, des algorithmes d'évaluation sont utilisés pour sélectionner les meilleurs candidats pour le docking. Cette thèse présente de nouveaux algorithmes de protocoles de docking qui facilitent la prédiction des structures de complexes protéinaires, une des cibles les plus importantes parmi les cibles visées par les méthodes de conception de médicaments. Une première contribution concerne l‘algorithme Docktrina qui permet de prédire les conformations de trimères protéinaires triangulaires. Celui-ci prend en entrée des prédictions de contacts paire-à-paire à partir d'hypothèse de corps rigides. Ensuite toutes les combinaisons possibles de paires de monomères sont évalués à l'aide d'un test de distance RMSD efficace. Cette méthode à la fois rapide et efficace améliore l'état de l'art sur les protéines trimères. Deuxièmement, nous présentons RigidRMSD une librairie C++ qui évalue en temps constant les distances RMSD entre conformations moléculaires correspondant à des transformations rigides. Cette librairie est en pratique utile lors du clustering de positions de docking, conduisant à des temps de calcul améliorés d'un facteur dix, comparé aux temps de calcul des algorithmes standards. Une troisième contribution concerne KSENIA, une fonction d'évaluation à base de connaissance pour l'étude des interactions protéine-protéine. Le problème de la reconstruction de fonction d'évaluation est alors formulé et résolu comme un problème d'optimisation convexe. Quatrièmement, CARBON, un nouvel algorithme pour l'affinage des candidats au docking basés sur des modèles corps-rigides est proposé. Le problème d'optimisation de corps-rigides est vu comme le calcul de trajectoires quasi-statiques de corps rigides influencés par la fonction énergie. CARBON fonctionne aussi bien avec un champ de force classique qu'avec une fonction d'évaluation à base de connaissance. CARBON est aussi utile pour l'affinage de complexes moléculaires qui comportent des clashes stériques modérés à importants. Finalement, une nouvelle méthode permet d'estimer les capacités de prédiction des fonctions d'évaluation. Celle-ci permet d‘évaluer de façon rigoureuse la performance de la fonction d'évaluation concernée sur des benchmarks de complexes moléculaires. La méthode manipule la distribution des scores attribués et non pas directement les scores de conformations particulières, ce qui la rend avantageuse au regard des critères standard basés sur le score le plus élevé. Les méthodes décrites au sein de la thèse sont testées et validées sur différents benchmarks protéines-protéines. Les algorithmes implémentés ont été utilisés avec succès pour la compétition CAPRI concernant la prédiction de complexes protéine-protéine. La méthodologie développée peut facilement être adaptée pour de la reconnaissance d'autres types d'interactions moléculaires impliquant par exemple des ligands, de l'ARN… Les implémentations en C++ des différents algorithmes présentés seront mises à disposition comme SAMSON Elements de la plateforme logicielle SAMSON sur http://www.samson-connect.net ou sur http://nano-d.inrialpes.fr/software. / Molecular docking is a method that predicts orientation of one molecule with respect to another one when forming a complex. The first computational method of molecular docking was applied to find new candidates against HIV-1 protease in 1990. Since then, using of docking pipelines has become a standard practice in drug discovery. Typically, a docking protocol comprises different phases. The exhaustive sampling of the binding site upon rigid-body approximation of the docking subunits is required. Clustering algorithms are used to group similar binding candidates. Refinement methods are applied to take into account flexibility of the molecular complex and to eliminate possible docking artefacts. Finally, scoring algorithms are employed to select the best binding candidates. The current thesis presents novel algorithms of docking protocols that facilitate structure prediction of protein complexes, which belong to one of the most important target classes in the structure-based drug design. First, DockTrina - a new algorithm to predict conformations of triangular protein trimers (i.e. trimers with pair-wise contacts between all three pairs of proteins) is presented. The method takes as input pair-wise contact predictions from a rigid-body docking program. It then scans and scores all possible combinations of pairs of monomers using a very fast root mean square deviation (RMSD) test. Being fast and efficient, DockTrina outperforms state-of-the-art computational methods dedicated to predict structure of protein oligomers on the collected benchmark of protein trimers. Second, RigidRMSD - a C++ library that in constant time computes RMSDs between molecular poses corresponding to rigid-body transformations is presented. The library is practically useful for clustering docking poses, resulting in ten times speed up compared to standard RMSD-based clustering algorithms. Third, KSENIA - a novel knowledge-based scoring function for protein-protein interactions is developed. The problem of scoring function reconstruction is formulated and solved as a convex optimization problem. As a result, KSENIA is a smooth function and, thus, is suitable for the gradient-base refinement of molecular structures. Remarkably, it is shown that native interfaces of protein complexes provide sufficient information to reconstruct a well-discriminative scoring function. Fourth, CARBON - a new algorithm for the rigid-body refinement of docking candidates is proposed. The rigid-body optimization problem is viewed as the calculation of quasi-static trajectories of rigid bodies influenced by the energy function. To circumvent the typical problem of incorrect stepsizes for rotation and translation movements of molecular complexes, the concept of controlled advancement is introduced. CARBON works well both in combination with a classical force-field and a knowledge-based scoring function. CARBON is also suitable for refinement of molecular complexes with moderate and large steric clashes between its subunits. Finally, a novel method to evaluate prediction capability of scoring functions is introduced. It allows to rigorously assess the performance of the scoring function of interest on benchmarks of molecular complexes. The method manipulates with the score distributions rather than with scores of particular conformations, which makes it advantageous compared to the standard hit-rate criteria. The methods described in the thesis are tested and validated on various protein-protein benchmarks. The implemented algorithms are successfully used in the CAPRI contest for structure prediction of protein-protein complexes. The developed methodology can be easily adapted to the recognition of other types of molecular interactions, involving ligands, polysaccharides, RNAs, etc. The C++ versions of the presented algorithms will be made available as SAMSON Elements for the SAMSON software platform at http://www.samson-connect.net or at http://nano-d.inrialpes.fr/software.