Molecular simulations and binding free energy calculations for drug discovery

Early stage drug discovery would change dramatically if computational methods could accurately and quickly predict binding modes and affinities of compounds in advance of experiments. Simulation based approaches like classical molecular dynamics (MD) simulations have gained traction as a useful tool for early stage drug discovery, as MD provides a full atomistic and dynamic view of the biological system of interest. In principle, MD simulations can be a powerful tool for lead optimization as MD can provide knowledge of the ligand's binding mode, dynamics, and even binding affinity. In order to accurately compute binding affinities or predict ligand binding modes, simulations must run long enough to capture the relevant biological event or sufficiently sample all the physically relevant conformations. My research presents the development of new simulation approaches for accelerated sampling and demonstrates the use of non-equilibrium candidate Monte Carlo moves with MD simulations for predicting ligand binding modes to a pharmaceutically relevant target

Aeronautical engineering: A continuing bibliography with indexes (supplement 225)

This bibliography lists 429 reports, articles, and other documents introduced into the NASA scientific and technical information system in March, 1988

Aeronautical engineering: A continuing bibliography with indexes (supplement 272)

This bibliography lists 719 reports, articles, and other documents introduced into the NASA scientific and technical information system in November, 1991. Subject coverage includes: design, construction and testing of aircraft and aircraft engines; aircraft components, equipment, and systems; ground support systems; and theoretical and applied aspects of aerodynamics and general fluid dynamics

Algorithmes adaptatifs pour la simulation moléculaire

Les simulations moléculaires sont devenues un outil essentiel en biologie, chimie et physique. Malheureusement, elles restent très couteuses. Dans cette thèse, nous proposons des algorithmes qui accélèrent les simulations moléculaires en regroupant des particules en plusieurs objets rigides. Nous étudions d'abord plusieurs algorithmes de recherche de voisins dans le cas des grands objets rigides, et démontrons que les algorithmes hiérarchiques permettent d'obtenir des accélérations importantes. En conséquence, nous proposons une technique pour construire une représentation hiérarchique d'un graphe moléculaire arbitraire. Nous démontrons l'usage de cette technique pour la mécanique adaptative en angles de torsion, une méthode de simulation qui décrit les molécules comme des objets rigides articulés. Enfin, nous introduisons ARPS - Adaptively Restrained Particle Simulations ("Simulations de particules restreintes de façon adaptative") - une méthode mathématiquement fondée capable d'activer et de désactiver les degrés de liberté en position. Nous proposons deux stratégies d'adaptation, et illustrons les avantages de ARPS sur plusieurs exemples. En particulier, nous démontrons comment ARPS permet de choisir finement le compromis entre précision et vitesse, ainsi que d'obtenir rapidement des statistiques non biaisées sur les systèmes moléculaires.Molecular simulations have become an essential tool in biology, chemistry and physics. Unfortunately, they still remain computationally challenging. In this dissertation, we propose algorithms that accelerate molecular simulations by clustering particles into rigid bodies. We first study several neighbor-search algorithms for large rigid bodies, and show that hierarchy-based algorithms may provide significant speedups. Accordingly, we propose a technique to build a hierarchical representation of an arbitrary molecular graph. We show how this technique can be used in adaptive torsion-angle mechanics, a simulation method that describes molecules as articulated rigid bodies. Finally, we introduce ARPS - Adaptively Restrained Particle Simulations - a mathematically-grounded method able to switch positional degrees of freedom on and off. We propose two switching strategies, and illustrate the advantages of ARPS on various examples. In particular, we show how ARPS allow us to smoothly trade between precision and speed, and efficiently collect unbiased statistics on molecular systems.SAVOIE-SCD - Bib.électronique (730659901) / SudocGRENOBLE1/INP-Bib.électronique (384210012) / SudocGRENOBLE2/3-Bib.électronique (384219901) / SudocSudocFranceF

Studying protein-ligand interactions using a Monte Carlo procedure

[eng] Biomolecular simulations have been widely used in the study of protein-ligand interactions; comprehending the mechanisms involved in the prediction of binding affinities would have a significant repercussion in the pharmaceutical industry. Notwithstanding the intrinsic difficulty of sampling the phase space, hardware and methodological developments make computer simulations a promising candidate in the resolution of biophysically relevant problems. In this context, the objective of the thesis is the development of a protocol that permits studying protein-ligand interactions, in view to be applied in drug discovery pipelines. The author contributed to the rewriting PELE, our Monte Carlo sampling procedure, using good practices of software development. These involved testing, improving the readability, modularity, encapsulation, maintenance and version control, just to name a few. Importantly, the recoding resulted in a competitive cutting-edge software that is able to integrate new algorithms and platforms, such as new force fields or a graphical user interface, while being reliable and efficient. The rest of the thesis is built upon this development. At this point, we established a protocol of unbiased all-atom simulations using PELE, often combined with Markov (state) Models (MSM) to characterize the energy landscape exploration. In the thesis, we have shown that PELE is a suitable tool to map complex mechanisms in an accurate and efficient manner. For example, we successfully conducted studies of ligand migration in prolyl oligopeptidases and nuclear hormone receptors (NHRs). Using PELE, we could map the ligand migration and binding pathway in such complex systems in less than 48 hours. On the other hand, with this technique we often run batches of 100s of simulations to reduce the wall-clock time. MSM is a useful technique to join these independent simulations in a unique statistical model, as individual trajectories only need to characterize the energy landscape locally, and the global characterization can be extracted from the model. We successfully applied the combination of these two methodologies to quantify binding mechanisms and estimate the binding free energy in systems involving NHRs and tyorsinases. However, this technique represents a significant computational effort. To reduce the computational load, we developed a new methodology to overcome the sampling limitations caused by the ruggedness of the energy landscape. In particular, we used a procedure of iterative simulations with adaptive spawning points based on reinforcement learning ideas. This permits sampling binding mechanisms at a fraction of the cost, and represents a speedup of an order of magnitude in complex systems. Importantly, we show in a proof-of-concept that it can be used to estimate absolute binding free energies. Overall, we hope that the methodologies presented herein help streamline the drug design process.[spa] Las simulaciones biomoleculares se han usado ampliamente en el estudio de interacciones proteína-ligando. Comprender los mecanismos involucrados en la predicción de afinidades de unión tiene una gran repercusión en la industria farmacéutica. A pesar de las dificultades intrínsecas en el muestreo del espacio de fases, mejoras de hardware y metodológicas hacen de las simulaciones por ordenador un candidato prometedor en la resolución de problemas biofísicos con alta relevancia. En este contexto, el objetivo de la tesis es el desarrollo de un protocolo que introduce un estudio más eficiente de las interacciones proteína-ligando, con vistas a diseminar PELE, un procedimiento de muestreo de Monte Carlo, en el diseño de fármacos. Nuestro principal foco ha sido sobrepasar las limitaciones de muestreo causadas por la rugosidad del paisaje de energías, aplicando nuestro protocolo para hacer analsis detallados a nivel atomístico en receptores nucleares de hormonas, receptores acoplados a proteínas G, tirosinasas y prolil oligopeptidasas, en colaboración con una compañía farmacéutica y de varios laboratorios experimentales. Con todo ello, esperamos que las metodologías presentadas en esta tesis ayuden a mejorar el diseño de fármacos

Aeronautical engineering: A continuing bibliography with indexes (supplement 255)

This bibliography lists 529 reports, articles, and other documents introduced into the NASA scientific and technical information system in June 1990. Subject coverage includes: design, construction and testing of aircraft and aircraft engines; aircraft components, equipment and systems; ground support systems; and theoretical and applied aspects of aerodynamics and general fluid dynamics

A cumulative index to a continuing bibliography on aeronautical engineering

This bibliography is a cumulative index to the abstracts contained in NASA-SP-7037(184) through NASA-SP-7037(195) of Aeronautical Engineering: A Continuing Bibliography. NASA SP-7037 and its supplements have been compiled through the cooperative efforts of the American Institute of Aeronautics and Astronautics (AIAA) and the National Aeronautics and Space Administration (NASA). This cumulative index includes subject, personal author, corporate source, foreign technology, contract, report number, and accession number indexes

Aeronautical Engineering: A cumulative index to the 1984 issues of the continuing bibliography

This bibliography is a cumulative index to the abstracts contained in NASA SP-7037(171) through NASA SP-7037(182) of Aeronautical Engineering: A Continuing Bibliography. NASA SP-7037 and its supplements have been compiled through the cooperative efforts of the American Institute of Aeronautics and Astronautics (AIAA) and the National Aeronautics and Space Administration (NASA). This cumulative index includes subject, personal author, corporate source, foreign technology, contract, report number, and accession number indexes

Aeronautical engineering: A cumulative index to a continuing bibliography

This bibliography is a cumulative index to the abstracts contained in NASA SP-7037(210) through NASA SP-7037(221) of Aeronautical Engineering: A Continuing Bibliography. NASA SP-7037 and its supplements have been compiled through the cooperative efforts of the American Institute of Aeronautics and Astronautics (AIAA) and the National Aeronautics and Space Administration (NASA). This cumulative index includes subject, personal author, corporate source, foreign technology, contract number, report number, and accession number indexes