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This thesis describes the development a new swarm-enhanced sampling methodology and its application to the exploration of biologically relevant molecules. First, the development of a new multi-dimensional swarm-enhanced sampling molecular dynamics (msesMD) approach is detailed. Relative to the original swarm-enhanced sampling molecular dynamics (sesMD) methodology, the msesMD method demonstrates improved parameter transferability, resulting in more extensive sampling when scaling to larger systems such as alanine heptapeptide. The implementation and optimisation of the swarm-enhanced sampling algorithms in the AMBER software suite are also described. Through the use of the newer pmemd molecular dynamics (MD) engine and asynchronous MPI routines, speedups of up to three times the original sesMD implementation were achieved. The msesMD method is then applied to the investigation of carbohydrates, first looking at rare conformational changes in Lewis oligosaccharides. Validating against multi-microsecond unbiased MD trajectories and other enhanced sampling methods, the msesMD simulations identified rare conformational changes leading to the adoption of non-canonical unstacked core trisaccharide structures. Next, the use of msesMD as a tool to probe pyranose ring pucker events is explored. Evaluating against four benchmark monosaccharide systems, msesMD simulations accurately recover puckering details not easily obtained via multi-microsecond unbiased MD. This was followed by an exploration of the impact of ring substituents on conformation in glycosaminoglycan monosaccharides: through msesMD simulations, the influence of specific sulfation patterns were explored, finding that in some cases, such as 4-O-sulfation in N-acetyl-galactosamine, large changes in the relative stability of ring conformers can arise. Finally, the msesMD method was coupled with a thermodynamic integration scheme and used to evaluate solvation free energies for small molecule systems. Comparing against independent trajectory TI simulations, it was found that although the correct solvation free energies were obtained, the msesMD based method did not offer an advantage over unbiased MD for these small molecule systems. However, interesting discrepancies in free energy estimates arising from the use of hydrogen mass repartitioning were found.

Orientador: Alex Antonelli / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Física Gleb Wataghin / Made available in DSpace on 2018-08-20T22:54:46Z (GMT). No. of bitstreams: 1 Brito_BraulioGabrielAlencar_D.pdf: 3210920 bytes, checksum: 1140e372f96bf86f5f06d96119eeb8e7 (MD5) Previous issue date: 2012 / Resumo: Neste trabalho apresentaremos a extensão dos métodos adiabatic switching (AS), reversible scaling (RS) e integração dinâmica de Clausius-Clapeyron (d-CCI) para o formalismo de integral de tragetória. Desenvolvemos programas de Monte Carlo de integrais de trajetória (PIMC) para implementar esses métodos a fim de incluir efeitos quânticos nos cálculos das energias livres e na determinação das curvas de coexistência de fase de sistemas a baixa temperatura. Aplicamos as aproximações primitivas e Li-broughton para a ação para escrever as matrizes densidade de alta temperatura dos sistemas estudados. Calculamos a curva de fusão do neônio utilizando o método de integração dinâmica de Clausius-Clapeyron quantico (q-dCCI) e comparamos nossos resultados com resultados encontrados na literatura. Determinamos a curva de coexistência diamante-grafite utilizando o potencial AIREBO e os métodos AS, RS e q-dCCI. Estudamos os efeitos da pressão sobre algumas propriedades termodinâmicas do grafite e do grafeno e a diversas temperaturas aplicando método PIMC juntamente dos métodos AS e RS / Abstract: In this work we present the extension of the methods adiabatic switching (AS), reversible scaling (RS), dynamical Clausius-Clapeyron integration (d-CCI) within the path integral formalism. We developed Path Integral Monte Carlo computer codes to implement these methods in order to include quantum effects in the calculation of free energies and in the determination of the phase coexistence curves of systems at low temperature. We applied the primitive and Li-Broughton approximations to the action to write the high temperature density matrices of the systems we studied. We calculated the melting curve of the neon using the quantum dynamical Clausius-Clapeyron (q-dCCI) and compare our results with results found at the literature. We determined the diamond-graphite coexistence curve using the AIREBO inter-atomic potential and the AS, RS e q-dCCI methods. We studied the pressure effects on some thermodynamic properties of the graphite and graphene at several temperatures using the method PIMC together with the AS and RS methods / Doutorado / Física / Doutor em Ciências

[pt] O coeficiente de partição octanol-água do composto 1,2-dipalmitoilsn-glicero-3-fosfatidilcolina (DPPC) foi investigado utilizando os métodos de integração termodinâmica e amostragem guarda-chuva através de simulações de dinâmica molecular atomística. Os campos de força AMBER/GAFF e CHARMM/CGenFF foram usados com seis modelos de água (SPC, TIP3P, TIP4P, TIP5P, OPC3 e OPC4) amplamente utilizados em simulações de dinâmica molecular. Dentre os modelos utilizados, o modelo de água OPC4 com os dois campos de força em estudo forneceu a melhor concordância com o coeficiente de partição experimental octanol-água do DPPC. No entanto, ainda existe muito espaço para melhorias nos modelos de água que estimam a tensão superficial de forma apropriada. Usando o modelo de água OPC4, a energia livre de Gibbs de transferência do DPPC do octanol para a fase aquosa foi calculada em 19,8(mais ou menos)0,3 e 20,2(mais ou menos)0,3 kcal mol-1 , estimando um coeficiente de partição octanol-água de 14,5(mais ou menos)0,4 e 14,8(mais ou menos)0,3 para os campos de força AMBER/GAFF e CHARMM/CGenFF, respectivamente. A amostragem guarda-chuva apresentou problemas de arrastes de moléculas de uma fase para outra, gerando artefatos e consequentemente subestimando os valores de energia livre e de coeficiente de partição octanol-água. Este estudo mostra a importância do desenvolvimento de novos modelos de água que reproduzam com precisão todas as suas características experimentais. A conciliação entre medições experimentais e cálculos teóricos do coeficiente de partição de moléculas anfifílicas poderia ser resolvida através do ajuste dos parâmetros do modelo de água. Este estudo possui grande importância na simulação de propriedades moleculares de importância em muitas áreas de aplicações científicas e industriais, tais como biofísica, surfactante, coloides, membranas, medicina, nanotecnologia, e indústrias alimentícias e farmacêuticas. / [en] The octanol-water partition coefficient of the compost 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) molecule wasinvestigated using the methods of thermodynamic integration and umbrellasampling through atomistic molecular dynamics simulations. TheAMBER/GAFF and CHARMM/CGenFF force fields were used with sixwater models (SPC, TIP3P, TIP4P, TIP5P, OPC3, and OPC4) widely usedin molecular dynamics simulations. Among the models used, the OPC4water model with the two force fields provided the best agreement with theexperimental octanol-water partition coefficient of the DPPC. However,there is still much room for improvement in water models that correctlyestimate the surface tension. Using the OPC4 water model, the Gibbs freeenergy of transferring DPPC from octanol to the aqueous phase wascalculated to be 19.8(plus minus)0.3 and 20.2(plus minus)0.3 kcal mol-1, estimating an octanolwater partition coefficient of 14.5(plus minus)0.4 and 14.8(plus minus)0.3 for the AMBER/GAFFand CHARMM/CGenFF force fields, respectively. Umbrella samplingpresented issues of molecules being dragged between the two phases,generating artifacts, and consequently underestimating the values of freeenergy and octanol-water partition coefficient. This study shows theimportance of developing new models of water that accurately reproduceall its experimental characteristics. The reconciliation betweenexperimental measurements and theoretical calculations of partitioncoefficients of amphiphilic molecules. This study may have greatimportance in many areas of scientific and industrial applications, such asbiophysics, surfactant, colloids, membranes, medicine, nanotechnology,and food and pharmaceutical industries.

Abstract Spontaneous changes in protein systems, such as the binding of a ligand to an enzyme or receptor, are characterized by a decrease of free energy. Despite the recent developments in computing power and methodology, it remains challenging to accurately estimate free energy changes. Major issues are still concerned with the accuracy of the underlying model to describe the protein system and how well the calculation in fact emulates the behaviour of the system. This thesis is largely concerned with the quality of current free energy calculation methods as applied to protein-ligand systems. Several methodologies were employed to calculate Gibbs standard free energies of binding for a collection of protein-ligand complexes, for which experimental affinities were available. Calculations were performed using system description with different levels of accuracy and included a continuum approach, which considers the protein and the ligand at the atomic level but includes solvent as a polarizable continuum, and an all-atom approach that relies on molecular dynamics simulations. In most such applications, the effects of ionic strength are neglected. However, the severity of this approximation, in particular when calculating free energies of charged ligands, is not very clear. The issue of incorporating ionic strength in free energy calculations by means of explicit ions was investigated in greater detail and considerable attention was given to the affinities of charged peptides in the presence of explicit counter-ions. A second common approximation is concerned with the description of ligands that exhibit multiple protonation states. Because most of current methods do not model changes in the acid dissociation constants of titrating groups upon binding, protonation equilibria of such ligands are not taken into account in free energy calculations. The implications of this approximation when predicting affinities were analysed. Finally, when calculating free energies of binding, a correct description of the interactions between the protein and the ligand is of fundamental importance. However, active sites of enzymes, where strained conformations may hold a functional role, are not always accurately modelled by molecular mechanics force fields. The case of a strained planar proline in the active site of triosephosphate isomerase was investigated using an hybrid quantum mechanics/molecular mechanics method, which implies a higher level of accuracy.

La résistance aux antibiotiques est une menace sérieuse pour la santé publique. En effet, si on ne change pas rapidement notre consommation excessive d'antibiotiques, la situation actuelle va se dégrader jusqu'à basculer dans une ère dite "post-antibiotique", dans laquelle plus aucun antibiotique ne sera efficace contre les infections microbiennes. Bien que ce phénomène de résistance apparaît naturellement, l'utilisation abusive d'antibiotiques accélère le processus. De plus, la présence de pathogènes multi-résistants neutralise l'effet des traitements existants et dans le cas de chirurgies courantes (césariennes, transplantations d'organe...), la situation peut rapidement s'aggraver voire devenir mortelle. C'est pourquoi des directives, émanant des autorités sanitaires, doivent être mises en place afin de contrôler l'utilisation des médicaments, et ce, à tous les niveaux de la société, des individus au secteur agricole en passant par les professionnels de santé et les industries pharmaceutiques. Le monde de la recherche scientifique, quant à elle, doit trouver des nouvelles stratégies pour enrayer la propagation de la résistance. Dans ce contexte, cette thèse a pour objectif le développement d'une méthode de prédiction, par calculs d'énergie libre, des mutations de β-lactamases favorables à l'hydrolyse des β-lactames. Ces travaux méthodologiques ont donc conduit au développement : (1) de nouveaux paramètres pour les enzymes à zinc, implémentés dans le champ de force OPLS-AA et validés par des simulations de dynamique moléculaire sur un panel de métalloenzymes représentatives, (2) d'un protocole de paramétrisation de ligands covalents pour étudier le comportement de certains β-lactames dans CMY-136, une nouvelle β-lactamase caractérisée au laboratoire, et (3) d'un protocole de calcul d'énergie libre évalué au moyen de compétitions internationales de prédiction. Ce dernier a ensuite été utilisé pour tenter d'expliquer pourquoi la carbamylation de la sérine catalytique n'a pas lieu dans certaines oxacillinases. Au travers de ces travaux, nous avons pu améliorer significativement notre approche computationnelle et désormais tout est en place pour une exploration exhaustive des mutations possibles dans les β-lactamases. / Antibiotic resistance is a global concern threatening worldwide health. Indeed, if we don't change our overconsumption of antibiotics, the current situation could worsen until a "post-antibiotic" era in which existing treatment would be ineffective against microbial infections. Despite the natural occurrence of antibiotic resistance, the misuse of antibiotics is speeding up the process. Furthermore, presence of multi-resistant pathogens negates the effect of modern treatments and usual surgeries (caesarean sections, organ transplantations...) might be riskier in the future, or even lethal. That's why, common guidelines have to be edicted by health authorities in order to control antibiotic use at every level of society, from individuals to healthcare industry including health professionals and agriculture sector. As for scientific research, new strategies have to be considered in order to limit the spread of antibiotic resistance. In that context, the presented thesis aimed at developing a protocol to predict, by free energy calculations, β-lactamase mutations which could promote the hydolysis of β-lactams antibiotics. In order to achieve that, we developed several methodological approaches including: (1) new parameters for zinc enzymes implemented in OPLS-AA force field and thereafter validated using molecular dynamics simulations of representative zinc-containing metalloenzymes, (2) a protocol to parameterize covalent ligands in order to analyze the dynamical behavior of some β-lactams in CMY-136, a novel β-lactamase recently characterized in our laboratory, and (3) a pmx-based free energy protocol. The latter was also assessed through several international blinded prediction challenges, and finally used to find out why carbamylation of the catalytic serine is not observed in certain OXA enzymes. Throughout this work, we made significant improvements in our protocol, and now everything is in place for an exhaustive prediction of possible mutations in β-lactamases.

Ce travail présente quelques résultats sur les systèmes de particules en interaction pour l'interprétation probabiliste des équations aux dérivées partielles, avec des applications à des questions de dynamique moléculaire et de chimie quantique. On présente notamment une méthode particulaire permettant d'analyser le processus de la force biaisante adaptative, utilisé en dynamique moléculaire pour le calcul de différences d'énergies libres. On étudie également la sensibilité de dynamiques stochastiques par rapport à un paramètre, en vue du calcul des forces dans l'approximation de Born-Oppenheimer pour rechercher l'état quantique fondamental de molécules. Enfin, on présente un schéma numérique basé sur un système de particules pour résoudre des lois de conservation scalaires, avec un terme de diffusion anormale se traduisant par une dynamique de sauts sur les particules / This work presents some results on stochastically interacting particle systems and probabilistic interpretations of partial differential equations with applications to molecular dynamics and quantum chemistry. We present a particle method allowing to analyze the adaptive biasing force process, used in molecular dynamics for the computation of free energy differences. We also study the sensitivity of stochastic dynamics with respect to some parameter, aiming at the computation of forces in the Born-Oppenheimer approximation for determining the fundamental quantum state of molecules. Finally, we present a numerical scheme based on a particle system for the resolution of scalar conservation laws with an anomalous diffusion term, corresponding to a jump dynamics on the particles