No / Two force fields, the GROMOS53A5/53A6 (united atom) and the AMBER95 (all atom) parameter sets, coupled with partial atomic charges derived from quantum mechanical calculations were evaluated for their ability to reproduce the known crystalline forms of the polyols mannitol and sorbitol. The force fields were evaluated using molecular dynamics simulations at 10 K (which is akin to potential energy minimization) with the simulation cell lengths and angles free to evolve. Both force fields performed relatively poorly, not being able to simultaneously reproduce all of the crystal structures within a 5% deviation level. The parameter sets were then systematically optimized using sensitivity analysis, and a revised AMBER95 set was found to reproduce the crystal structures with less than 5% deviation from experiment. The stability of the various crystalline forms for each of the parameter sets (original and revised) was then assessed in extended MD simulations at 298 K and 1 bar covering 1 ns simulation time. The AMBER95 parameter sets (original and revised) were found to be effective in reproducing the crystal structures in these more stringent tests. Remarkably, the performance of the original AMBER95 parameter set was found to be slightly better than that of the revised set in these simulations at 298 K. The results of this study suggest that, whenever feasible, one should include molecular simulations at elevated temperatures when optimizing parameters.

no / The two known crystalline phases of resorcinol and their phase transitions are of considerable interest. The crystals exhibit pyro- and piezo-electricity and, remarkably, the higher temperature phase is the denser phase. Furthermore, crystals of the phase, by virtue of having a polar axis, have played a crucial role in investigating fundamental issues of crystal growth. We report an optimized force field for the molecular simulation of crystalline phases of resorcinol. The hydroxyl groups of the resorcinol molecule have a torsional degree of freedom and the molecule adopts a different conformation in each of the two phases of resorcinol. The torsional barrier, therefore, was considered to be critical and has been characterized using ab initio methods. Although the atomic partial charges showed some dependence on the molecular conformation, a single set of partial charges was found to be sufficient in describing the electrostatic potential for all conformations. The parameters for the van der Waals interactions were optimized using sensitivity analysis. The proposed force field reproduces not only the static structures but also the stability of the crystalline phases in extended molecular dynamics simulations.

Public strategy is a widely discussed concept, which especially in an election year is often proposed as a means to improving administrative operations. Over the last 40 years, there has been an explosion in the number of books written about strategy. The academic community and the public have been bombarded with countless, theories, models, frameworks, approaches and schools about strategy. We have seen the rise and fall of strategic planning and the movement from strategic management to strategic leadership to strategic thinking. Despite the plethora of solutions, some to problems yet to be discovered, both the private and public sectors continue to see strategies fail. How can it be that strategies still fail when we have so many people available who know how to make them succeed? This study uses an information technology project in the Department of Defense as a field study to determine why the strategies for that project succeeded or why they failed. The research draws on concepts from the Delphi Technique, Force Field Theory, classic strategy literature and public administration to identify and map various levels of forces extant in the implementation environment for those strategies. / Ph. D.

"The accurate, fast and low cost computational tools are indispensable for studying the structure and dynamics of biological macromolecules in aqueous solution. The goal of this thesis is development and validation of continuum Fuzzy-Border (FB) solvation model to work with the Polarizable Simulations Second-order Interaction Model (POSSIM) force field for proteins developed by Professor G A Kaminski. The implicit FB model has advantages over the popularly used Poisson Boltzmann (PB) solvation model. The FB continuum model attenuates the noise and convergence issues commonly present in numerical treatments of the PB model by employing fixed position cubic grid to compute interactions. It also uses either second or first-order approximation for the solvent polarization which is similar to the second-order explicit polarization applied in POSSIM force field. The FB model was first developed and parameterized with nonpolarizable OPLS-AA force field for small molecules which are not only important in themselves but also building blocks of proteins and peptide side chains. The hydration parameters are fitted to reproduce the experimental or quantum mechanical hydration energies of the molecules with the overall average unsigned error of ca. 0.076kcal/mol. It was further validated by computing the absolute pKa values of 11 substituted phenols with the average unsigned error of 0.41pH units in comparison with the quantum mechanical error of 0.38pH units for this set of molecules. There was a good transferability of hydration parameters and the results were produced only with fitting of the specific atoms to the hydration energy and pKa targets. This clearly demonstrates the numerical and physical basis of the model is good enough and with proper fitting can reproduce the acidity constants for other systems as well. After the successful development of FB model with the fixed charges OPLS-AA force field, it was expanded to permit simulations with Polarizable Simulations Second-order Interaction Model (POSSIM) force field. The hydration parameters of the small molecules representing analogues of protein side chains were fitted to their solvation energies at 298.15K with an average error of ca.0.136kcal/mol. Second, the resulting parameters were used to reproduce the pKa values of the reference systems and the carboxylic (Asp7, Glu10, Glu19, Asp27 and Glu43) and basic residues (Lys13, Lys29, Lys34, His52 and Lys55) of the turkey ovomucoid third domain (OMTKY3) protein. The overall average unsigned error in the pKa values of the acid residues was found to be 0.37pH units and the basic residues was 0.38 pH units compared to 0.58pH units and 0.72 pH units calculated previously using polarizable force field (PFF) and Poisson Boltzmann formalism (PBF) continuum solvation model. These results are produced with fitting of specific atoms of the reference systems and carboxylic and basic residues of the OMTKY3 protein. Since FB model has produced improved pKa shifts of carboxylic residues and basic protein residues in OMTKY3 protein compared to PBF/PFF, it suggests the methodology of first-order FB continuum solvation model works well in such calculations. In this study the importance of explicit treatment of the electrostatic polarization in calculating pKa of both acid and basic protein residues is also emphasized. Moreover, the presented results demonstrate not only the consistently good degree of accuracy of protein pKa calculations with the second-degree POSSIM approximation of the polarizable calculations and the first-order approximation used in the Fuzzy-Border model for the continuum solvation energy, but also a high degree of transferability of both the POSSIM and continuum solvent Fuzzy Border parameters. Therefore, the FB model of solvation combined with the POSSIM force field can be successfully applied to study the protein and protein-ligand systems in water. "

Master of Science / Department of Chemistry / Paul E. Smith / The increasing importance of ion-water interactions in the field of chemistry and biology is leading us to examine the structure and dynamic properties of molecules of interest, based on the application of computer-aided models using molecular dynamics simulations. To enable this type of MD study, a molecular mechanics force field was developed and implemented. Kirkwood-Buff theory has been proved to be a powerful tool to provide a link between molecular quantities and corresponding thermodynamic properties. Parameters are the vital basis of a force field. KB integrals and densities were used to guide the development of parameters which could describe the activity of aqueous solutions of interest accurately. In this work, a Kirkwood-Buff Force Field (KBFF) for MD simulation of ammonium sulfate, sodium sulfate, sodium perchlorate and sodium nitrate are presented. Comparison between the KBFF models and existing force fields for ammonium sulfate was also performed and proved that KBFF is very promising. Not only were the experimentally observed KB integrals and density reproduced by KBFF, but other properties like self diffusion constant and relative permittivity are also well produced.

The use of computational simulation to study the dynamics and interactions of macromolecules has become an important tool in the field of biochemistry. A common method to perform these simulations is to use all-atom explicit-solvent molecular dynamics (MD). However, due to the limitations in computational power currently available, this method is not practical for simulating large-scale biomolecular systems on long timescales. An alternative is to perform implicit-solvent Brownian dynamics (BD) simulations using a coarse grained (CG) model that allows for increased computational efficiency. However, if simulations using the CG model are not realistic, then the gain in computational efficiency from using a CG model is not worthwhile. This thesis describes the derivation of a set of bonded and nonbonded CG potential functions for use in implicit-solvent BD simulations of proteins derived from all-atom explicit-solvent MD simulations of amino acids. To determine which force field and water model to use in the MD simulations, Chapter II describes 1 Μs all-atom explicit-solvent MD simulations of glycine, asparagine, phenylalanine, and valine solutions at 50, 100, 200 and 300 mg/ml concentrations performed using eight different force field and water model combinations. To evaluate the accuracy of the force fields at high solute concentrations, the density, viscosity, and dielectric increments of the four amino acids were calculated from the simulations and compared to experimental results. Additionally, the change in the strength of hydrophobic and electrostatic interactions with increasing solute concentration was calculated for each force field and water model combination. As a result of this study, the Amber ff99SB-ILDN force field and TIP4P-Ew explicit-solvent water model were chosen for all subsequent MD simulations. Chapter III describes the derivation of CG bonded potential functions from 1 Μs all-atom explicit-solvent MD simulations of each of the twenty amino acids, including a separate simulation for protonated histidine. The angle and dihedral probability distributions sampled during the MD simulations were used to optimize the bonded potential functions using the iterative Boltzmann inversion (IBI) method. Chapter IV describes the derivation of CG nonbonded potential functions from 1 Μs all-atom explicit-solvent MD simulations of every possible pairing of the amino acids (231 different systems). The radial distribution functions calculated from these MD simulations were used to optimize a set of nonbonded CG potential functions using the IBI method. The optimized set of bonded and nonbonded potential functions, which is termed COFFDROP (COarse-grained Force Field for Dynamic Representation Of Proteins), quantitatively reproduced all of the calculated MD distributions. To determine if COFFDROP would be useful for simulations of bimolecular systems, Chapter V describes the testing of the transferability of the force field. First, COFFDROP was used to simulate concentrated amino acid solutions. The clustering of the solutes in these simulations was directly compared with results from corresponding all-atom explicit-solvent MD simulations and found to be in excellent agreement. Next, BD simulations of 9.2 mM solutions of the small protein villin headpiece were performed. The proteins aggregated during these simulations, which is in agreement with results from MD simulation but in disagreement with experiment. After scaling the strength of COFFDROP's nonbonded potential functions by a factor of 0.8 and rerunning the BD simulations, the amount of aggregation was comparable to experimental observations. Based on these results, COFFDROP is likely to be applicable in CG BD simulations of large, highly concentrated, biomolecular systems.

Accurate prediction of protein-ligand binding affinity is essential to computational drug discovery. Current approaches are limited by the accuracy of the underlying potential energy model that describes atomic interactions. A more rigorous physical model is critical for evaluating molecular interactions to chemical accuracy. The objective of this thesis research is to develop a polarizable force field with an accurate representation of electrostatic interactions, and apply this model to protein-ligand recognition and to ultimately solve practical problems in computer aided drug discovery. By calculating the hydration free energies of a series of organic small molecules, an optimal protocol is established to develop the electrostatic parameters from quantum mechanics calculations. Next, the systematical development and parameterization procedure of AMOEBA protein force field is presented. The derived force field has gone through extensive validations in both gas phase and condensed phase. The last part of the thesis involves the application of AMOEBA to study protein-ligand interactions. The binding free energies of benzamidine analogs to trypsin using molecular dynamics alchemical perturbation are calculated with encouraging accuracy. AMOEBA is also used to study the thermodynamic effect of constraining and hydrophobicity on binding energetics between phosphotyrosine(pY)-containing tripeptides and the SH2 domain of growth receptor binding protein 2 (Grb2). The underlying mechanism of an "entropic paradox" associated with ligand preorganization is explored. / text

Le cadre général de cette thèse est une étude théorique par chimie quantique et dynamique moléculaire de la relation entre la structure et la fluorescence des protéines fluorescentes, en particulier, de la protéine fluorescente jaune (YFP). Dans cette protéine l'énergie de transition électronique est réduite par rapport à celle de la protéine fluorescente verte (GFP) en raison de l'empilement π entre le chromophore (la partie qui peut absorber et émetre de la lumiere visible au cœur de la protéine) et une tyrosine. Cet effet constitue la base de son utilité au laboratoire (transfert d'énergie par résonance «FRET» avec d’autres protéines). Ce travail comporte deux parties. D’une part, nous avons cherché à déterminer si un champ de force classique (ff99 de la suite AMBER) permet de représenter l’effet de π -stacking sur la dynamique à l’état excité. Pour cela nous avons effectué une série de calculs CASPT2 sur une grille de points. La conclusion est que la différence entre les surfaces d’énergie d’interaction résultant du champ de force et des calculs de chimie quantique CASPT2 ne semblent pas déterminante pour les propriétés de fluorescences.D’autre part, nous avons utilisé un modèle développé dans le groupe ThéoSim pour décrire le déclin à partir d’une série de dynamique (300ns) utilisant un champ de force classique. Cette méthode conduit à déterminer des paramètres en principe transférables d’une protéine fluorescente à une autre. Nous avons comparé la GFP et l’YFP. Cette approche ouvre la voie à une méthode rapide pour des propriétés de fluorescences pour de nouvelles protéines fluorescentes. Une prochaine étape serait d'améliorée la description du déclin radiatif utilisée dans ce modèle. / The general framework of this PhD is a theoretical study by quantum chemistry and molecular dynamics of the relationship between the structure and the fluorescence properties of fluorescent proteins, particulary, of the yellow fluorescent protein (YFP). In this protein, the electron transition energy is reduced with respect to that of the green fluorescent protein (GFP) as a result of a π stacking between the chromophore (the part that absorbs and emits visible light in the protein) and a tyrosine . This effect is the basis of the usefulness of YFP in the laboratory (resonance energy transfer "FRET" with other proteins).This study has two parts. First, we have tried to determine if a classical force field (ff99 of the AMBER suite) can represent the effect of π stacking on the dynamics in the excited state. For this goal, we performed a series of CASPT2 calculations on a grid of points. The conclusion is that the difference between the interaction energy surfaces resulting from the force field and the CASPT2 calculations does not seem decisive for the fluorescence properties. Second, we used a model developed in the ThéoSim group to extract the fluorescence decay time from a series of dynamics (300ns) using a classical force field. This method leads to the determination of parameters in principle transferable across fluorescent protein. We compared GFP and YFP. This approach opens the way to a fast method for determining fluorescence properties for new fluorescent proteins. A next step would be to improve the description of radiative decay used in this model.

Yes / A reliable description of ion pair interactions for biological systems, particularly those involving polyatomic ions such as carboxylate and divalent ions such as Ca2+, using biomolecular force-fields is essential for making useful predictions for a range of protein functions. In particular, the interaction of divalent ions with the double carboxylate group present in γ-carboxyglutamic acid (Gla), relevant to the function of many proteins, is relatively understudied using biomolecular force-fields. Using force-field based metadynamics simulations to predict the free energy of binding between Ca2+ and the carboxylate group in liquid water, we show that a widely-used biomolecular force-field, CHARMM22*, substantially over-estimates the binding strength between Ca2+ and the side-chains of both glutamic acid (Glu) and Gla, compared with experimental data obtained for the analogous systems of aqueous calcium–acetate and calcium–malonate. To correct for this, we propose and test a range of modifications to the σ value of the heteroatomic Lennard–Jones interaction between Ca2+ and the oxygen of the carboxylate group. Our revised parameter set can recover the same three association modes of this aqueous ion pair as the standard parameter set, and yields free energies of binding for the carboxylate–Ca2+ interaction in good agreement with experimental data. The revised parameter set recovers other structural properties of the ion pair in agreement with the standard CHARMM22* parameter set.

Molecular dynamics (MD) simulation studies were considered in this study in the fields of phosphonium based ionic liquids (PBILs) and heterogeneous (solid/liquid) zeolite systems. A new generation of ionic liquids (ILs) called phase-separable ionic liquids (PSILs) are able to dissolve cellulose and lignin, a necessary step, for conversion of biomass to fuels and chemicals with co-solvents and are immiscible with water or saline solutions. Molecular simulations on these systems will provide insights of phase behavior and dissolution phenomenon. The knowledge of interfacial phase behavior of ionic liquids/solvent systems is critical for materials discovery for designing efficient dissolution processes. Transition zone from miscible to immiscible behavior was observed for alkyl chain lengths varying from 6 to 8. Emulsion phase was observed for [P8888]+ ion. Result from molecular dynamics (MD) simulations shows excellent agreement with experimental data for both chloride and acetate anions. These contributions will be helpful in modeling PBILs system for cellulose dissolution, liquid-liquid extraction and biomass studies. Another important aspect in biofuel conversion is glucose isomerization step using zeolites. Zeolites are crystalline solids that have wide applications in industrial areas for its hydrocarbon conversion, adsorption of molecules. In this study, we report MD simulation studies on glucose solution diffusion into zeolite structure as a function of temperature and pressure. Development of united-atom force field for PBILs, for phosphonium cation with anions of chloride and acetate, is considered in this study. Force field parameterization was considered for these ionic liquids with a variation of alkyl chain length in phosphonium ion with chloride and acetate anions. Performance of force field parameters was analyzed by calculating properties such as density and viscosity at various temperature and compared with available experimental data. Efficient algorithm techniques were developed in molecular simulations that will reduce computational load in calculating non-bonded interactions. We introduce theory of local sample (TLS) in calculating non-bonded interactions acting on atoms. Another algorithmic improvement in MD simulations is calculating force acting on atoms based on previous time steps, that achieves up to 50 % reduction in computational time