The first project in this work used classical molecular dynamics to study the ice recrystallization inhibition potential of a series of carbohydrates and alcochols, using the hydration index, partial molar volumes and isothermal compressibilities as parameters for measuring their cryogenic efficacy. Unfortunately, after 8 months of testing, this work demonstrates that the accuracy and precision of the density extracted from simulations is not sufficient in providing accurate partial molar volumes. As a result, this work clearly demonstrates that current classical molecular dynamics technology cannot probe the volumetric properties of interest with sufficient accuracy to aid in the research and development of novel cryoprotectants.The second project in this work used molecular dynamics simulations to evaluate the Gibbs free energy change of substituting CO2 in sI clathrate hydrates by N2,CH4, SO2 and H2S flue gas impurities under conditions proposed for CO2 capture (273 K, 10 bar). Our results demonstrate that CO2 substitutions by N2 in the small sI cages were thermodynamically favored. This substitution is problematic in terms of efficient CO2 capture, since the small cages make up 25% of the sI clathrate cages, therefore a significant amount of energy could be spent on removing N2 from the flue gas rather than CO2. The thermodynamics of CO2 substitution by CH4, SO2 and H2S in sI clathrate hydrates was also examined. The substitution of CO2 by these gases in both the small and large cages were determined to be favorable. This suggests that these gases may also disrupt the CO2 capture by sI clathrate hydrates if they are present in large concentrations in the combustion flue stream. Similar substitution thermodynamics at 200 K and 10 bar were also studied. With one exception, we found that the substitution free energies do not significantly change and do not alter the sign of thermodynamics. Thus, using a lower capture temperature does not significantly change the substitution free energies and their implications for CO2 capture by sI clathrate hydrates.

The current thesis presents work on the structure and dynamics of oligosaccharides and polysaccharides as well as the free energetics of carbohydrate-protein interactions. By applying various computational tools such as molecular dynamics simulation, our in-house fast sugar structure prediction software, replica exchange molecular dynamics, homology modeling, umbrella sampling, steered molecular dynamics as well as the thermodynamic integration formalism, we have been able to study the role of water on the surface of homopolysaccharides as well as complex oligosachharides, we have been able to produce a prediction of the bound structure of triantennary oligosaccride on the asialoglycoprotein receptor, we have been able to estimate the free energy of binding of ManΑ1→2Man to the HIV-1 inactivating protein, Cyanovirin-N as well as the relative binding free energies of mutants of Cyanovirin-N to the same ligand.

The first project in this work used classical molecular dynamics to study the ice recrystallization inhibition potential of a series of carbohydrates and alcochols, using the hydration index, partial molar volumes and isothermal compressibilities as parameters for measuring their cryogenic efficacy. Unfortunately, after 8 months of testing, this work demonstrates that the accuracy and precision of the density extracted from simulations is not sufficient in providing accurate partial molar volumes. As a result, this work clearly demonstrates that current classical molecular dynamics technology cannot probe the volumetric properties of interest with sufficient accuracy to aid in the research and development of novel cryoprotectants.The second project in this work used molecular dynamics simulations to evaluate the Gibbs free energy change of substituting CO2 in sI clathrate hydrates by N2,CH4, SO2 and H2S flue gas impurities under conditions proposed for CO2 capture (273 K, 10 bar). Our results demonstrate that CO2 substitutions by N2 in the small sI cages were thermodynamically favored. This substitution is problematic in terms of efficient CO2 capture, since the small cages make up 25% of the sI clathrate cages, therefore a significant amount of energy could be spent on removing N2 from the flue gas rather than CO2. The thermodynamics of CO2 substitution by CH4, SO2 and H2S in sI clathrate hydrates was also examined. The substitution of CO2 by these gases in both the small and large cages were determined to be favorable. This suggests that these gases may also disrupt the CO2 capture by sI clathrate hydrates if they are present in large concentrations in the combustion flue stream. Similar substitution thermodynamics at 200 K and 10 bar were also studied. With one exception, we found that the substitution free energies do not significantly change and do not alter the sign of thermodynamics. Thus, using a lower capture temperature does not significantly change the substitution free energies and their implications for CO2 capture by sI clathrate hydrates.

The first project in this work used classical molecular dynamics to study the ice recrystallization inhibition potential of a series of carbohydrates and alcochols, using the hydration index, partial molar volumes and isothermal compressibilities as parameters for measuring their cryogenic efficacy. Unfortunately, after 8 months of testing, this work demonstrates that the accuracy and precision of the density extracted from simulations is not sufficient in providing accurate partial molar volumes. As a result, this work clearly demonstrates that current classical molecular dynamics technology cannot probe the volumetric properties of interest with sufficient accuracy to aid in the research and development of novel cryoprotectants.The second project in this work used molecular dynamics simulations to evaluate the Gibbs free energy change of substituting CO2 in sI clathrate hydrates by N2,CH4, SO2 and H2S flue gas impurities under conditions proposed for CO2 capture (273 K, 10 bar). Our results demonstrate that CO2 substitutions by N2 in the small sI cages were thermodynamically favored. This substitution is problematic in terms of efficient CO2 capture, since the small cages make up 25% of the sI clathrate cages, therefore a significant amount of energy could be spent on removing N2 from the flue gas rather than CO2. The thermodynamics of CO2 substitution by CH4, SO2 and H2S in sI clathrate hydrates was also examined. The substitution of CO2 by these gases in both the small and large cages were determined to be favorable. This suggests that these gases may also disrupt the CO2 capture by sI clathrate hydrates if they are present in large concentrations in the combustion flue stream. Similar substitution thermodynamics at 200 K and 10 bar were also studied. With one exception, we found that the substitution free energies do not significantly change and do not alter the sign of thermodynamics. Thus, using a lower capture temperature does not significantly change the substitution free energies and their implications for CO2 capture by sI clathrate hydrates.

No description available.

The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are inhibited by nerve agents such as sarin and tabun. In general, the inhibited enzymes are reactivated by bisquaternary ammonium compounds (oximes). The binding free energies of the oximes; 2-PAM, MMB-4, HI-6, and obidoxime bound to human AChE (hAChE) and human BChE (hBChE) inhibited by sarin and tabun and also to the uninhibited enzymes were calculated using various computational methods. Using thermodynamic integration, the binding free energies of all the inhibited and uninhibited systems of MMB-4 and obidoxime were evaluated. The standard binding free energies (dA) were more negative than the experimental values due to limitations of the ff99 forcefield. The RMS error of dA for the inhibited systems of MMB-4 was 2.1 kcal/mol, and for obidoxime systems it was 4.8 kcal/mol with respect to the experimental free energies. The binding enthalpies calculated using MM-GBSA and MM-PBSA methods for 2-PAM, MMB-4, HI-6, and obidoxime systems were negative, except for hBChE-sarin-MMB-4 and hBChE-sarin-obidoxime. For all the systems the TdS values calculated using normal mode analysis were equal to or lower in magnitude than their corresponding binding enthalpies. As a result, the estimated free energies were positive for most of the systems. Clearly, the present algorithms cannot effectively estimate the binding entropies for a protein-ligand system. Met81 has commonly shown favorable interactions, and lysine or arginine exhibited unfavorable interactions with the reactivator in all the systems. Second, the interactions between chloropyrifos-oxon (Cpo) and experimentally tested neutral and monopyridinium oximes bound to the Q192 or R192 polymorphs of human paraoxonase1 (hPON1) were studied. The equilibrated Q192 and R192 hPON1 were structurally different than the crystal structure of recombinant PON1. The neutral oximes have shown more favorable interactions with Cpo in Q192 hPON1 + Cpo system compared to R192 hPON1 + Cpo. Whereas the monopyridinium oximes interacted more affectively with Cpo in R192 hPON1 than Q192 hPON1. The relative deprotonation energy of the monopyridinium oxime was lower than the neutral oxime. Hence, the monopyridinium oxime can hydrolyze an organophosphate at a higher rate than a neutral oxime.

No description available.

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.