"Polarizable force field has been successfully used in molecular modeling for years, especially in biological and protein simulations. In this research thesis, development of a new polarizable force field ―POSSIM (POlarizable Simulations with Second order Interaction Model) involving electrostatic polarization is described and parameters for several protein residues were produced. In this research thesis, the POSSIM force field was extended to the side chains of the following residues: lysine, glutamic acid, prontonated hisidine, phenylalanine and tryptophan. This work involved producing parameters for methyl ammonium, acetate ion, imidazolium cation, benzene and pyrrole molecules. The parameters fitting procedure starts from the molecular complex with dipolar electrostatic probes of a many-body system to produce polarizabilities, compute the energies, then charges and Lennard-Jones parameters are produced by fitting to gas-phase dimerization calculations, followed by the torsional parameters fitting and end up with the pure liquid simulations. In all the cases, three-body energies, dimerization energies and distances agree well to the accurate quantum mechanical results. The final parameters obtained assured the error of less than 2% in the heat of vaporization and average volume results compared with the available experimental data. Unlike the quantum mechanical calculations, the polarizable force field computations require a relatively small amount of computational resources. Moreover, compared to fixed-charges empirical force fields, polarizable force fields are much more accurate in a number of energy calculations. In the following chapters, the results obtained with this particular polarizable force field are discussed."

Until such a time that computers are powerful enough to routinely perform ab initio simulation of large biomolecules, there will remain a demand for less expensive computational tools. Classical force field methods are widely used for the simulation of large molecules. However, their low computational cost comes at the price of introducing approximations to the description of the system, for example atomic point charges and Hooke type potentials. The quantum chemical topological force field, QCTFF, removes the classical approximations and uses a machine learning method, kriging, to build models that map ab initio atomic properties to changes in the internal coordinates of a chemical system. The atomic properties come from quantum chemical topology, QCT, and include atomic multipole moments and also energy terms from the interacting quantum atoms (IQA) energy decomposition scheme. By using atomic multipole moments, the electrostatic interactions between atoms is described in a more rigorous fashion than most classical force fields, and polarisation is captured through the use of kriging models. In this thesis, the QCTFF approach has been applied to a selection of test cases including small molecular dimers and amino acids. Kriging models are built using a “training set” of molecular geometries, and an investigation of different approaches for sampling amino acids is provided. The concept of the “atomic horizon sphere” is discussed, where the effect on the multipole moments of an atom in an increasingly large environment is investigated. This is an important investigation required to guide the development of future QCTFF training sets. Investigations into the effect of deprotonation of basic and acidic amino acids side chains is provided, as well as a study of the short range repulsion between atoms.

Molecular dynamics (MD) simulations play a pivotal role in understanding the behavior of complex molecular systems, offering insights into the behavior of molecules at the atomic level, while their accuracy heavily depends on the force field parameters used. In this study, we present an investigation focusing on two distinct aspects: the validation of MD simulations for plasticizers, and the development of a quantitative structure property relationship (QSPR) model to fit data derived from these simulations. Our goal is to provide researchers with valuable insights into the choice of force fields to improve the accuracy of simulations in various scientific domains and the modeling of prediction of properties of plasticizers. In the first part, We explore various aspects of validation, including force field accuracy, equilibration protocols, and comparison of simulation results of plasticizers with experimental data. We begin by validating popular force fields: PCFF, SciPCFF and COMPASS. By examining the behavior of small molecules, we aim to ensure the reliability of force fields for these compounds with specific desired functional groups. Density, heat of vaporization and shear viscosity results are used for the validation of force fields. We compare various equilibration methods and their impact on simulation outcomes to address issues related to system stability and convergence, for enhancing the efficiency and accuracy of simulations. The second part of our research shifts focus to the prediction modeling of plasticizers, a class of chemical additives commonly used in the polymer industry to enhance the flexibility of plastic materials. We attempt to predict the solubility parameters of plasticizers by QSPR. Simple counts, Wiener Indices and Randic Branching Indices are used as descriptors in the QSPR. Our prediction model results show the dependence of plasticizers on the descriptors while the QSPR equation obtained from our current data-set with five descriptors has the R2 = 0.73. In conclusion, this comprehensive study bridges the gap between force field validation and equilibration for plasticizers. Moreover, the integration of QSPR models offers insights to a robust approach for predicting molecular behaviors. / Thesis / Master of Applied Science (MASc)

The overall objective of this thesis has been to develop accurate computational methods for the diffusion and adsorption of small gases in zeolites. Firstly, the effect of the zeolite framework flexiblity on the single component and binary diffusion of various gases were discussed. Results indicate that for tight fitting molecules the rigid framework approximation can produce order(s) of magnitude difference in diffusivities as compared to the simulations performed with a fully flexible framework. We proposed two simple methods in which the flexible structure of a zeolite is approximated as a set of discrete rigid snapshots. Both methods are orders of magnitude more efficient than the simulations with the fully flexible structure. Secondly, we use a combined classical and quantum chemistry based approach to systematically develop the force fields based on DFT calculations for interactions of simple molecules like CH4, N2, linear alkanes, and linear alkenes in zeolites. We used a higher level of theory known as the DFT/CC method to correct DFT energies that were used in the periodic DFT calculations to develop force fields. Our results show that DFT-derived force fields give good predictions of macroscopic properties like adsorption isotherms in zeolites. The force fields are transferrable across zeolites and hence can be further used to screen materials for different storage and separation applications.

No description available.

One of the purposes of this work is to investigate modifications that have to be made to a standard source-modulation microwave spectrograph so that it can be used to study gases at various temperatures. Another objective in this work is to determine experimentally the function of temperature that describes how the line widths of microwave spectral lines vary with changing temperature. The most important segment of the study is the temperature dependence of the line width since from an accurate knowledge of this temperature dependence one is able to determine what molecular force fields are present and the relative importance of parts of the molecular force field.

Doctor of Philosophy / Department of Chemistry / Paul E. Smith / Computer simulations have provided a wealth of information concerning a wide range of systems. The precision of computer simulation results depends on the degree of sampling (time scales) achieved, while the accuracy of the results (given sufficient sampling) depends on the quality of force field used. A force field provides a description of the energy for a system of interest. Recently, we have been developing a Kirkwood Buff (KB) force field for molecular dynamics simulations of biological systems. This force field is based on the KB Theory of solutions, emphasizing the accurate description of intermolecular interactions, and reasonably reproducing a range of other physical properties from experiment. In this approach simulation results in terms of KB integrals can be directly compared with experimental data through a KB analysis of the solution properties. The approach therefore provides a simple and clear method to test the capability of a force field. Here we firstly studied a series of alcohol-water mixtures in an attempt to validate the transferability and additivity of the force field. A general fluctuation theory was applied to investigate the properties of these systems, and to compare with computer simulation results. The possible effects of cosolvents on peptides and proteins were then investigated using N-methylacetamide as model for the peptide backbone and urea as cosolvent. A possible explanation for the urea denaturation of protein structure was provided using a thermodynamics point of view involving transfer free energies and preferential interactions obtained from the KB integrals. Finally, potentials for protein backbone and sidechain torsions were developed by fitting to quantum mechanical calculations and NMR data. Simulations of a variety of peptides and proteins in aqueous solutions were then performed to demonstrate the overall reliability of the force field.

Computational simulations of chemical systems play an ever-increasing role in many areas of biochemical research from rational drug design to probing fundamental physiological processes. Depending on the method, a vast array of properties are able to be predicted. Here we report the design and implementation of two methods for investigating diverse problems in protein biochemistry. In order to better understand protein–metal interactions—most importantly for the difficult to model transition metal ions— empirical force field parameters were developed for Pt(II), cisplatin, and other Pt(II) coordination compounds. Two force field frameworks were used: a modified version of the fixed- charge OPLS-AA and the polarizable POSSIM force field. A seven-site model was used for the Pt(II) ion. The produced parameters are compatible with the OPLS-AA and POSSIM force fields and can be used in protein–metal binding simulations in which—contrary to the common treatment of metal ions in such simulations—the position or even coordination of the ion does not have to be constrained using preexisting knowledge. It has been demonstrated that the produced models are capable of reproducing key properties of relevant Pt(II) complexes but that the POSSIM formalism yields more accurate values for energies of formation than the OPLS-AA model. This Pt(II) model was employed—along with previously developed Cu(I) parameters—to investigate the binding of platinum to the protein Atox1, a human copper chaperone implicated in the resistance mechanism of cisplatin and other platinum antitumor compounds. In collaboration with the Dmitriev and Bernholc groups, we used our models to inform and refine spectroscopic experiments as well as to serve as starting points for high-performance quantum calculations. It was shown that under physiological redox conditions, copper(I) and cisplatin can form large polymers with glutathione. These polymers were capable of transferring copper(I) to apo-Atox1 or to platinum(II) to copper-loaded Atox1. Analysis of the simultaneous binding of copper(I) and platinum(II) to Atox1 was found to occur through the formation of copper–sulfur–platinum bridges, where copper is coordinated by three sulfur atoms and platinum by four sulfur atoms. With the goal of using a simple model to be able to quickly estimate the acid disassociation constants of proteins, PKA17 has been developed and tested. PKA17 is a coarse-grain grid-based method and software tool for accurately and rapidly calculating protein pKa values given an input PDB structure file. During development, parameter fitting was carried out using a compilation of 442 Asp, Glu, His, and Lys residues that had both high-resolution PDB structures and published experimental pKa values available. Applying our PKA17 model, the calculated average unsigned error and RMSD for the residue set were found to be 0.628 and 0.831 pH units, respectively. As a benchmark for comparison, the same residue set was evaluated with the PROPKA software package which resulted in an average unsigned error of 0.761 pH units and an RMSD of 1.063 pH units. Finally, a web interface for the PKA17 software was developed and deployed (http://users.wpi.edu/~jpcvitkovic/pka_calc.html) to make PKA17 available to the wider scientific community.

Computational simulations using empirical force fields are frequently used to model guest-host interactions in porous periodic systems, where the interaction energy is broken into electrostatic and van der Waals contributions. While simulations such as these have been instrumental in progressing our understanding of neutral periodic systems, limitations in deriving partial atomic charges has largely contributed to the difficulty in modeling charged periodic frameworks. However, many nanoporous materials possess frameworks that have a net charge, which is balanced by counter-ions that intercalate through the pores. For example, virtually all zeolites used in practice contain a proportion of Al, which bestows the framework with a negative charge. In this respect, we investigate two methods for the generation of partial atomic charges in periodic systems having a net framework charge. First, we examine the validity of generating REPEAT electrostatic potential fitted charges derived from periodic electronic structure calculations, where a constant background charge is added to neutralize the net charge on the framework without adding neutralizing counter-ions. The second method we explore is the split charge equilibration (SQE) method for very rapid charge generation. In its original formulation, the SQE model cannot be applied to systems with a net charge. In this work, we reformulate the SQE method for non-neutral systems to be treated. The new SQE model, which we call SQEAB, was shown to give equivalent results to those of the original SQE model for neutral systems. For charged frameworks, the model was shown to provide partial atomic charges in good agreement with the DFT derived REPEAT method. Taking advantage of that work, we next focus on the development of a force field for modeling CO2, N2, and CH4 gas adsorption in both neutral and charged zeolites, which we call the AMP (Aluminosilicate MicroPorous) force field. Commonly, the electrostatic potential of zeolites is represented through the use of generic charges, where every atom of the same type in the framework is assigned the same atomic charge. Though this model is fast, it fails to account for structural differences between framework geometries. In this work, we have optimized a set of SQEAB parameters to reproduce the DFT derived electrostatic potentials (ESPs) of a structurally representative set of both neutral and charged zeolite frameworks. Comparing with other popular models, the SQEAB-AMP charges are shown to better reproduce the QM ESP by more than 30%, on average. Gas uptakes obtained using SQEAB AMP charges were found to be within 5% of those obtained using DFT derived charges. We have further optimized a set of Lennard-Jones parameters to be combined the SQEAB-AMP charges that reproduce experimental uptake data in zeolites.

Density functional theory B3LYP and ab initio MP2 calculations were carried out to study the structures and vibrational spectra of bis(ethylenedithio)tetrathiafulvalene (BEDT-TTF) and the related compounds, 1,3-dithiole-2-thione (DTT), tetrathiafulvalene (TTF), and 4,5-ethylenedithio-1,3-dithiole-2-thione (EDT-DTT). It is found that B3LYP functional overestimates C-S bond lengths significantly and underestimates frequencies of modes involving C-S stretching accordingly. The errors in B3LYP force fields are shown to be satisfactorily corrected by scaled quantum mechanical force field procedure. After applying the scale factors derived from DTT, the scaled B3LYP force fields reproduce the observed frequencies of TTF, EDT-DTT, and BEDT-TTF satisfactorily, with a mean deviation between the calculated and observed frequencies of less than 10 cm-1. On the basis of agreement between the calculated and observed frequencies, isotope shifts, as well as IR and Raman intensities, assignments of the fundamental vibrational modes of these molecules are given in terms of the true molecular symmetries of the equilibrium structures. This study shows that the scaled density functional force field procedure is a powerful approach for understanding the spectral features of large and low symmetry molecules.