The Langevin equation is a stochastic differential equation frequently used in molecular dynamics for simulating systems with a constant temperature. Recent developments have given rise to wide uses of Langevin dynamics at different levels of spatial resolution, which necessitate time step and friction parameter choices outside of the range for which many existing temporal discretization methods were originally developed. We first study the GJ--F, BAOAB and BBK numerical algorithms, originally developed for atomistic simulations, on a coarse-grained polymer melt, paying close attention to the large time step regime. The results of this study then inspire our search for new algorithms and lead to a general class of velocity Verlet-based time-stepping schemes designed to perform well for all parameter regions, by ensuring that they faithfully reproduce statistical quantities for the case of a free particle and harmonic oscillator. This family of methods depends on the choice of a single free parameter function and we explore some of the methods defined for certain choices of this parameter on realistic coarse-grained and atomistic molecular systems relevant in material and bio-molecular science. In addition, we provide an equivalent splitting formulation of this one-parameter family which allows for enhanced insight into the hidden time scaling induced by the choice of the free parameter in the Hamiltonian and stochastic time scales. / Mathematics

Protein-ligand binding and protein allostery play a crucial role in cell signaling, cell regulation, and modern drug discovery. In recent years, experimental studies of protein structures including crystallography, NMR, and Cryo-EM are widely used to investigate the functional and inhibitory properties of a protein. On the one hand, structural classification and feature identification of the structures of protein kinases, HIV proteins, and other extensively studied proteins would have an increasingly important role in depicting the general figures of the conformational landscape of those proteins. On the other hand, free energy calculations which include the conformational and binding free energy calculation, which provides the thermodynamics basis of protein allostery and inhibitor binding, have proven its ability to guide new inhibitor discovery and protein functional studies. In this dissertation, I have used multiple different analysis and free energy methods to understand the significance of the conformational and binding free energy landscapes of protein kinases and other disease-related proteins and developed a novel alchemical-based free energy method, restrain free energy release (R-FEP-R) to overcome the difficulties in choosing appropriate collective variables and pathways in conformational free energy methods like umbrella sampling and metadynamics. / Chemistry

<p> The organic ions studied in this thesis were generated in the rarefied gas phase of the mass spectrometer by electron ionization of selected precursor molecules. The characterization of their structure and reactivity was probed by using a variety of tandem mass spectrometry techniques. These include metastable ion spectra to probe the dissociation chemistry of the low energy ions and collision experiments to establish the atom connectivity of the ions. The technique of neutralization-reionization mass spectrometry (NRMS) was used to probe the structure and stability of the neutral counterparts of the ions. Computational results involving the CBS-QB3 model chemistry formed an integral component in the interpretation of the experimental findings.</p> <p> The above approach was used to study proton-transport catalysis in the formaldehyde elimination from low energy 1,3-dihydroxyacetone radical cations. Solitary ketene-water ions, CH2=C(=O)OH2·+, do not readily isomerize into its more stable isomer, CH2=C(OH)2·+. A mechanistic analysis using the CBS-QB3 model chemistry shows that metastable 1,3-dihydroxyacetone radical cations will rearrange into hydrogen-bridged radical cations [CH2C(=O)O(H)-H•••OCH2]·+, where the CH2=O will catalyze the transformation of CH2=C(=O)OH2·+ into CH2=C(OH)2·+.</p> <p> Metastable pyruvic acid radical cations, CH3C(=O)COOH·+, have been shown to undergo decarboxylation to yield m/z 44 ions, C2H4O·+, in competition with the formation of CH3C=O+ + COOH· by direct bond cleavage. Collision induced dissociation experiments agree with an earlier report that oxycarbene ions CH3COH·+ are formed but they also suggest the more stable isomer CH3C(H)=O·+ may be co-generated. Using the CBS-QB3 model chemistry, a mechanism is proposed to rationalize these results.</p> <p> Next, the isomeric ions CH3O-P=S·+ and CH3S-P=O·+ were characterized and differentiated by tandem mass spectrometry. Metastable CH3O-P=S·+ and CH3S-P=O·+ ions both spontaneously lose water to yield m/lz 74 cyclic product ion [-S-CH=]P·+. Using the CBS-QB3 model chemistry a mechanism is proposed for the water loss from CH3O-P=S·+ and CH3S-P=O·+. Our calculations also show that these two isomers communicate via a common intermediate, the distonic ion CH2S-P-OH·+, prior to the loss of water.</p> <p> The final component of this work details the computational study addressing the long standing question on the mechanism for the water elimination from metastable ethyl acetate radical cations. The CBS-QB3 results show that low energy ethyl acetate ions isomerize into ionized 4-hydroxy-2-butanone prior to the loss of water.</p> / Thesis / Master of Science (MSc)

<p dir="ltr">This thesis explores the intersection of quantum interference, entanglement, and quantum algorithms in the context of chemical reactions. The initial exploration delves into the constructive quantum interference in the photoassociation reaction of a 87Rb Bose Einstein condensate (BEC), where a coherent superposition of multiple bare spin states is achieved and it’s impact on photo-association (PA) was studied. Employing a quantum processor, the study illustrates that interferences can function as a resource for coherent control in photochemical reactions, presenting a universally applicable framework relevant to a spectrum of ultracold chemical reactions. The subsequent inquiry scrutinizes the entanglement dynamics between the spin and momentum degrees of freedom in an optically confined BEC of 87Rb atoms, induced by Raman and RF fields. Significantly, this study unveils substantial spin momentum entanglement under specific experimental conditions, indicating potential applications in the realm of quantum information processing. Finally, the third study advances a quantum algorithm for the computation of scattering matrix elements in chemical reactions, adeptly navigating the complexities of quantum interactions. This algorithm, rooted in the time-dependent method and Möller operator formulation, is applied to scenarios such as 1D semi-infinite square well potentials and co-linear hydrogen exchange reactions, showcasing its potential to enhance our comprehension of intricate quantum interactions within chemical systems.</p>

Computational studies have become an essential tool in biochemistry, providing detailed insight into biological systems alongside experimental studies. Molecular simulation can predict protein conformational dynamics and the impact of mutations, enabling rapid and low-cost investigation of potential therapeutic targets and better understanding of biological systems. Molecular dynamics (MD) is a computational method able to model ensembles of biomolecular conformations in solution by simulating atomic motion at high temporal resolution. The principle limitation of MD is the ability to collect sufficient data for equilibrium sampling. However, with the progression of high-performance computing (HPC) clusters and distributed computing platforms, timescales previously inaccessible to MD can be reached and relevant protein parameters can be extracted using modeling. From these simulations, Markov state models (MSMs) are used extract system-relevant kinetic and thermodynamic information. An MSM represents a series of memoryless, probabilistic transitions between discrete states in a kinetically meaningful way. The obtained information is used to understand the relationships between relevant protein conformations, thus enabling a comprehensive understanding of the modelled system in a human-readable format. Recent advancements in model scoring and hyper-parameterization moved MSM construction away from anecdotal, case-by-case basis to a highly systematic approach that focuses on optimization and validity. Thus, modern MSMs are employed to investigate protein properties, and predict experimental observables using system-representative ensembles of conformations. Additionally, a comprehensive MSM can be combined with sparse experimental data to generate an improved interpretation of the system. My work focuses on performing all-atom massively-parallel MD simulation using the Folding@home distributed computing platform in order to build comprehensive MSMs that are used in improving simulation accuracy and protein design. This work results in the development of an unbiased framework for MSM building that is used to lend insight into simulation parameters, extract novel system behavior and enable clear comprehension of a target function, such as impact of mutations or emphasis of rare events. / Chemistry

Serine/threonine protein kinases (STKs) are extremely ancient and ubiquitous signaling enzymes; despite their common name “eukaryotic protein kinases”, these protein domains are also present in archaea and bacteria suggesting their presence in the last universal common ancestor 3-4 billion years ago. It is known that tyrosine kinases (TKs) descended from this lineage much later, just prior to the emergence of the first metazoans. TKs share a great deal of structural homology with even the most distantly related STKs, however their ability to phosphorylate Tyr instead of Ser and Thr along with their unique domain organizations sets them apart from STKs in both sequence and function. This thesis explores the distinct conformational “landscapes” of these two important protein families, dealing with a ~20 residue long “activation loop” which has multiple inactive conformations but only one active conformation. By employing a statistical energy Potts Hamiltonian model of protein sequences and using molecular dynamics free-energy simulations, major sequence features of the catalytic domain were determined which control the shape of the free-energy landscape i.e., the relative depths of the “active” and “inactive” basins, a quantity termed the reorganization free-energy ΔG_reorg. A key finding from this approach is the marked divergence in the conformational landscapes of TKs from STKs that is encoded in the sequences of extant family members, which was detected by threading their Potts sequence energies over the active “DFG-in” (catalytic “Asp-Phe-Gly motif oriented “in”) basin relative to an inactive “DFG-out” basin where the activation loop is “folded up” by ~20 Å. This free-energy basin autoinhibits the kinase because the activation loop behaves as a pseudo-substrate in cis. The Potts couplings threaded over the active and inactive basins suggest that TKs evolved to have a smaller free-energy difference between the active and inactive basins compared with STKs, by 4-6 kcal/mol. The sequence and structural basis for this effect was explored in detail by decomposing the threaded Potts Hamiltonian into pairwise interactions and analyzing the statistical energy effects of natural sequence variation at evolutionary divergent positions in the sequence. These effects were then verified by performing mutations of amino acid sidechains using FEP (Free Energy Perturbation) molecular dynamics simulations in both the active and inactive conformational states and comparing the results with analogous sequence-based calculations by making mutations in the Potts model. The results are highly consistent (Pearson correlation of 0.81) suggesting that the Potts model is comparable to FEP in its ability to capture the physical free-energy balance of amino acid sidechain interactions between two different conformational basins and validates the Potts model-predicted evolutionary divergent landscapes of TKs and STKs. This divergence can in part be attributed to autoinhibitory pseudo-substrate interactions involving the activation loop; the evolved peptide-substrate specificity of TKs compared with STKs, and the functional surfaces that have been evolutionarily molded to complement Tyr vs Ser/Thr-containing peptides, appear to have energetic feedback with the propensity of the kinase’s own activation loop to “fold” against these surfaces when the DFG is flipped from “in” to “out”, and TKs have evolved to exploit this as a means of regulation. / Chemistry

Currently, there is a great interest towards developing organic semiconductors for use in solar cells and lighting displays. Derivatives of one of the most important chromophores, diketopyrrolopyrrole (DPP), are commonly employed as the active material in field-effect transistors, as they exhibit high hole mobilities. The intramolecular structure of 2T-DPP-2T with four thiophene units(T) is classified as a donor-acceptor-donor (DAD) chromophore, where the bithiophene units are donors and the DPP unit is the acceptor. The absorption spectrum of the aggregated form of a polymer based on the 2T-DPP-2T repeat units in 1,1,2,2-tetrachloroethane solution (TCE) was measured by Janssen et. al. The spectrum is red-shifted relative to a unaggregated polymer, which is an identifying feature of a J-aggregate. In addition, the ratio of the first two vibronic peaks decreases substantially in going from the unaggregated phase to the aggregate, which is an identifying feature of an H-aggregate. These contradicting behaviors were also observed by Punzi et. al. for an aggregate of the 2T-DPP-2T chromophore. Such behavior cannot be explained by the classical Frenkel-Holstein model. One challenge has been that the intermolecular charge transfer (ICT) plays an important role in the absorption and emission spectrum in the molecular aggregates of DPP. The bulk of this thesis has been to expand the Frenkel-CT-Hosltein model to include intramolecular and intermolecular charge transfer. The model accounts unusual red-shifted H-aggregates observed in the experiments. The experimental spectra of two different DPP-based chromophores are successfully reproduced with our theoretical model. Furthermore, based on perturbative expression for ICT coupling, an effective Frenkel Holstein (EFH) model is proposed and employed to successfully simulate the absorption and emission spectrum of DPP4T aggregates, as long as charge-transfer coupling is smaller than the energy gap between the Frenkel- and ICT excitations. The emission spectrum of DPP4T is also successfully reproduced by this new model, including the temperature dependence. / Chemistry

Living systems possess seemingly bottomless complexity. Attempts to parse the details of one cellular process from all other concurrent processes are challenging, if not daunting undertakings. The apparent depth of this problem, as it pertains to biomineralization, is related to the small number of existing studies focused on the development of a mechanism-based understanding of intracellular mineralization processes. Molecular biologists and geneticists have only begun to turn their attention towards identification and characterization of molecules involved in regulating and controlling biomineral formation. With this new knowledge, a number of new and exciting research opportunities are currently awaiting development upon a barren landscape. Silica biomineralization is one of these emerging frontiers. As new information about the chemical and structural nature of the macromolecules involved in biosilicification is revealed, the means these species employ to control the temporal and spatial onset of silica deposition in vivo become available for exploration. The first chapter of this dissertation outlines those aspects of silicate metabolism that are directly relevant to the controlled biomineralization of silica in eukaryotic organisms and identifies pervasive and unanswered questions surrounding biosilica formation. Particular attention is paid to the diatoms, which are the most abundant, and extensively investigated silica-mineralizing organisms in modern seas. The extent, and mechanism through which specific organic moieties work individually or in concert to direct mineral formation at biological interfaces is a central concern of modern biomineralization research. Chapter two addresses this forefront issue for silica mineralizing systems, and reports the results of an experimental investigation designed to measure the effects of individual surface-bound organic functional groups on the rate of surface-directed silica nucleation. Chapter three discusses an additional aspect of this research aimed at investigating the reactivity of nanoparticulate biogenic silica produced by marine phytoplankton and terrestrial plants in natural environments. Density Functional Theory and ab initio molecular orbital calculations are employed to explore potential mechanisms underlying the catalytic activity of divalent metal cations during the hydrolysis of Si – O bonded networks. / Ph. D.

Inkjet additive manufacturing is the next step toward ubiquitous manufacturing by enabling multi-material printing that can exhibit various mechanical, electronic, and thermal properties. These characteristics are realized in the careful formulation of the inks and their functional materials, but there are many constraints that need to be satisfied to allow optimal jetting performance and build quality when used in an inkjet 3-D printer. Previous research has addressed the desirable rheology characteristics to enable stable drop formation and how the metallic nanoparticles affect the viscosity of inks. The contending goals of increasing nanoparticle-loading to improve material deposition rates while trying to maintain optimal flow dynamics is the closely held trade secret in formulating these inkjet compositions. We use data from previous experiments and the CRC Handbook of Chemistry and Physics to train machine learning regression models to predict the relevant factors of inkjet printability at a standardized temperature of 25ºC: viscosity, surface tension, and density. These models were used to predict the rheological factors of the main components of a UV-curable inkjet ink formulation: UV-curable monomers and oligomers, photoinitiators, dispersants, and humectants. This paper compares the relative performance of five machine learning algorithms to assess the effectiveness of each approach for chemoinformatics regression tasks.

Kovalente Inhibition stellt einen effektiven Weg dar, die Verweildauer des Liganden innerhalb einer Bindetasche zu erhöhen. In dieser Arbeit wurden theoretische Methoden angewendet, um die Reaktivität und den nichtkovalenten Zustand vor der Reaktion zu modellieren. Im Rahmen einer Fallstudie zu Cathepsin K wurden nichtkovalente Modelle von kovalenten Inhibitoren generiert. Für verschiedene Komplexe aus Cathepsin K und einem kovalent gebundenem Liganden wurde der Zustand vor der Reaktion modelliert und dessen Stabilität im Rahmen einer klassischen MD-Simulation überprüft. Die Stabilität des Warheads in der Bindetasche hing hauptsächlich vom gewählten Protonierungszustand der katalytischen Aminosäuren ab. Für eine Reihe von Inhibitoren der ChlaDUB1 wurde ein Protokoll aus quantenmechanischen Rechnungen genutzt, um die Reaktivität verschiedener Warheads abzuschätzen. Die erhaltenen Aktivierungsenergien korrelierten mit experimentell bestimmten Raten zur Inaktivierung des Enzyms. Im Rahmen eines Wirkstoffdesign-Projektes zur Deubiquitinase USP28 wurden von unpublizierten Kristallstrukturen ausgehend erste Docking-Experimente durchgeführt. Es konnte gezeigt werden, dass ein literaturbekannter Inhibitor von USP28 mit einem Warhead so modifiziert werden kann, dass die reaktive Einheit in direkter Nachbarschaft zu einem Cystein positioniert wird. Für diese Warheads wurden ebenfalls quantenmechanische Rechnungen zur Bestimmung der Aktivierungsenergie durchgeführt. Um besser nachvollziehen zu können, warum bei einem Photoswitch-Inhibitor der Butyrylcholin-Esterase der cis-Zustand des Moleküls besser inhibiert als der trans-Zustand, wurde eine Docking-Studie des Zustandes vor der Reaktion durchgeführt. Es konnte ein qualitatives Modell aufgestellt werden, das zeigt, dass der trans-Zustand aufgrund seiner längeren Form mit wichtigen Aminosäuren am Eingang der Bindungstasche kollidiert. / Covalent inhibition is an effective way to increase the residence time of a ligand within the active site. In this work theoretical methods were used to model the reactivity and the noncovalent pre-reaction state. Noncovalent models of covalent inhibitors were generated as part of a case study of Cathepsin K. Several complexes of Cathepsin K and a covalently bound ligand were modeled in their state before the reaction, and their stability was assessed by classical molecular dynamics simulations. In most cases the warhead was positioned in close proximity to the catalytic unit, remaining there for up to several hundred nanoseconds. This stable positioning was largely dependent on the protonation state of the catalytic amino acids. To estimate the reactivity of a series of ChlaDUB1 inhibitors, a protocol of quantum mechanical calculations was adapted. The obtained activation energies correlated with experimentally obtained rate constants of enzyme inactivation. Using unpublished crystal structures, first design steps for the inhibition of the deubiquitinase USP28 were performed. Docking studies showed that modification of a literature-known inhibitor of USP28 with a warhead allowed to place this reactive unit close to a cysteine. Activation energies were also obtained for these structures via quantum mechanical calculations. To better rationalize the differences in inhibition between the cis- and trans-state of a photoswitch inhibitor of butyrylcholine esterase, a docking study of the noncovalent state was performed. The different ring conformers and stereochemical properties of the photoswitch were critical for a sensible model of the ligand. A qualitative model could be obtained which explains that the cis-isomer is more active than the trans-isomer due to a steric clash of the latter with amino acids at the entrance of the pocket.