Theses and Dissertations from UMD
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Item A UNITED-ATOM REPRESENTATION FOR SPHINGOLIPIDS IN THE CHARMM MOLECULAR DYNAMICS FORCE FIELD(2023) Lucker, Joshua; Klauda, Jeffery B; Biophysics (BIPH); Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The development of the CHARMM force field (FF) in the late 1970’s and early 1980’s was groundbreaking at the time. For the first time, a computer program was created that could simulate biological systems on a macromolecular scale. Starting with the simulation of simple proteins, CHARMM has since expanded to include such macromolecules as nucleic acids and lipids, now being able to model complex biological systems and processes. Force fields like CHARMM can be represented in different ways. For example, force fields can be represented through an all-atom representation, in which all atoms in a system are modeled as distinct interaction units. This representation can be simplified into a united-atom representation, which shall be the primary focus of this thesis. A united atom FF has no explicit interaction sites for hydrogen. Instead, the hydrogens are lumped onto the atoms they are connected to, termed ‘heavy atoms’ as these atoms have a greater atomic weight than hydrogen. The CHARMM FF originally had a united-atom representation for proteins, which was abandoned to focus on all-atom representations. However, in certain cases, such as lipid tails, united-atom representations are often useful in certain situations; as compared to all-atom representations, united-atom models often speed up simulation times, which is useful in the simulation of large enough systems of molecules. Although there are currently united-atom representations for many types of biomolecules in the CHARMM FF, including multiple types of membrane lipids, there has yet to be a united-atom model for sphingolipids, a type of membrane lipid most commonly found in the myelin sheath of neurons, although its presence has been noted in many types of eukaryotic cells. The goal of this thesis is thus to develop such a model and implement it in the CHARMM FF.Item PARAMETERIZATION OF THE CHARMM LIPID FORCE FIELD AND APPLICATIONS TO MEMBRANE MODELING(2022) Yu, Yalun; Klauda, Jeffery B.; Biophysics (BIPH); Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Computational modeling of lipids at the atomistic level provides insights into the chemical physics of biological membranes and opens the possibility to model membrane-protein interactions. This dissertation presents contributions to the CHARMM/Drude family of lipid force fields and applications of the CHARMM36 lipid force field to model membranes.Long-range Lennard-Jones interactions are critical for membrane simulations but were excluded from the CHARMM lipid force field for historical reasons. Re-parameterization of the CHARMM36 (C36) lipid force field for phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, and ether lipids is performed to incorporate these interactions through the Lennard-Jones particle-mesh Ewald (LJ-PME) method. The resulting force field is denoted C36/LJ-PME. C36/LJ-PME is in excellent agreement with experimental structure data for lipid bilayers and reproduces the experimental compression isotherm of monolayers. A semi-automated protocol is developed and used during this parameterization and significantly accelerates the whole process. The same protocol is used for the optimization of the Drude polarizable lipid force field. The optimization of this force field focuses on the structural and mechanical properties of bilayers and ab initio results of model compounds representing the lipid headgroup. Long-range dispersion interactions are incorporated into the force field as well. The resulting force field is validated against more structural and dynamic properties of bilayers and the compression isotherm of monolayers and demonstrates significant improvements over the past versions of the force field. In addition to these fully atomistic models, this dissertation also discusses the update to the CHARMM36 united atom chain model. Both the original model (C36UA) and the revised model (C36UAr) adopt the all-atom C36 lipid force field parameters for the headgroup and a united atom representation for the chain. The update focuses on the Lennard-Jones parameters of the hydrocarbon chain and related dihedrals. Bulk liquid properties (density, heat of vaporization, isothermal compressibility, and diffusion constant) of linear alkanes and alkenes and ab initio torsional scans are used as initial fitting targets. Bilayer surface area is used to fine-tune the dihedral parameters. Bilayer simulations of various headgroups and tails using C36UAr demonstrate significant improvements over C36UA from a structural perspective. The last part of this dissertation presents the applications of the C36 lipid force field. The inner membrane of Pseudomonas aeruginosa (P. aeruginosa) is modeled in two modes (planktonic and biofilm) to study the influence of lipid composition on bilayer structural and mechanical properties. The hydrophobic thicknesses of the model membrane agree with the P. aeruginosa transmembrane proteins in the Orientations of Proteins in Membranes (OPM) database. Symmetric and asymmetric models for the Arabidopsis thaliana plasma membrane are modeled. Molecular dynamics (MD) simulations indicate that the outer leaflet is more rigid and tightly packed to the inner leaflet. The interplay between glycolipids and sterols is found to be critical in lipid clustering and a possible mechanism for lipid phase separation has been proposed.Item EXPLORING THE EFFECTS OF PHYSIOLOGICAL ENVIRONMENT ON AMYLOID AGGREGATION(2022) Sahoo, Abhilash; Matysiak, Silvina; Biophysics (BIPH); Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Molecular level self-assembly/aggregation processes are common in biomolecular systems. Specifically, aggregation of protein molecules results in formation of amyloid deposits, that has been associated with neuronal dysfunction leading up to neurodegeneration. The protein aggregation is often influenced by several external physiological features, which can modulate this pathological process in a specific or non-specific manner. This thesis aims to elucidate the role of such factors in amyloid aggregation in the context of neurodegeneration. As test cases, we have focused on different fragments of Amyloid-beta peptide and Huntingtin protein and explored common interaction schemes in the presence of phospholipid membranes, solvated glucose molecules and added trailing sequences. Phospholipid membranes, composed of a heterogeneous distribution of lipid molecules, serve as packaging envelopes in cellular systems. But several studies have suggested a role of cellular membranes in abetting protein aggregation in neurodegenerative diseases. The first section of this thesis explores Amyloid-beta 16-22 aggregation in the presence of membranes. Lipid membranes have been shown to modulate peptide aggregation in a charge dependent manner with anionic membranes promoting faster peptide aggregation into ordered fibrillar structures compared to zwitterionic membranes. In this work, we evaluate the role of this electrostatic membrane headgroup charge on Amyloid-beta 16-22 peptide aggregation with model lipid membranes composed of POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) and POPS (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine) lipids. Beyond, membrane charge, membrane's physical organization can also affect peptide-peptide and peptide-membrane interactions. Here, we have curated the effects of applied surface-tension, as a proxy for membrane curvature, on peptide fibrillation propensities. Apart from ordered structures such as membranes, solvated small molecules are a large class of molecules that can affect aggregation patterning by affecting peptides through both specific and non-specific interactions. The second section of this thesis explores Amyloid-beta 16-22 aggregation in varying hyperglycemic conditions, to draw correlations between Alzheimer's disease and type 2 diabetes. Here, we discovered that the glucose prefers partitioning onto the aggregate-water interface in a specific manner, leading to a loss in rotational entropy that propels peptide aggregation. In the final section, we discuss the case of pathological peptide aggregation in the case of Huntington's disease. Broadly, Huntinting protein's N-terminal region which consists of 17-residue N-terminal domain (N17) and the following Glutamine repeat tract (Poly-Q) are our objects of interest and associated with pathological aggregation. The aggregation landscape of N17 is analyzed in presence of added different lengths of trailing Poly-Q tract and the presence of curved membranes. We have approached our research through a computational lens using molecular dynamics simulations. To address the relevant concerns of large spatio-temporal scales necessary to study peptide aggregation systems with molecular simulations, we have developed a coarse-grained forcefield (ProMPT: Protein Model with Polarizability and Transferability) that uses reduced spatial resolution to accelerate phase-space exploration. The forcefield can capture secondary and tertiary folding of protein structures with minimal constraints, and is transferable across biomolecular systems without a need for re-parametrization. My dissertation presents a holistic picture of peptide aggregation and various physiological factors that affect it, with biomolecular simulation across multiple scales.Item EPIGENETICS TUNE CHROMATIN MECHANICS, A COMPUTATIONAL APPROACH(2021) Pitman, Mary; Papoian, Garegin A; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The base unit of DNA packaging in eukaryotes, the nucleosome, is adaptively modified for epigenetic control. Given the vast chemical space of chromatin and complexity of signaling and expression, much of our knowledge about genetic regulation comes from a biochemical or structural perspective. However, the architecture and function of chromatin also mechanically responds to non-equilibrium forces. Mechanical and biochemical properties are not independent of one another and the interplay of both of these material properties is an area of chromatin physics with many remaining questions. Therefore, I set out to determine how the material properties of chromatin are altered by biochemical variations of nucleosomes. All-atom molecular dynamics is employed coupled with new computational and theoretical tools. My findings and predictions were collaboratively validated and biologically contextualized through multiscale experimental methods. First, I computationally discover that epigenetic switches buried within the nucleosome core alter DNA accessibility and the recruitment of essential proteins for mitosis. Next, using new computational tools, I report that centromeric nucleosomes are more elastic than their canonical counterparts and that centromeric nucleosomes rigidify when seeded for kinetochore formation. We conclude that the material properties of variants and binding events correlate with modified loading of transcriptional machinery. Further, I present my theoretical approach called Minimal Cylinder Analysis (MCA) that uses strain fluctuations to determine the Young's modulus of nucleosomes from all-atom molecular dynamics simulations. I show and explain why MCA achieves quantitative agreement with experimental measurements. Finally, the elasticity of hybrid nucleosomes in cancer is measured from simulation, and I implicate this oncogenic variant in potential neocentromere formation. Together, these data link the physics of nucleosome variations to chromatin states' plasticity and biological ramifications.Item ATOMISTIC AND THEORETICAL DESCRIPTION OF LIQUID FLOWS IN POLYELECTROLYTE-BRUSH-GRAFTED NANOCHANNELS(2021) Sachar, Harnoor Singh; Das, Siddhartha; Mechanical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Polyelectrolyte (PE) chains grafted in close proximity stretch out to form a “brush”-like configuration. Such PE brushes can represent a special class of nanomaterials that are capable of exhibiting stimuli-responsive behavior. They can be manipulated as needed by changing the environmental conditions like pH, solvent quality, salt concentration, temperature, etc. This responsiveness renders them very useful for a plethora of applications such as lubrication, emulsion stabilization, current rectification, nanofluidic energy conversion, drug delivery, oil recovery, etc. Therefore, gaining fundamental insights into PE brush systems is of utmost importance for both industrial as well as academic research. In this dissertation, we make use of theoretical and computational tools to improve our understanding of planar PE brushes and then use this understanding to probe flows in PE brush-grafted nanochannels. We begin our quest by conducting all-atom Molecular Dynamics (MD) simulations to probe the microstructure of planar PE brushes with an unprecedented atomistic resolution. This allows us to not only investigate the properties of the PE chains but also the local structure and arrangement of the counterions and water molecules trapped within the brushes. Next, we use our atomistic model to probe the effects of variation in charge density on the microstructure of weak polyionic brushes. Such a variation in the charge density is typically enforced by a change in the surrounding pH and is a characteristic behavior of pH-responsive (annealed) PE brushes. Furthermore, we go on to develop the most exhaustive theoretical model for pH-responsive PE brushes known as the augmented Strong Stretching Theory (SST). Our model is an improvement over the existing state-of-the-art as it considers the effects of the excluded volume interactions and an expanded form of the mass action law. We further improve this model by including several non-Poisson Boltzmann effects, especially relevant at high salt concentrations. This improved model is in excellent agreement with the results of our all-atom MD simulations. Next, we use our augmented SST to model pressure-driven transport in backbone-charged PE brush-grafted nanochannels. Our results are an improvement over previous electrokinetic studies that did not consider a thermodynamically self-consistent description of the brushes. Finally, we conduct all-atom MD simulations to probe the pressure-driven transport of water in PE brush-grafted nanochannels using an all-atom framework. The nanoscale energy conversion characteristics obtained from our simulations are in reasonable agreement with the predictions of our continuum framework and lie within the range of values reported by a prior experimental study.Item Advancements in Label-free Biosensing Using Field-Effect Transistors and Aided by Molecular Dynamics Simulations(2019) Guros, Nicholas; Klauda, Jeffery B; Balijepalli, Arvind; Chemical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Biosensors are used to characterize or measure concentrations of physiologically or pathologically significant biomarkers that indicate the health status of a patient, for example, a biomarker associated with a specific disease or cancer. Presently, there is a need to improve the capabilities of biosensors, which includes their rate of detection, limit of detection, and usability. With respect to usability, it is advantageous to develop biosensors that can detect a biomarker that is not labeled, such as with a conventional fluorescent, magnetic, or radioactive label, prior to characterization or measurement by that biosensor. Such biosensors are known as label-free biosensors and are the primary focus of this work. Biosensors are principally evaluated by two standards: their sensitivity to detect a target biomarker at physiologically relevant concentrations and their specificity to detect only the target biomarker in the presence of other molecules. The elements of biosensing critical to improving these two standards are: biorecognition of the biomarker, immobilization of the biorecognition element on the biosensor, and transduction of biomarker biorecognition to a measurable signal. Towards the improvement of sensitivity, electrostatically sensitive field-effect transistors (FET) were fabricated in a dual-gate configuration to enable label-free biosensing measurements with both high sensitivity and signal-to-noise ratio (SNR). This high performance, quantified with several metrics, was principally achieved by performing a novel annealing process that improved the quality of the FET’s semiconducting channel. These FETs were gated with either a conventional oxide or an ionic liquid, the latter of which yielded quantum capacitance-limited devices. Both were used to measure the activity of the enzyme cyclin-dependent kinase 5 (Cdk5) indirectly through pH change, where the ionic-liquid gated FETs measured pH changes at a sensitivity of approximately 75 times higher than the conventional sensitivity limit for pH measurements. Lastly, these FETs were also used to detect the presence of the protein streptavidin through immobilization of a streptavidin-binding biomolecule, biotin, to the FET sensing surface. To study the biomolecular factors that govern the specificity of biomarker biorecognition in label-free biosensing, molecular dynamics (MD) simulations were performed on several proteins. MD simulations were first performed on the serotonin receptor and ion channel, 5-HT3A. These simulations, which were performed for an order of magnitude longer than any previous study, demonstrate the dynamic nature of serotonin (5-HT) binding with 5-HT3A. These simulations also demonstrate the importance of using complex lipid membranes to immobilize 5-HT3A for biosensing applications to adequately replicate native protein function. The importance of lipid composition was further demonstrated using MD simulations of the ion channel alpha-hemolysin (αHL). The results of these simulations clearly demonstrate the lipid-protein structure-function relationship that regulates the ionic current though a lipid membrane-spanning ion channel. Finally, to demonstrate the impact of MD simulations to inform the design of FET biosensing, a strategy to use FETs to measure the ultra-low ionic currents through the ion channel 5-HT3A is outlined. This strategy leverages critical elements of 5-HT biorecognition and ion channel immobilization extracted from MD simulations for the design of the proposed FET sensing surface interface.Item TOWARD IN SITU MEASUREMENT OF LIQUID DENSITY USING OPTICAL KERR EFFECT SPECTROSCOPY(2016) Bender, John S.; Fourkas, John T; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Optical Kerr effect (OKE) spectroscopy is a widely used technique for probing the low-frequency, Raman-active dynamics of liquids. Although molecular simulations are an attractive tool for assigning liquid degrees of freedom to OKE spectra, the accurate modeling of the OKE and the motions that contribute to it rely on the use of a realistic and computationally tractable molecular polarizability model. Here we explore how the OKE spectrum of liquid benzene, and the underlying dynamics that determines its shape, are affected by the polarizability model employed. We test a molecular polarizability model that uses a point anisotropic molecular polarizability and three others that distribute the polarizability over the molecule. The simplest and most computationally efficient distributed polarizability model tested is found to be sufficient for the accurate simulation of the liquid polarizability dynamics. The high-frequency portion of the OKE spectrum of benzene shifts to higher frequency with decreasing temperature at constant pressure. Molecular dynamics simulations of benzene are used to isolate the effects of temperature and density on the spectrum. The simulations show that, at constant density, the high-frequency portion of the spectrum shifts to lower frequency with decreasing temperature. In contrast, at constant temperature, the high-frequency portion of the spectrum shifts to higher frequency with increasing density. Line shape analyses of simulated spectra under isochoric and isothermal conditions shows that the effects of density and temperature are separable, suggesting that OKE spectroscopy is a viable technique for in situ measurement of the density of van der Waals liquids. OKE spectroscopy is then used to investigate the density of benzene confined in nanoporous silica. The high-frequency portion of the OKE spectrum shifts to the blue with increasing confinement, which is consistent with densification. Molecular dynamics simulations show that the tumbling vibrational density of states of benzene confined in silica pores exhibit behavior similar to that of the OKE spectrum. The dependence of the structure of the simulated liquid with increasing confinement resembles that of the bulk liquid at constant temperature and increasing density, further supporting the premise that benzene is densified upon confinement in silica pores.Item Coarse Graining to Invesitigate Peptide-Lipid Interactions(2016) Ganesan, Sai Janani; Matysiak, Silvina; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Experimental characterization of molecular details is challenging, and although single molecule experiments have gained prominence, oligomer characterization remains largely unexplored. The ability to monitor the time evolution of individual molecules while they self assemble is essential in providing mechanistic insights about biological events. Molecular dynamics (MD) simulations can fill the gap in knowledge between single molecule experiments and ensemble studies like NMR, and are increasingly used to gain a better understanding of microscopic properties. Coarse-grained (CG) models aid in both exploring longer length and time scale molecular phenomena, and narrowing down the key interactions responsible for significant system characteristics. Over the past decade, CG techniques have made a significant impact in understanding physicochemical processes. However, the realm of peptide-lipid interfacial interactions, primarily binding, partitioning and folding of amphipathic peptides, remains largely unexplored compared to peptide folding in solution. The main drawback of existing CG models is the inability to capture environmentally sensitive changes in dipolar interactions, which are indigenous to protein folding, and lipid dynamics. We have used the Drude oscillator approach to incorporate structural polarization and dipolar interactions in CG beads to develop a minimalistic peptide model, WEPPROM (Water Explicit Polarizable PROtein Model), and a lipid model WEPMEM (Water Explicit Polarizable MEmbrane Model). The addition of backbone dipolar interactions in a CG model for peptides enabled us to achieve alpha-beta secondary structure content de novo, without any added bias. As a prelude to studying amphipathic peptide-lipid membrane interactions, the balance between hydrophobicity and backbone dipolar interactions in driving ordered peptide aggregation in water and at a hydrophobic-hydrophilic interface, was explored. We found that backbone dipole interactions play a crucial role in driving ordered peptide aggregation, both in water and at hydrophobic-hydrophilic interfaces; while hydrophobicity is more relevant for aggregation in water. A zwitterionic (POPC: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) and an anionic lipid (POPS: 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine) are used as model lipids for WEPMEM. The addition of head group dipolar interactions in lipids significantly improved structural, dynamic and dielectric properties of the model bilayer. Using WEPMEM and WEPPROM, we studied membrane-induced peptide folding of a cationic antimicrobial peptide with anticancer activity, SVS-1. We found that membrane-induced peptide folding is driven by both (a) cooperativity in peptide self interaction and (b) cooperativity in membrane-peptide interactions. The dipolar interactions between the peptide and the lipid head-groups contribute to stabilizing folded conformations. The role of monovalent ion size and peptide concentration in driving lipid domain formation in anionic/zwitterionic lipid mixtures was also investigated. Our study suggest monovalent ion size to be a crucial determinant of interaction with lipid head groups, and hence domain formation in lipid mixtures. This study reinforces the role of dipole interactions in protein folding, lipid membrane properties, membrane induced peptide folding and lipid domain formation. Therefore, the models developed in this thesis can be used to explore a multitude of biomolecular processes, both at longer time-scales and larger system sizes.Item Molecular Dynamic Simulations of Nucleosomes and Histone Tails: The Effects of Histone Variance and Post-Translational Modification(2015) Winogradoff, David; Papoian, Garegin; Chemical Physics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The packaging of genomic information and the regulation of gene expression are both fundamentally important to eukaryotic life. Meters of human DNA must fit inside the micron-diameter nucleus while still rapidly becoming available for templated processes such as transcription, replication, and repair. Therefore, the DNA-protein complex known as chromatin must dynamically transition between more compact, closed states and more accessible, open ones. To fully understand chromatin structure and dynamics, it is necessary to employ a multifaceted approach, integrating different general philosophies and scientific techniques that include experiment and computation. Since the DNA in chromatin is organized into arrays of nucleosomes, we take a bottom-up approach in this dissertation, striving first to understand the structure and dynamics of an individual nucleosome and subdomains thereof. Atomistic computational methods have provided useful tools to study DNA and protein dynamics at the nanosecond, and recently microsecond, timescale. In this dissertation, we present recent developments in the understanding of the nucleosome though atomistic molecular dynamics (MD) simulations. By applying different all-atom MD computational techniques, we demonstrate that replacing the canonical H3 histone with the centromere-specific variant CENP-A translates to greater structural flexibility in the nucleosome, that replacing H3 with CENP-A increases the plasticity of an individual histone dimer, and that the effects of acetylation on the H4 histone tail are cumulative and specific to lysine 16 mono-acetylation.Item Microscopic Rearrangements within Granular Shear Flows: Segregation, Subdiffusion, & Rotation(2015) Harrington, Matthew John; Losert, Wolfgang; Physics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Granular materials constitute a class of complex systems that can exhibit global behaviors that are reminiscent of solids, liquids, gases, or otherwise uniquely their own. The macroscopic size of individual grains tends to render the standard tools of thermodynamics and statistical mechanics inapplicable, while opening the possibility of directly measuring and probing individual particle motion. This thesis details three investigations in which the characterization of microscopic motion provides a bridge to understanding bulk phenomena. The first study explores size-segregation in a cyclically shear-driven granular system, as observed using the refractive index matched scanning (RIMS) technique for three-dimensional (3D) imaging. While convective flows are implicated in many granular segregation processes, the associated particle-scale rearrangements are not well understood. A bidisperse mixture segregates under steady shear, but the cyclically driven system either remains mixed or segregates slowly. Individual grain motion shows no signs of particle-scale segregation dynamics that precede bulk segregation. Instead, we find that the transition from non-segregating to segregating flow is accompanied by significantly less reversible particle trajectories, and the emergence of a convective flow field. A granular system undergoing cyclic forcing is also seen to undergo subdiffusion beneath some threshold shear amplitude. The transition from subdiffusive to diffusive motion is rigorously tested in a simulated two-dimensional (2D) granular system. Motion in the subdiffusive regime is also seen to exhibit some behavior reminiscent of cage-breaking models, which had developed in the context of thermal systems. However, analysis of local displacements of a grain relative to its cage of neighbors reveals key distinctions from thermal systems. Finally, we have made progress in the measurement of rotational motion of individual grains. While 2D experimental systems readily yield both translational and rotational motion, a challenge in 3D experiments is the tracking of rotational motion of spherically symmetric particles. We propose an extension of the RIMS technique as a method of simultaneously measuring particle-scale translation and rotation. Partial measurements of 3D rotations indicate that shear-driven rotational motion may stem from gear-like motion within the shear zone. This suggests that the prevalence of collective rotation between grains can play a significant role in dictating bulk phenomena such as reversibility and segregation.