Physics
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Item Progress in Nitrogen Vacancy Nuclear Magnetic Resonance Detection(2023) Huckestein, Emma Kaye; Walsworth, Ronald L; Chemical Physics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful analytic tool of use in the physics, chemistry, and biology disciplines, yet the resource costs to buy, maintain, and use the spectrometer limit the tool's accessibility and the limited sensitivity and spectral resolution limit its application space. In recent years, Nitrogen Vacancy (NV) centers have emerged as an alternative NMR sensor due to their atomic-scale resolution and minimal resource costs. However, NV-NMR similarly suffers from limited sensitivity and spectral resolution due to the technical challenges associated with increasing the applied magnetic field. In this work, the sensitivity of an existing NV-NMR setup is characterized to determine the experimental modifications necessary for measurements at higher magnetic fields (>0.5 T). As a consequence of this characterization, a coplanar waveguide integrated with a microfluidic channel is designed. Finally, metabolomics, particularly spheroids, are reviewed for a potential high-impact NV-NMR application given historically relevant sample concentration sensitivities.Item Phase Transitions Affected by Molecular Interconversion(2023) Longo, Thomas; Anisimov, Mikhail; Chemical Physics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Typically, pure substances may be found with only one gaseous or liquid state, while their solid state may exist in various polymorphic states. The existence of two distinct liquid forms in a single component substance is more unusual since liquids lack the long-range order common to crystals. Yet, the existence of multiple amorphous states in a single component substance, a phenomenon known as "liquid polyamorphism," has been observed or predicted in a wide variety of substances. In contrast to standard phase transitions, it has been suggested that polyamorphic liquid-liquid transitions are caused by the interconversion of molecular or supramolecular states. To investigate this phenomenon, a nonequilibrium thermodynamic model was developed to quantitatively describe the interplay between the dynamics of molecular interconversion and fluid-phase separation. The theory has been compared to a variety of interconverting systems, and has demonstrated a quantitative agreement with the results of Monte Carlo and Molecular Dynamics simulations. In this thesis, it is shown that there are two major effects of molecular interconversion on the thermodynamics and the kinetics of fluid-phase separation: if the system evolves to an equilibrium state, then the growth of one of the alternative phases may result in the destruction of phase coexistence - a phenomenon referred to as "phase amplification." It is demonstrated that depending on the experimental or simulation conditions, either phase separation or phase amplification would be observed. Previous studies of polyamorphic substances report conflicting observations of phase formation, which may be explained by the possibility of phase amplification occurring. Alternatively, if the system evolves to a nonequilibrium steady state, the phase domain growth could be restricted at a mesoscopic length scale. This phenomenon (referred to as "microphase separation") is one of the simplest examples of steady-state dissipative structures, and may be applicable to active matter systems, hydrodynamic instabilities, and bifurcations in chemical reactions, in which the nonequilibrium conditions could be imposed by an external flux of matter or energy.Item Non Traditional Solvent Effect On Protein Behavior(2022) Lee, Pei-Yin; Matysiak, Silvina; Chemical Physics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Protein preservation has been a long lasting research topic due to its importance in many bio-pharmaceutical applications. A ”cold chain” is a commonplace solution to protein preservation, which stores biochemical products at a refrigerated temperature. A big advantage of cold chain is that the storing process is straightforward, without many further processes before the use of stored bio-products. However, it can also experience malfunction of the cooling system and results in economic lost and health care crisis. Ionic liquids (ILs), as a type of non traditional solvents, consist only of ions and are reported to be a potential candidate to replace the use of cold chain. The advantages of ILs include low flammability, high conductivity and less toxicity compared to some organic solvents. The most interesting feature of ILs is their extremely large number of cation-anion combinations, that can be tailored for specific use according to different needs. This thesis aims to investigate specific mechanism behind how ILs modulate protein behavior, specifically, how ILs affect protein stability, activity, and aggregation. We approach the research questions through the lens of molecular dynamics (MD) simulations and complement with experimental findings. In the first part of the thesis we first investigate the effects of two imidazolium based ILs (1-ethyl-3-methylimidazolium ethylsulfate, [EMIM]+[EtSO4]− and 1-ethyl-3-methylimidazolium diethylphosphate, [EMIM]+[Et2PO4]−) on lysozyme stability and activity. We collaborate with an experiment group at the University of Massachusetts (Bermudez lab) to complement our simulation results. Both ILs are found to destabilize lysozyme stability. In addition, both the cation and anions lower the stability of lysozyme, but in a different fashion. [EMIM]+ interacts with an Arg-Trp-Arg bridge that is critical in lysozyme stability through π–π and cation–π interactions, leading to a local induced destabilization. On the other hand, both anions interact with the whole protein surface through short-range electrostatic interactions, with [Et2PO4]− having a stronger effect than [EtSO4]−. Lysozyme activity is also reduced by the presence of the two ILs, but can be recovered after rehydration. It is found that the protein-ligand complex is less stable in the presence of ILs. In addition, a dense cloud of [EMIM]+ is found in the vicinity of the lysozyme active site residues, possibly leading to a competition with the sugar ligand. A fast leaving of these [EMIM]+ is observed after rehydration, which explains the reappearance of the active site and the recover of lysozyme activity. Although classical all-atom MD simulations can provide us with a great deal of microscopic information, they are often limited by the temporal-spatial scale of the simulated systems. For example, systems with high viscosity solvents or systems involving large number of atoms will be difficult to reach convergence for all-atom MD. In this case, coarse grained (CG) MD can come into play to achieve the desired time- and length- scales. The faster sampling obtained from CG MD is achieved by reducing the degree of freedom of the system and by removing local energetic barriers. In CG MD, similar atoms are grouped to functional groups and thus the free energy landscape is smoothen. We develop a novel CG MD named ”Protein Model with Polarizability and Transferability (ProMPT)”. The novelty of this model is the inclusion of the charged dummies that can result in change of dipoles. These dipoles can reflect the change of environments and thus allow the model to respond to different environmental stimulus. We validate ProMPT with several benchmark proteins: Trp-cage, Trpzip4, villin, ww-domain, and β-α-β. ProMPT is able to simulate folding-unfolding and secondary structure transformation with minimal constraints, which is not feasible with previous CG models. In addition, ProMPT can also reproduce the experimental results for the dimerization of glycophorin A (GpA) with different point mutations. Here we demonstrate the ability of the model to capture the change of conformational space caused by point mutation. In the last part of this thesis, we combine ProMPT and an in-house CG IL model to study the effects of [TEA]+[Ms]− on amyloid beta 16-22 (Aβ16−22) aggregation. Aβ16−22 is the hydrophobic core region and is the smallest fragment of Aβ that can fibrilize. Aβ has been extensively linked to the pathogenesis of the Alzheimer’s disease. [TEA]+[Ms]− is reported to suppress the formation of β-sheets and induce helices at high concentration. From our results, both β-sheet content and the aggregate size decrease with the increase of IL concentration, which are in agreement with experiments. Aggregates can form in both water and IL, but with different morphologies. In water, a nice hydrophobic core involving Phe-Phe interactions can form as well as intact β-sheet contacts. In addition, a cross β-sandwich structure is also observed, as seen from previous literature. However, the same hydrophobic core can not persist in the presence of IL. Aggregate structures in IL are not stable over time due to the [TEA]+-Phe interaction. Helicity is also computed for Aβ16−22 in water and in IL at different concentrations and a positive correlation is found. The increase in helicity at high [TEA]+[Ms]− concentration can be explained by the reduction of the inter-peptide contacts, which then increases the opportunity for the peptides to form helical structures. Single peptide studies also reveal that [TEA]+[Ms]− increases the helicity, possibly through cation-induced dipole enhancement. In this thesis, a series of detailed investigations on the effects of ILs on protein behavior is performed. Specific interactions between IL functional groups and protein local/global structures are examined. The mechanisms we studied here will help constructing a holistic view for the design of IL-protein pair applications. The construction of the new CG protein/IL model provides another tool for the scientific community to study secondary structure transformation, folding- unfolding, and other biochemical processes that are sensitive to the environment with CG MD.Item UNCOVERING BIOPHYSICAL PROPERTIES AND FUNCTIONS OF DISORDERED HISTONES USING COMPUTER SIMULATIONS(2020) Wu, Hao; Papoian, Garegin A; Biophysics (BIPH); Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)It is a crucial task for the continuation of every species to safely store genetic information and precisely pass it on to the next generation. For all the eukaryotes including humans, this mission is carried out by chromatin, a polymer chain consisting of repeating structural units called the nucleosome, in which 146 bp of DNA wraps around a histone protein octamer. In a typical eukaryotic cell, about two meters of DNA is compacted into a micrometer-sized nucleus, where transcription and replication activities are regulated in part via modulating chromatin's condensation. A comprehensive understanding of chromatin structure and dynamics provides the necessary foundation for explaining the genome organization, which, for example, will help better understand the mechanisms of diseases caused by epigenetic modifications. As the building blocks of chromatin and nucleosome, the histone proteins are the key players in chromatin structure regulation and epigenetic control. However, studying histones has been challenging in part because histone tails lack well-defined structures, staying disordered when carrying out many functions. In this dissertation, we focus on exploring the biophysical mechanisms related to these intrinsically disordered histones using computer simulations, carefully comparing our results with related experiments. We present recent progress in the development and applications of state-of-art molecular dynamics force fields for disordered histones and histone-DNA interactions. We used these force fields to investigate the structural, dynamical, and thermodynamical properties of various disordered histones, including histone tails, linker histones, and histone monomers, in the nucleosomal environment. Our investigations have uncovered the structural preferences and binding/folding dynamics of these disordered histones, which provide novel insights into how they aid chromatin condensation.Item LOCAL MOLECULAR FIELD THEORY FOR NON-EQUILIBRIUM SYSTEMS(2019) Baker III, Edward Bigelow; Weeks, John D; Chemical Physics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Local Molecular Field (LMF) theory is a framework for modeling the long range forces of a statistical system using a mimic system with a modified Hamiltonian that includes a self consistent molecular potential. This theory was formulated in the equilibrium context, being an extension of the Weeks Chandler Andersen (WCA) theory to inhomogeneous systems. This thesis extends the framework further into the nonequilibrium regime. It is first shown that the equilibrium derivation can be generalized readily by using a nonequilibrium ensemble average and its relevant equations of motion. Specifically, the equations of interest are fluid dynamics equations which can be generated as moments of the BBGKY hierarchy. Although this approach works well, for the application to simulations it is desirable to approximate the LMF potential dynamically during a single simulation, instead of a nonequilibrium ensemble. This goal was pursued with a variety of techniques, the most promising of which is a nonequilibrium force balance approach to dynamically approximate the relevant ensemble averages. This method views a quantity such as the particle density as a field, and uses the statistical equations of motion to propagate the field, with the forces in the equations computed from simulation. These results should help LMF theory become more useful in practice, in addition to furthering the theoretical understanding of near equilibrium molecular fluids.Item Topics in equilibrium and nonequilibrium thermodynamics: computing crystalline free energies and engineering Maxwell’s demon.(2015) Lu, Zhiyue; Jarzynski, Christopher; Chemical Physics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)This dissertation covers two separate topics in statistical physics. The first part of the dissertation focuses on computational methods of obtaining the free energies (or partition functions) of crystalline solids. We describe a method to compute the Helmholtz free energy of a crystalline solid by direct evaluation of the partition function. In the many-dimensional conformation space of all possible arrangements of N particles inside a periodic box, the energy landscape consists of localized islands corresponding to different solid phases. Calculating the partition function for a specific phase involves integrating over the corresponding island. Introducing a natural order parameter that quantifies the net displacement of particles from lattices sites, we write the partition function in terms of a one-dimensional integral along the order parameter, and evaluate this integral using umbrella sampling. We validate the method by computing free energies of both face-centered cubic (FCC) and hexagonal close-packed (HCP) hard sphere crystals with a precision of $10^{-5}k_BT$ per particle. In developing the numerical method, we find several scaling properties of crystalline solids in the thermodynamic limit. Using these scaling properties, we derive an explicit asymptotic formula for the free energy per particle in the thermodynamic limit. In addition, we describe several changes of coordinates that can be used to separate internal degrees of freedom from external, translational degrees of freedom. The second part of the dissertation focuses on engineering idealized physical devices that work as Maxwell's demon. We describe two autonomous mechanical devices that extract energy from a single heat bath and convert it into work, while writing information onto memory registers. Additionally, both devices can operate as Landauer's eraser, namely they can erase information from a memory register, while energy is dissipated into the heat bath. The phase diagrams and the efficiencies of the two models are solved and analyzed. These two models provide concrete physical illustrations of the thermodynamic consequences of information processing.Item Visualizing Quantum Reactive Scattering Dynamics(2015) Warehime, Michael; Alexander, Millard H; Chemical Physics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The Born-Oppenheimer approximation, which allows a decoupling of electronic and nuclear motion, underlies the investigation of molecular dynamics. In some cases this decoupling is not possible, so that nuclear motion can induce changes in electronic state. It is then necessary to account for collision-induced transitions between multiple potential energy surfaces. This is an inherently quantum phenomena. In this dissertation we present a new way to visualize these non-adiabatic transitions in chemical reactions of open-shell atoms. Toward this end, we have developed new algorithms and developed a MATLAB-based software suite for simulating non-adiabatic reactions. We have also determined new molecular potential energy surfaces and their couplings required to simulate the reactive dynamics.Item From Structure to Thermodynamics with Local Molecular Field Theory(2013) Remsing, Richard Charles; Weeks, John D; Chemical Physics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)A fundamental goal of statistical mechanics is to connect a description of the intermolecular interactions and the accompanying microscopic structural details of a molecular system to its macroscopic thermodynamic properties. When the interactions between molecular components are treated with sufficient simplicity, as in an ideal gas or a hard sphere fluid for example, the link between structure and thermodynamics can be apparent. In contrast, when both local and non-local interactions are present in the system, competition between the various short and long ranged forces can lead to surprising thermodynamic behaviors as exemplified by the complexities of liquid water. Local molecular field (LMF) theory provides a physically motivated formalism for systematically decomposing the structure and thermodynamics of molecular systems into portions arising from local and non-local interactions. In this thesis, LMF theory is employed to examine the structure and thermodynamics of molecular systems, with a focus on aqueous solutions. LMF-motivated truncations of classical water models are first developed as analysis tools to explore the roles of the local hydrogen bond network, dispersion interactions, and long ranged multipolar interactions in the determination of sev- eral anomalous thermodynamic properties of bulk water. This type of analysis is then extended to the study the relative importance of hydrogen bonding and inter- facial unbalancing potentials in hydrophobic effects. The underlying ideas of LMF theory are then utilized to study local and non-local interactions in ion solvation. Modifications to classical dielectric continuum theories are explored with a focus on determining the electrostatic potentials inside ionic cores. LMF ideas are then used to develop the concept of a Gaussian test charge. We then argue that this type of test charge is the appropriate generalization of a classical point test charge to probe the dielectric response of molecularly detailed systems and develop an accurate for- malism for the description of the dielectric response to such probes. Finally, a LMF theoretic foundation for performing free energy calculations is developed and tested before concluding the thesis with a discussion of future work involving LMF theory.Item Exploring Equilibrium Systems with Nonequilibrium Simulations(2012) Ballard, Andrew James; Jarzynski, Christopher; Chemical Physics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Equilibrium sampling is at the core of computational thermodynamics, aiding our understanding of various phenomena in the natural sciences including phase coexistence, molecular solvation, and protein folding. Despite the widespread development of novel sampling strategies over the years, efficient simulation of large complex systems remains a challenge. While the majority of current methods such as simulated tempering, replica exchange, and Monte Carlo methods rely solely on the use of equilibrium techniques, recent results in statistical physics have uncovered the possibility to sample equilibrium states through nonequilibrium simulations. In our first study we present a new replica exchange sampling strategy, "Replica Exchange with Nonequilibrium Switches," which uses nonequilibrium simulations to enhance equilibrium sampling. In our method, trial swap configurations between replicas are generated through nonequilibrium switching simulations which act to drive the replicas towards each other in phase space. By means of these switching simulations we can increase an effective overlap between replicas, enhancing the probability that these moves are accepted and ultimately leading to more effective sampling of the underlying energy landscape. Simulations on model systems reveal that our method can be beneficial in the case of low replica overlap, able to match the efficiency of traditional replica exchange while using fewer processors. We also demonstrate how our method can be applied for the calculation of solvation free energies. In a second, separate study, we investigate the dynamics leading to the dissociation of Na-Cl in water. Here we employ tools of rare event sampling to deduce the role of the surrounding water molecules in promoting the dissociation of the ion pair. We first study the thermodynamic forces leading to dissociation, finding it to be driven energetically and opposed entropically. In further analysis of the system dynamics, we deduce a) the spatial extent over which solvent fluctuations influence dissociation, b) the role of sterics and electrostatics, and c) the importance of inertia in enhancing the reaction probability.Item Molecular basis of the kinematics of the kinesin step(2012) Zhang, Zhechun; Thirumalai, Devarajan; Biophysics (BIPH); Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Kinesin is an ATP-dependent cellular transporter that ferries cargos towards the plus-end of a microtubule. Despite significant advances in experiments, which have provided deep insights into the motility of kinesin, the molecular events that occur in a single step have not been fully resolved. In order to provide these details, this thesis develops a structure of the complex between kinesin and microtubule, and devises new simulation methods to probe the stepping kinetics over a wide range of conditions. Hundreds of molecular movies of kinesin walking on the microtubule are generated using coarse-grained simulation methods. Analysis of these movies shows that there are three major stages in the stepping kinetics of kinesin. In addition, an allosteric network within kinesin, responsible for controlling nucleotide release, is identified using microsecond all-atom simulations. These simulations are used to answer two important questions. First, does kinesin move by a "power stroke" or by diffusion? During a single step, the trailing head of the kinesin detaches from the microtubule, passes the microtubule-bound leading head, and attaches to the target binding site 16 nm away. The target binding site, however, is one of eight accessible binding sites on the microtubule. Is it possible that the "power stroke" (a large conformational change) in the leading head, pulls the trailing head into the neighborhood of the target binding site? This remained unclear because the fraction of the 16 nm step associated with the power stroke and diffusion had never been quantified. Second, how does the microtubule accelerate ADP release from kinesin, which is a key step in completing a single step? The ADP binding site of kinesin is more than 1.5 nm away from the microtubule binding surface. Therefore, the microtubule must affect the ADP binding site through an allosteric mechanism. However, the structural basis for transmitting signals through the underlying allosteric network was previously unknown. Analysis of hundreds of kinesin steps generated using coarse-grained simulations showed that the power stroke associated with the docking of the neck linker to the leading head, is responsible for only 4 nm of the 16 nm step, and the remaining 12 nm is covered by diffusion. However, the power stroke in the leading head constrains the diffusion of the trailing head, decreases the probability of side steps, and therefore biases the trailing head, to the target binding site. Additional all-atom simulations of the ADP-kinesin-microtubule complex, revealed a surprisingly simple allosteric network within kinesin that explains the acceleration of ADP release upon microtubule binding. The allosteric network also explains two additional experimental observations on ADP release from kinesin.