Browsing by Subject "Molecular dynamics"

Now showing 1 - 9 of 9
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    Application of molecular modeling techniques to study the structure, dynamics, and interactions of membrane proteins.
    (2011-08) Shi, Lei
    Membrane proteins constitute ~30% of all the genomes and ~70% of the drug targets. However, less than 1% of the entries in the protein data bank are membrane proteins. The underrepresentation of membrane protein structures limits our understanding of their functions. This thesis summarizes my effects to apply theoretical methods to understand the structure and function relationships of membrane proteins. Specifically, we developed computational techniques to interpret solution and solid-state NMR data of membrane proteins and determine their high resolution structures. We further performed molecular dynamics simulations to study their dynamics, interaction with other proteins and the lipid bilayer environment. We applied these approaches to phospholamban, which is a membrane protein that is involved in cardiac muscle relaxation by regulating Ca2+-ATPase activity. Our results provide new insights to understand how membrane proteins elicit their function.
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    Computational Insights into the Antimicrobial Mechanism of Action of Class II Bacteriocins.
    (2017-05) Kyriakou, Panagiota
    Antibiotic resistance is a global problem and poses an alarming threat to public health. Microorganisms resistant to all commercially available antibiotics have emerged, undermining the ability to fight infectious diseases. The antibiotic resistance crisis has been attributed to the overuse of antibiotics, as well as a lack of new drug development. Coordinated efforts are needed to overcome this challenge, including discovery of alternative drugs. Bacteriocins are bacteria-produced, antimicrobial peptides that are potentially powerful antibiotic drug candidates. Despite considerable scientific interest around bacteriocins, and despite their promise as potent, latent antibiotics, their everyday medical value has been negligible. In order to more effectively utilize the full potential of bacteriocins as a platform to develop new antibacterial agents, a detailed understanding of their mechanism of action is required. This mechanistic insight will offer ways to control and optimize their activity and selectivity against specific pathogens, greatly enhancing their potential for medical applications. The goal of this work is to elucidate the mechanism of action of class II bacteriocins by employing a variety of computational methods that are built around atomistic molecular dynamics simulations. First, we studied Plantaricin EF, a two-peptide class IIb bacteriocin. This bacteriocin was simulated in different environments including water, micelles, and lipid bilayers. The interaction between the two peptides that promotes dimerization, and the interaction between the dimer and the membrane were elucidated. Guided by experimental studies, a transmembrane model of the dimer embedded in the bilayer was additionally designed. Results obtained from a 1 μs long atomistic molecular dynamics simulation, demonstrated for the first time that a bacteriocin, with a narrow antimicrobial activity range, can by itself form a water (and potentially ion) permeable, toroidal pore in a lipid bilayer. This pore was characterized in detail. It is not unlikely that the mechanism of action of bacteriocins can involve poration of the membrane as well as receptor-mediation. Therefore, the interaction of a bacteriocin with its putative receptor was also examined. Lacking the structure of a receptor, we employed structure-prediction techniques in combination with docking calculations, and molecular dynamics simulations. For the first time a class II bacteriocin-receptor complex was built, setting the ground for investigating the role that receptors play in the bactericidal activity of these antimicrobial peptides. We believe that our findings could be of importance to the designing of new antibiotic agents, as it would guide the search for better bacteriocins toward peptides with improved activity and specificity, that form stable pores, increase water or ion permeability, and interact more efficiently with a receptor.
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    Computational methods for understanding RNA catalysis: a molecular approach
    (2014-09) Radak, Brian K.
    Molecular simulation is a powerful technology for providing a detailed picture of a wide range of chemical phenomena. The results of simulation studies are now increasingly used in supplementing experimental studies both as a predictive tool and as a lens through which to interpret results and generate new hypotheses. This dissertation describes several advancements in the development and application of molecular simulation methods to the study of RNA catalysis. Such reactions are representative of a broad class of chemistry associated with important biological functions including storage of genetic information, metabolism, and cell signaling and replication. Furthermore, the existence of naturally occuring RNA sequences that catalyze these reactions has significant implications for the origins of life and the potential design of new RNA based technologies. The work presented here offers new insights into these problems and contributes to a detailed, molecular understanding of the fundamental chemical principles that are in action.
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    Modeling air-silica surface catalysis in hypersonic environments using ReaxFF molecular dynamics
    (2010-05) Norman, Paul E.
    The goal of this work is to model surface catalysis in partially dissociated Air-SiO2 systems, which is of interest for accurately predicting heating on hypersonic vehicles. This is accomplished through molecular dynamics simulations using the ReaxFF potential, which is able to accurately model chemical reactions. The performance of the ReaxFF potential for predicting the bulk structures of several different types of SiO2 is evaluated, and we find that it most accurately reproduces the structure of fi-quartz. Potential energy surfaces for several reactions of interest in catalysis show that the potential may need further training to reproduce results from Quantum Chemical Calculations. Based on a literature review of experimental results and the capabilities of the potential, we choose to model oxygen catalysis on Fi-Quartz. A methodology for measuring recombination coefficients on a silica surface is developed, and tested for gases at 10atm and 100 atm over the temperature range(600-2000K).We find that recombination coefficients are much higher than those measured experimentally, however, the trend in recombination coefficients is exponential with temperature as seen in experiment.
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    Multiscale Computational Analysis of Nitrogen and Oxygen Gas-Phase Thermochemistry in Hypersonic Flows
    (2016-02) Bender, Jason
    Understanding hypersonic aerodynamics is important for the design of next generation aerospace vehicles for space exploration, national security, and other applications. Ground-level experimental studies of hypersonic flows are difficult and expensive; thus, computational science plays a crucial role in this field. Computational fluid dynamics (CFD) simulations of extremely high-speed flows require models of chemical and thermal nonequilibrium processes, such as dissociation of diatomic molecules and vibrational energy relaxation. Current models are outdated and inadequate for advanced applications. We describe a multiscale computational study of gas-phase thermochemical processes in hypersonic flows, starting at the atomic scale and building systematically up to the continuum scale. The project was part of a larger effort centered on collaborations between aerospace scientists and computational chemists. We discuss the construction of potential energy surfaces for the N4, N2O2, and O4 systems, focusing especially on the multi-dimensional fitting problem. A new local fitting method named L-IMLS-G2 is presented and compared with a global fitting method. Then, we describe the theory of the quasiclassical trajectory (QCT) approach for modeling molecular collisions. We explain how we implemented the approach in a new parallel code for high-performance computing platforms. Results from billions of QCT simulations of high-energy N2 + N2, N2 + N, and N2 + O2 collisions are reported and analyzed. Reaction rate constants are calculated and sets of reactive trajectories are characterized at both thermal equilibrium and nonequilibrium conditions. The data shed light on fundamental mechanisms of dissociation and exchange reactions – and their coupling to internal energy transfer processes – in thermal environments typical of hypersonic flows. We discuss how the outcomes of this investigation and other related studies lay a rigorous foundation for new macroscopic models for hypersonic CFD. This research was supported by the Department of Energy Computational Science Graduate Fellowship and by the Air Force Office of Scientific Research Multidisciplinary University Research Initiative.
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    Structure and Dynamics of Micelle-Forming Asymmetric Diblock Copolymer Chains
    (2021-09) Chawla, Anshul
    Experiments on micelle-forming asymmetric diblock copolymer melts have shown the existence of a liquid-like state of micelles at temperatures greater than the order-disorder transition temperature (ODT).These micelles have been hypothesized to appear at an even greater temperature called the critical micelle temperature (CMT). The regime between the CMT and ODT, called the disordered micellar regime, has been known to affect the formation of many exotic phases like the Frank-Kasper and the Laves phases due to its slow dynamics. Self-Consistent Field Theory (SCFT), one of the most commonly employed theoretical tools, only predicts the appearance of micelles in stationary and periodic configurations, and hence is incapable of capturing the disordered micellar regime. Some previous theoretical studies do provide predictions of the structural properties of the disordered micelles, however, these studies used SCFT predictions of free energies of isolated micelles to approximate the free energy of disordered micelles. We have used coarse-grained classical molecular dynamics to simulate melts of asymmetric diblock copolymer chains having a minority block volume fraction, $f = 0.125$.At high $\chi N$, where $\chi$ is the Flory-Huggins interaction parameter and $N$ is the degree of polymerization, SCFT predicts the formation of ordered micellar phases for this volume fraction. Our simulations show the existence of a disordered micellar regime for $\chi N$ above the $\cNso$, where $\cNso$ is the value of $\chi N$ corresponding to the ODT predicted from SCFT. We study melts having two significantly different invariant degree of polymerization, $\overline {N} = 960$ and $3820$, that span the disordered homogenous phase, disordered micellar regime, and the ordered body-centered cubic (BCC) phase. The first part of this thesis pertains to analyzing the evolution of the structure of these melts as a function of $\chi N$.By using a cluster identification algorithm, we show that micelle-like clusters appear at a CMT with the appearance being much more sudden for the higher $\overline {N}$ simulations. Moreover, micelles appear when $\chi N$ is near $\cNso$. We also show that the signature of the presence of disordered micelles in scattering experiments (SAXS and SANS) arises at a somewhat higher $\chi N$ as compared to $\cNso$. Comparisons of the free energy derivative, peak wavenumber, micelle aggregation number and the free chain fraction obtained from simulations with these quantities calculated from SCFT show close agreement, thus emphasizing similarities in the structure of the disordered micelles and the ordered micelles predicted by SCFT at the same $\chi N$. Analysis of the shape of the identified clusters also reveal a rapid formation/breaking of bridges between micelles present in both disordered and ordered phases. The latter part of this thesis considers the dynamics of these melts, namely single chain diffusion and structural relaxation.Signatures of the sudden appearance of micelles at the CMT is also reflected in the analysis of the dynamic properties as a sudden slowdown in the molecular relaxation and an even more significant slow down in the structural relaxation. We measure the rate at which polymers are expelled from micelles, and relate this to the polymer diffusivity.
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    A study of bending deformations in carbon nanotubes using the objective molecular dynamics method.
    (2010-09) Nikiforov, Ilia A.
    Bending of carbon nanotubes is a topic which has applications in several areas of nanotechnology, including nanotoxicology and NEMS. Atomistic simulations are necessary to understand in detail the fundamentals and the phenomena observed in experiments. Objective molecular dynamics allows the imposition of angular boundary conditions on atomistic systems. Coupled with the Tersoff potential, objective MD is used to systematically investigate reversible elastic bending in carbon nanotubes up to 4:2 nm in diameter. A contrasting behavior is revealed. Single-wall tubes buckle in a gradual way, with a clear intermediate regime before they fully buckle and significant hysteresis between bending and unbending cycles, in agreement with previous studies. Multi-walled tubes with closed cores, not commonly studied using direct atomistic methods, exhibit a hysteresis-free, rate- and size-independent direct transition to an unusual wavelike mode with a 1 nm characteristic length. This rippling mode has a nearly-linear bending response and causes a #24; 35% reduction in the stiffiness of the thickest multi-walled tubes.
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    Toward Simulation of Complex Reactive Systems: Development and Application of Enhanced Sampling Methods
    (2018-03) Fetisov, Evgenii
    redictive modeling of fluid phase and sorption equilibria for reacting systems presents one of the grand challenges in the field of molecular simulation. Difficulties in the study of such systems arise from the need (i) to accurately model both strong, short-ranged interactions leading to the formation of chemical bonds and weak interactions representing the environment, and (ii) to sample the range of time scales involving frequent molecular collisions, slow diffusion, and infrequent reactive events. This thesis showcases some of my efforts in developing and applying advanced simulation methods to a variety of important systems. Chapters 2 and 3 describe how a novel Monte Carlo method (reactive first principles Monte Carlo or RxFPMC) can be used to overcome some limitations of existing methods for simulation of reactive systems. Chapter 4 shows how advanced sampling techniques in combination with sophisticated interatomic potentials can be used to elucidate nucleation pathways. Chapters 5 and 6 manifest how first principles simulations can be leveraged to understand liquid structure of novel complex solvents as well as reactive processes in such solvents. Finally, the last chapter discusses the use of smart sampling algorithms to study chemisorption of mixed ligands on nanoparticles.
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    Understanding the membrane biophysics of alpha-Synuclein and its role in membrane curvature induction and structural remodeling
    (2014-07) Braun, Anthony Robert
    Alpha-Synuclein (aSyn) is a 140 amino acid, intrinsically disordered protein that adopts an extended amphipathic alpha-helical structure upon binding the membrane. aSyn is the major proteinaceous component of insoluble fibrillar Lewy bodies, a hallmark of Parkinson's disease (PD). The precise roles of both native and pathological forms of aSyn remain unclear. However, the interaction of aSyn with cellular membranes is now thought to be critical to its native function, and potentially to its role in PD. In vivo studies with overexpressed aSyn shows a stalling of vesicle fusion at the plasma membrane, whereas in vitro studies of small lipid vesicles and aSyn demonstrate an inhibition of vesicle fusion. In addition, numerous biophysical studies have identified potential curvature sensing and curvature inducing characteristics for aSyn, however the mechanism behind these processes is not well understood. The work in this thesis explores the membrane remodeling capacity of aSyn using a combination of computational (molecular dynamics simulation, MD) and experimental (x-ray scattering) methods to try to understand how aSyn interacts with lipid bilayers and potentially gain insight into the native function of the protein. Using a novel set of analysis algorithms we show that binding of aSyn to lipid bilayers thins the membrane and induces a stabilized intrinsic curvature field--whose magnitude matches the curvature of vesicles that aSyn has the highest binding affinity for. We also show that with equal surface density of protein, aSyn vesiculates giant unilamellar vesicles in a lipid-headgroup charge dependent manner. Using an extensive series of MD simulations we demonstrate that aSyn induced membrane remodeling is driven by the protein's binding affinity, partition depth, and induced inter-leaflet order asymmetry. In order to study the more physiologically relevant vesicle bound state, we have also simulated a series of lipid vesicles (with and without bound aSyn). Analysis of these systems required a new algorithm that employed spherical harmonics analysis to extract both structural and mechanical properties from the vesicles. We observe a reduction in bending rigidity and surface tension due to binding of aSyn. This result supports our hypothesis that aSyn stabilized highly curve vesicles--inhibiting vesicle fusion--through a relief of curvature stress (surface tension) inherent to the highly curved membrane.