Browsing by Subject "Molecular dynamics"
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Item Computational kinetics of a large scale biological process on GPU workstations : DNA bending(2013-05) Ruymgaart, Arnold Peter; Elber, RonIt has only recently become possible to study the dynamics of large time scale biological processes computationally in explicit solvent and atomic detail. This required a combination of advances in computer hardware, utilization of parallel and special purpose hardware as well as numerical and theoretical approaches. In this work we report advances in these areas contributing to the feasibility of a work of this scope in a reasonable time. We then make use of them to study an interesting model system, the action of the DNA bending protein 1IHF and demonstrate such an effort can now be performed on GPU equipped PC workstations. Many cellular processes require DNA bending. In the crowded compartment of the cell, DNA must be efficiently stored but this is just one example where bending is observed. Other examples include the effects of DNA structural features involved in transcription, gene regulation and recombination. 1IHF is a bacterial protein that binds and kinks DNA at sequence specific sites. The 1IHF binding to DNA is the cause or effect of bending of the double helix by almost 180 degrees. Most sequence specific DNA binding proteins bind in the major groove of the DNA and sequence specificity results from direct readout. 1IHF is an exception; it binds in the minor groove. The final structure of the binding/bending reaction was crystallized and shows the protein arm like features "latched" in place wrapping the DNA in the minor grooves and intercalating the tips between base pairs at the kink sites. This sequence specific, mostly indirect readout protein-DNA binding/bending interaction is therefore an interesting test case to study the mechanism of protein DNA binding and bending in general. Kinetic schemes have been proposed and numerous experimental studies have been carried out to validate these schemes. Experiments have included rapid kinetics laser T jump studies providing unprecedented temporal resolution and time resolved (quench flow) DNA foot-printing. Here we complement and add to those studies by investigating the mechanism and dynamics of the final latching/initial unlatching at an atomic level. This is accomplished with the computational tools of molecular dynamics and the theory of Milestoning. Our investigation begins by generating a reaction coordinate from the crystal structure of the DNA-protein complex and other images generated through modelling based on biochemical intuition. The initial path is generated by steepest descent minimization providing us with over 100 anchor images along the Steepest Descent Path (SDP) reaction coordinate. We then use the tools of Milestoning to sample hypersurfaces (milestones) between reaction coordinate anchors. Launching multiple trajectories from each milestone allowed us to accumulate average passage times to adjacent milestones and obtain transition probabilities. A complete set of rates was obtained this way allowing us to draw important conclusions about the mechanism of DNA bending. We uncover two possible metastable intermediates in the dissociation unkinking process. The first is an unexpected stable intermediate formed by initial unlatching of the IHF arms accompanied by a complete "psi-0" to "psi+140" conformational change of the IHF arm tip prolines. This unlatching (de-intercalation of the IHF tips from the kink sites) is required for any unkinking to occur. The second intermediate is formed by the IHF protein arms sliding over the DNA phosphate backbone and refolding in the next groove. The formation of this intermediate occurs on the millisecond timescale which is within experimental unkinking rate results. We show that our code optimization and parallelization enhancements allow the entire computational process of these millisecond timescale events in about one month on 10 or less GPU equipped workstations/cluster nodes bringing these studies within reach of researchers that do not have access to supercomputer clusters.Item Computational statistical mechanics of protein function(2014-08) Mugnai, Mauro Lorenzo; Elber, RonMolecular dynamics (MD) provides an atomically detailed description of the dynamics of a system of atoms. It is a useful tool to understand how protein function arises from the dynamics of the atoms of the protein and of its environment. When the MD model is accurate, analyzing a MD trajectory unveils features of the proteins that are not available from a single snapshot or a static structure. When the sampling of the accessible configurations is accurate, we can employ statistical mechanics (SM) to connect the trajectory generated by MD to experimentally measurable kinetic and thermodynamic quantities that are related to function. In this dissertation I describe three applications of MD and SM in the field of biochemistry. First, I discuss the theory of alchemical methods to compute free energy differences. In these methods a fragment of a system is computationally modified by removing its interactions with the environment and creating the interactions of the environment with the new species. This theory provides a numerical scheme to efficiently compute protein-ligand affinity, solvation free energies, and the effect of mutations on protein structure. I investigated the theory and stability of the numerical algorithm. The second research topic that I discuss considers a model of the dynamics of a set of coarse variables. The dynamics in coarse space is modeled by the Smoluchowski equation. To employ this description it is necessary to have the correct potential of mean force and diffusion tensor in the space of coarse variables. I describe a new method that I developed to extract the diffusion tensor from a MD simulation. Finally, I employed MD simulations to explain at a microscopic level the stereospecificity of the enzyme ketoreductase. To do so, I ran multiple simulations of the enzyme bound with the correct ligand and its enantiomer in a reactive configuration. The simulations showed that the enzyme retained the correct stereoisomer closer to the reactive configuration, and highlighted which interactions are responsible for the specificity. These weak physical interactions enhance binding with the correct ligand even prior to the steps of chemical modification.Item Controlled self-assembly of charged particles(2010-05) Shestopalov, Nikolay Vladimirovic; Rodin, G. J. (Gregory J.); Henkelman, GraemeSelf-assembly is a process of non-intrusive transformation of a system from a disordered to an ordered state. For engineering purposes, self-assembly of microscopic objects can benefit significantly from macroscopic guidance and control. This dissertation is concerned with controlling self-assembly in binary monolayers of electrically charged particles that follow basic laws of statistical mechanics. First, a simple macroscopic model is used to determine an optimal thermal control for self-assembly. The model assumes that a single rate-controlling mechanism is responsible for the formation of spatially ordered structures and that its rate follows an Arrhenius form. The model parameters are obtained using molecular dynamics simulations. The optimal control is derived in an analytical form using classical optimization methods. Two major lessons were learned from that work: (i) isothermal control was almost as effective as optimal time-dependent thermal control, and (ii) neither electrostatic interactions nor thermal control were particularly effective in eliminating voids formed during self-assembly. Accordingly, at the next stage, the focus is on temperature-pressure control under isothermal-isobaric conditions. In identifying optimal temperature and pressure conditions, several assumptions, that allow one to relate the optimal conditions to the phase diagram, are proposed. Instead of verifying the individual assumptions, the entire approach is verified using molecular dynamics simulations. It is estimated that under optimal isothermal-isobaric conditions the rate of self-assembly is about five time faster than that under optimal temperature control conditions. It is argued that the proposed approach of relating optimal conditions to the phase diagram is applicable to other systems. Further, the work reveals numerous and useful parallels between self-assembly and crystal physics, which are important to exploit for developing robust engineering self-assembly processes.Item Dynamical simulation of molecular scale systems : methods and applications(2010-12) Lu, Chun-Yaung; Henkelman, Graeme; Rossky, Peter J.; Makarov, Dmitrii E.; Vanden Bout, David A.; Truskett, Thomas M.Rare-event phenomena are ubiquitous in nature. We propose a new strategy, kappa-dynamics, to model rare event dynamics. In this methodology we only assume that the important rare-event dynamics obey first-order kinetics. Exact rates are not required in the calculation and the reaction path is determined on the fly. kappa-dynamics is highly parallelizable and can be implemented on computer clusters and distributed machines. Theoretical derivations and several examples of atomic scale dynamics are presented. With single-molecule (SM) techniques, the individual molecular process can be resolved without being averaged over the ensemble. However, factors such as apparatus stability, background level, and data quality will limit the amount of information being collected. We found that the correlation function calculated from the finite-size SM rotational diffusion trajectory will deviate from its true value. Therefore, care must be taken not to interpret the difference as the evidence of new dynamics occurred in the system. We also proposed an algorithm of single fluorophore orientation reconstruction which converts three measured intensities {I₀,I₄₅,I₉₀} to the dipole orientation. Fluctuations in the detected signals caused by the shot noise result in a different prediction from the true orientation. This difference should not be interpreted as the evidence of the nonisotropic rotational motion. Catalytic reactions are also governed by the rare-events. Studying the dynamics of catalytic processes is an important subject since the more we learn, the more we can improve current catalysts. Fuel cells have become a promising energy source in the past decade. The key to make a high performance cell while keeping the price low is the choice of a suitable catalyst at the electrodes. Density functional theory calculations are carried out to study the role of geometric relaxation in the oxygen-reduction reaction for nanoparticle of various transition metals. Our calculations of Pt nanoparticles show that the structural deformation induced by atomic oxygen binding can energetically stabilize the oxidized states and thus reduces the catalytic activity. The catalytic performance can be improved by making alloys with less deformable metals.Item Elastic network & finite element model to study actin protein mechanics & its molecular elasticity(2010-12) Marquez, Joel David; Moon, T. J. (Tess J.); Ren, PengyuWhile there have been many recently developed Elastic Network Models (ENM) to calculate the fluctuation dynamics of proteins, e.g., Gaussian Network Model (GNM), Anisotropic Network Model (ANM), Distance Network Model (DNM), the concept of loading these models to study the molecular mechanics and constitutive behavior of structural proteins has remained relatively untouched, until very recently. This work entails using the ANM as the framework for developing a finite element model of a 9–monomer strand of actin. Critical input parameters to the model, such as the cutoff radius, r[subscript c], and spring constant, k, are generated by matching the all-atom steered molecular dynamics (SMD) residue displacements to that of the ANM. The parameters yielding the best match between the SMD and structural ENM (SENM) simulations will then be input into the finite element model (FEM) for a more in depth analysis. The finite element model incorporates a 9–monomer strand of actin. The F–actin strand is subjected axial and torsional loads comparable to those seen in vivo. Key areas of interest in the protein are examined, such as the nucleotide binding pocket (NBP) and the DNase I binding loop, to demonstrate how loading affects the protein’s conformation. Local residue displacements are tracked in an effort to garner a better understanding of how various loads are transmitted through F–actin during key events. Insights and conclusions are discussed along with the implications of this work.Item Electronic decoherence and nonadiabatic chemical dynamics in betaine dye molecules(2003) Hwang, Hyonseok; Rossky, Peter J.The effect of electronic decoherence on nonadiabatic (NA) transition rate is investigated with nuclear overlap/phase function (NOPF) and mixed quantum/classical molecular dynamics (MQC-MD) simulations are performed to obtain the NA transition rate on betaine dye molecules. First of all, spinboson model with ohmic spectral density is used to explore electronic decoherence. We obtain a decoherence function by comparing two solutions for the canonical NOPF based on quantum mechanical and mixed quantum/classical methods, respectively. We provide an electronic decoherence time under short time and high temperature limits. Secondly, electronic decoherence only induced by intramolecular vibrational motions is studied with the NOPF in the simplest betaine molecule, pyridinium-N-phenoxide betaine [4-(1-pyridinio)phenolate]. Decoherence times from several approximations are obtained, including the role of frequency shifts and Duschinsky rotation. We find that the low frequency torsional motion does not make any significant contribution to the decay of the NOPF. Frequency shifts have more effect on the decay of the NOPF, than Duschinsky rotation does, but the simplest spinboson model alone describes coherence decay quite well. At longer times, we observe an exponential decay modulated by phase recurrence, but the contribution of the exponential decay to the relaxation is small. Calculated ultrafast decoherence time scales from intramolecular vibrational motions indicate that nuclear motions in solute can have more influence on the total electronic decoherence than does solvent. Thirdly, Frank-Condon (FC) density function in the simplest betaine molecule is calculated, combining the sum-over-states method and the time-dependent method. The FC density function for harmonic vibrational modes is computed by a modified three level-fixed binary tree algorithm including the role of frequency shifts and Duschinsky rotation. For the torsional mode, FC density is computed with the time-dependent method. We find that frequency shifts affect FC density function more than Duschinsky rotation does. The lack of a strong exponential decay in the high frequency region of the FC density function implies that the vibrational motions in the simplest betaine fall onto the strong coupling limit. Finally, Nuclear NA coupling matrix elements by intramolecular vibrational motions are analytically calculated with the spin-boson model. Limitations and applications of the calculation are discussed.Item Elucidating binding modes of zuonin A enantiomers to JNK1 via in silico methods(2013-05) Dykstra, Daniel William; Ren, PengyuAberrant JNK signaling can result in two main forms of disease in humans: 1) neurological, coronary, hepatobiliary, and respiratory diseases and 2) autoimmune, inflammatory, and cancer conditions. Enantiomers of the lignan zuonin A, (-)-zuonin A and (+)-zuonin A, have been shown to bind to JNK isoforms with similar affinity and disrupt protein-protein interactions at JNK's D-recruitment site, making them a good candidate for specific non-ATP competitive inhibitors. However, (-)-zuonin A inhibits 80% of JNK catalyzed reactions at saturating levels, while (+)-zuonin A only inhibits 15%. Molecular docking and molecular dynamics simulations were performed to gain a better understanding of how these inhibitors interact JNK. The results of this study provide an alternative binding mode for (-)-zuonin A, compared to one proposed in a previous study, that shows (-)-zuonin A interacting with JNK via an induced fit mechanism by forming a larger pocket for itself near the highly conserved [phi]A-X-[phi]B recognition site, a dynamic move not seen in (+)-zuonin A simulations, and may help explain their different inhibition patterns.Item Examination of focal adhesion kinase’s FAT domain structural response to applied mechanical load(2012-05) Alotaibi, Talal Eid; Moon, T. J. (Tess J.); Ren, PengyuFocal adhesion kinase (FAK) is a non-receptor tyrosine kinase. Activated FAK is crucial to many biological processes, such as cell proliferation, migration, and survival, all of which have been implicated in the progression and development of cancer. Tyrosine 925 is a Src-phosphorylation site that is located within the FAT domain in the C-terminal of FAK. It has been suggested that the helix containing Y925 (Helix 1) has to come out of the FAT bundle and the region flanking Y925 has to adopt β-strand conformation. In order to phosphorylate, the mechanisms promoting the required structural changes are unclear. So, Molecular Dynamics (MD) and Constant Force Molecular Dynamics (CFMD) simulations were used to study what makes Y925 accessible for phosphorylation. Under thermal fluctuation only and in the presence or the absence of LD motifs, MD simulations suggest that H1 does not appear to have a propensity to leave the bundle adopt β-strand conformation. Then, two different load scenarios were used; axial and perpendicular with 100 pN constant load applied to H1 N-terminus with the two paxillin LD motifs constrained. For both load scenarios, H1 has two different behaviors: typical and atypical. In the axial load scenario, the first two residues at the N-terminal of H1 (besides Y925) have low propensity to unfold. However, H1 does not show any proclivity to leave the bundle. For the perpendicular load scenario with the absence of P2 (LD motif binds to H1/H4 hydrophobic patch), one simulation out of 21 showed that H1 undergoes the required structural rearrangement. In general, CFMD simulations show that the FAT domain has a very low propensity (3%) to undergo the structural changes needed for Y925 phosphorylation. This has two implications: either mechanical load is insufficient to make Y925 available for phosphorylation and/or this kind of process (structural changes needed for Y925 phosphorylation) is slow process that needs a long time to occur.Item From polymer collapse to confined fluids : investigating the implications of nterfacial structuring(2009-08) Goel, Gaurav; Truskett, Thomas Michael, 1973-In the first part of this thesis, we present results from extensive molecular dynamics simulations of the collapse transitions of hydrophobic polymers in explicit water. The focus is to understand the roles that curvature and interactions associated with the polymer-water “interface” have on collapse thermodynamics. We show that model hydrophobic polymers can have parabolic, protein-like, temperature-dependent free energies of unfolding. Analysis of the water structure shows that the polymer-water interface can be characterized as soft and weakly dewetted. We also show that an appropriately defined surface tension for the polymer-water interface is independent of the attractive polymer-water interactions. This helped us to develop a perturbation model for predicting the effect of attractions on polymer collapse thermodynamics. In the second part, we explore connections between structure, thermodynamics, and dynamics of inhomogeneous fluids. First, we use molecular dynamics simulations and classical density functional theory (DFT) to study the hard-sphere fluid at approximately 103 equilibrium state points, spanning different confining geometries and particle-boundary interactions. We provide strong empirical evidence that both excess entropy and a new generalized measure of available volume for inhomogeneous fluids correlate excellently with self-diffusivity, approximately independent of the degree of confinement. Next, we study via simulations how tuning particle-wall interactions to flatten or enhance the particle layering of a model confined fluid impacts its self-diffusivity, viscosity, and entropy. Interestingly, interactions that eliminate particle layering can significantly reduce confined fluid mobility, whereas those that enhance layering can have the opposite effect. Excess entropy helps to understand and predict these trends. Finally, we explore the relationships between the effective interparticle interactions, static structure, and tracer diffusivity of a solute in a mixture. We show that knowledge of these relationships can allow one to “tune” the effective interparticle interactions of the solute in a way that increases its tracer diffusivity. One interesting consequence is that the mobility of a hard-sphere solute can be increased by adding a soft-repulsion to its interaction, effectively making it bigger.Item Modeling of gold nanocrystal assemblies in superlattices and vesicles, and the synthesis of nanocrystals for low-temperature solar cell fabrication(2015-05) Bosoy, Christian Alan; Korgel, Brian Allan, 1969-; Mullins, Charles B; Truskett, Thomas M; Milliron, Delia; Vanden Bout, David ARecently, nanocrystal (NC) research has grown substantially, due to their unique and diverse properties. Their flexibility has led to a wide set of proposed applications, such as contrast agents in biomedical fields, ordered nanostructures for microelectronics/plasmonics, and as a cheaper alternative to chemical vapor deposition (CVD) methods. While great advancements have been made in utilizing NCs, three challenges often arise – difficulty in characterizing complex nano-systems, a lack of theoretical exploration as to how or why nanocrystals assemble, and challenges in exploiting the benefits of nanocrystals while minimizing disadvantageous properties. This dissertation will address each of these issues in specific systems. First, thorough work has been done suggesting that hydrophobic gold nanocrystals can be encapsulated in vesicle bilayers. However, the primary characterization method for this system is Cryo-Transmission Electron Microscopy, which cannot provide adequate resolution and contrast to fully characterize nanostructures. Here, small angle x-ray scattering is explored as a method for revealing detailed information regarding the bilayer structure. vii Next gold nanocrystal superlattices are explored through molecular dynamics (MD) simulations. While many works have shown crystal structure transitions in a variety of systems, a detailed explanation as to why certain crystal structures are preferred has yet to be provided. This work offers detailed MD simulations to reveal details regarding the packing density of various crystal structures and to estimate diffusion coefficients in various packings. Furthermore, the free energy difference between BCC and FCC configurations for a small set of gold nanocrystals is explored by thermodynamic integration. The simulated properties are also compared to a small set of real systems. The second half of this dissertation addresses practical applications of NCs for photovoltaics. Despite manufacturing benefits, it is well known that the small NC grains and insulating capping ligands make it difficult to produce efficient solar cells. Therefore, two approaches to removing these ligands and growing nanocrystal grains are explored. The first approach focuses on further studying CuInSe2 synthesis as a window into grain growth. The second offers an example of a material with favorable properties for grain growth – Cu3BiS3 – and addresses difficulties in producing it.Item Modeling the structure, dynamics, and interactions of biological molecules(2013-05) Xia, Zhen, active 2013; Ren, PengyuBiological molecules are essential parts of organisms and participate in a variety of biological processes within cells. Understanding the relationship between sequence, structure, and function of biological molecules are of fundamental importance in life science and the health care industry. In this dissertation, a multi-scale approach was utilized to develop coarse-grained molecular models for protein and RNA simulations. By simplifying the atomistic representation of a biomolecular system, the coarse-grained approach enables the molecular dynamics simulations to reveal the biological processes, which occur on the time and length scales that are inaccessible to the all-atom models. For RNA, an "intermediate" coarse-grained model was proposed to provide both accuracy and efficiency for RNA 3D structure modeling and prediction. The overall potential parameters were derived based on structural statistics sampled from experimental structures. For protein, a general, transferable coarse-grain framework based on the Gay-Berne potential and electrostatic point multipole expansion was developed for polypeptide simulations. Next, an advanced atomistic model was developed to model electrostatic interaction with high resolution and incorporates electronic polarization effect that is ignored in conventional atomistic models. The last part of my thesis work involves applying all-atom molecular simulations to address important questions and problems in biophysics and structural biology. For example, the interaction between protein and miRNA, the recognition mechanism of antigen and antibody, and the structure dynamics of protein in mixed denaturants.Item Molecular dynamics simulation of montmorillonite and mechanical and thermodynamic properties calculations(2009-05-15) Atilhan, SelmaNanocomposites refer to the materials in which the defining characteristic size of inclusions is in the order of 10-100nm. There are several types of nanoparticle inclusions with different structures: metal clusters, fullerenes particles and molybdenum selenide, Our research focus is on polymer nanocomposites with inorganic clay particles as inclusions, in particular we used sodium montmorillonite polymer nanocomposite. In our study, modeling and simulations of sodium montmorillonite (Na+-MMT) is currently being investigated as an inorganic nanocomposite material. Na+-MMT clay consists of platelets, one nanometer thick with large lateral dimensions, which can be used to achieve efficient reinforcement of polymer matrices. This nanocomposite has different applications such as a binder of animal feed, a plasticizing agent in cement, brick and ceramic, and a thickener and stabilizer of latex and rubber adhesives. In this study, sodium montmorillonite called Na+-MMT structure is built with the bulk system and the layered system which includes from 1 to 12 layers by using Crystal Builder of Cerius2. An isothermal and isobaric ensemble is used for calculation of thermodynamic properties such as specific heat capacities and isothermal expansion coefficients of Na+-MMT. A canonical ensemble which holds a fixed temperature, volume and number of molecules is used for defining exfoliation kinetics of layered structures and surface formation energies for Na+-MMT layered structures are calculated by using a canonical ensemble. Mechanical properties are used to help characterize and identify the Na+-MMT structure. Several elastic properties such as compliance and stiffness matrices, Young's, shear, and bulk modulus, volume compressibility, Poisson's ratios, Lam? constants, and velocities of sound are calculated in specified directions. Another calculation method is the Vienna Ab-initio Simulation Package (VASP). VASP is a complex package for performing ab-initio quantum-mechanical calculations and molecular dynamic (MD) simulations using pseudopotentials and a plane wave basis set. Cut off energy is optimized for the unit cell of Na+-MMT by using different cut off energy values. Experimental and theoretical cell parameters are compared by using cell shape and volume optimization and root mean square (RMS) coordinate difference is calculated for variation of cell parameters. Cell shape and volume optimization are done for calculating optimum expansion or compression constant.Item Molecular dynamics study of solvation phenomena to guide surfactant design(2009-12) Dalvi, Vishwanath Haily; Rossky, Peter J.Supercritical carbon-dioxide has long been considered an inexpensive, safe and environmentally benign alternative to organic solvents for use in industrial processing. However, at readily accessible conditions of temperature and pressure, it is by itself too poor a solvent for a large number of industrially important solutes and its use as solvent necessitates concomitant use of surfactants. Especially desirable are surfactants that stabilize dispersions of water droplets in carbon-dioxide. So far only molecules containing substantially fluorinated moieties e.g. fluoroalkanes and perfluorinated polyethers, as the CO₂-philes have proved effective in stabilizing dispersions in supercritical carbon-dioxide. These fluorocarbons are expensive, non-biodegradable and can degrade to form toxic and persistent environmental pollutants. Hence there is great interest in developing non-fluorous alternatives. Given the development of powerful computers, excellent molecular models and standardized molecular simulation packages we are in a position to augment the experiment-driven search for effective surfactants using the nanoscopic insights gleaned from analysis of the results of molecular simulations. We have developed protocols by which to use standard and freely available molecular simulation infrastructure to evaluate the effectiveness of surfactants that stabilize solid metal nanoparticles in supercritical fluids. From the results, which we validated against experimental observations, we were able to determine that the alkane-based surfactants, that are so effective in organic fluids, are ineffective or only partially effective in CO₂ because the weak C-H dipoles cannot make up for the energetic penalty incurred at the surfactant-fluid interface by CO₂ molecules due to loss of quadrupolar interactions with other CO₂ molecules. Though the effectiveness of purely alkane-based surfactants in carbon-dioxide can be improved by branching, they cannot approach the effectiveness of the fluoroalkanes. This is because the stronger C-F dipole can supply the required quadrupolar interactions and a unique geometry renders repulsive the fluorocarbons' electrostatic interactions with each other. We have also determined the source of the fluoroalkanes' hydrophobicity to be their size which offsets the effect of favourable electrostatic interactions with water. Hence we can provide guidelines for CO₂-philic yet hydrophobic surfactants.Item Molecular dynamics: Hooke-Lennard-Jones hybrid method(2012-05) Blackwell, Morgan; Smith, Philip W.; Long, KevinIn this thesis we apply Hookes law and the Lennard-Jones potential together forming a hybrid potential energy function to model atomic interaction. These molecular dynamics simulations are then implemented in Matlab. For each simulation, we construct a cubic lattice of particles set at an equilibrium distance apart with most particles given an initial random velocity. The simulations are representative of generic solids. We observe how the system moves through time as the particles interact with one another. We are interested in investigating the e ciency of our Matlab implementation, evaluating the accuracy of the Runge-Kutta integration algorithm being used, and assessing the appropriateness of this hybrid potential to model cubic lattices. This paper discusses the advantages and disadvantages of applying the fourth order Runge-Kutta (RK4) quadrature method to Newtons second law of motion in order to produce the trajectories of each particle in the system as they vary with time. Knowing that the RK4 method will not conserve energy, we observe how large our simulations can get before it produces too much error resulting in the loss or gain of energy. We also report on the run time performance of the code and suggest future improvements.Item Molecular investigation of polypyrrole and surface recognition by affinity peptides(2011-12) Fonner, John Michael; Ren, Pengyu; Schmidt, Christine E.; Elber, Ron; Roy, Krishnendu; Georgiou, GeorgeSuccessful tissue engineering strategies in the nervous system must be carefully crafted to interact favorably with the complex biochemical signals of the native environment. To date, all chronic implants incorporating electrical conductivity degrade in performance over time as the foreign body reaction and subsequent fibrous encapsulation isolate them from the host tissue. Our goal is to develop a peptide-based interfacial biomaterial that will non-covalently coat the surface of the conducting polymer polypyrrole, allowing the implant to interact with the nervous system through both electrical and chemical cues. Starting with a candidate peptide sequence discovered through phage display, we used computational simulations of the peptide on polypyrrole to describe the bound peptide structure, explore the mechanism of binding, and suggest new, better binding peptide sequences. After experimentally characterizing the polymer, we created a molecular mechanics model of polypyrrole using quantum mechanics calculations and compared its in silico properties to experimental observables such as density and chain packing. Using replica exchange molecular dynamics, we then modeled the behavior of affinity binding peptides on the surface of polypyrrole in explicit water and saline environments. Relative measurements of the contributions of each amino acid were made using distance measurements and computational alanine scanning.Item Molecular simulations involving various potential functions and integration methods(2012-08) Hansen, Chris; Smith, Philip W.; Howle, Victoria E.This thesis focuses on molecular dynamics simulations utilizing different integration methods and analytic potential models. A model involving the elastic potential, a model utilizing the Lennard-Jones potential, and a model that combines the two are presented using a symplectic and non-symplectic integration scheme for each model. Changes in the energy of the system are tracked in order to observe any potential drift in total energy, and tradeoffs between accuracy and computational efficiency among the different models and integration schemes employed are explored. The size of the system is varied as well to gauge the impact of system size on a simulation's run time.Item Multi-disciplinary study of lanthanide chelates as multi-modal molecular imaging agents(Texas Tech University, 2004-05) Manning, Henry CharlesMolecular imaging is a powerful tool that has the ability to elucidate biochemical mechanisms and signal the early onset of disease. Lanthanide chelates represent a unique class of molecular imaging agents that can yield multi-modal signatures including long-lived fluorescence and magnetic resonance. The primary aim of this dissertation is to demonstrate the utility of Lanthanide chelate molecular imaging agents for contrast enhanced disease demarcation. Traditionally, Lanthanide chelate imaging agents have been non-targeted perfusion agents that distribute in-vivo based on charge and lipophilicity. It is shown here that the structural features of the chelate can be modified to facilitate tunable spectroscopic and biodistribution properties in-vivo. While our perfusion-based agents have demonstrated considerable utility, their principal limitation is specificity. For increased specificity, we synthesized a trifunctional Lanthanide chelate that possessed an antenna for metal sensitization, phosphonate acid pendant arms for chelation, and a carboxylate arm for conjugation to targeting moieties such as antibodies, peptides, or small molecule ligands. Recently, peripheral benzodiazepine receptor (PBR) overexpression has been reported in many types of disease. Small molecule ligands of the PBR, such as PK11195, have been shown to bind with high affinity and thus could be used as contrast agent targeting moieties. Therefore, we synthesized a structural analogue of PK11195 that facilitates C-terminal conjugation. This form was then coupled to the trifunctional Lanthanide chelate and complexed with Europium and Gadolinium (Ln-PK11195). With the Ln-PK11195 agent in hand, it was demonstrated that PBR overexpressing C6 glioma cells would actively uptake the agent and that Ln-PK11195 seemed to be localizing on the PBR. Additionally, multi-modal imaging (fluorescence and MR) was shown possible on a single group of cells incubated with a Eu-PKl 1195 and Gd- PK11195 cocktail. Next, we demonstrated PBR profiling on surgically resected human tissue samples using Eu-PKl 1195, indicating a possible use as a histopathology stain. Both cancerous and non-cancerous PBR expressing disease was labeled with the agent. Finally, we fully characterized the primary spectroscopic signatures of Ln- PK11195 (time-resolved fluorescence and MR) for sensitivity to pH. It was shown that Ln-PK11195 demonstrates adequate pH sensitivity to measure localized, intracellular pH in tissues.Item On the mechanical response of helical domains of biomolecular machines : computational exploration of the kinetics and pathways of cracking(2013-05) Kreuzer, Steven Michael; Murthy, JayathiProtein mechanical responses play a critical role in a wide variety of biological phenomena, impacting events as diverse as muscle contraction and stem cell differentiation. Recent advances in both experimental and computational techniques have provided the opportunity to explore protein constitutive properties at the molecular level. However, despite these advances many questions remain about how proteins respond to applied mechanical forces, particularly as a function of load magnitude. In order to address these questions, relatively simple helical structures were computationally tested to determine the mechanisms and kinetics of unfolding at a range of physiologically relevant load magnitudes. Atomically detailed constant force molecular dynamics simulations combined with the Milestoning kinetic analysis framework revealed that the mean first passage time (MFPT) of the initiation of unfolding of long (~16nm) isolated helical domains was a non-monotonic function of the magnitude of applied tensile load. The unfolding kinetics followed a profile ranging from 2.5ns (0pN) to a peak of 3.75ns (20pN) with a decreasing MFPT beyond 40pN reflected by an MFPT of 1ns for 100pN. The application of the Milestoning framework with a coarse-grained network analysis approach revealed that intermediate loads (15pN-25pN) retarded unfolding by opening additional, slower unfolding pathways through non-native [pi]-helical conformations. Analysis of coiled-coil helical pairs revealed that the presence of the second neighboring helix delayed unfolding initiation by a factor of 20, with calculated MFPTs ranging from 55ns (0pN) to 85ns (25pN per helix) to 20ns (100pN per helix). The stability of the coiled-coil domains relative to the isolated helix was shown to reflect a decreased propensity to break flexibility restraining intra-helix hydrogen bonds, thereby delaying [psi] backbone dihedral angle rotation and unfolding. These results show for the first time a statistically determined profile of unfolding kinetics for an atomically detailed protein that is non-monotonic with respect to load caused by a change in the unfolding mechanism with load. Together, the methods introduced for analyzing the mechanical response of proteins as well as the timescales determined for the initiation of unfolding provide a framework for the determination of the constitutive properties of proteins and non-biological polymers with more complicated geometries.Item Optimization of force fields for molecular dynamics(2014-12) Di Pierro, Michele; Elber, RonA technology for optimization of potential parameters from condensed phase simulations (POP) is discussed and illustrated. It is based on direct calculations of the derivatives of macroscopic observables with respect to the potential parameters. The derivatives are used in a local minimization scheme, comparing simulated and experimental data. In particular, we show that the Newton Trust-Region protocol allows for accurate and robust optimization. POP is illustrated for a toy problem of alanine dipeptide and is applied to folding of the peptide WAAAH. The helix fraction is highly sensitive to the potential parameters while the slope of the melting curve is not. The sensitivity variations make it difficult to satisfy both observations simultaneously. We conjecture that there is no set of parameters that reproduces experimental melting curves of short peptides that are modeled with the usual functional form of a force field. We then apply the newly developed technology to study the liquid mixture of tert-butanol and water. We are able to obtain, after 4 iterations, the correct phase behavior and accurately predict the value of the Kirkwood Buff (KB) integrals. We further illustrate that a potential that is determined solely by KB information, or the pair correlation function, is not necessarily unique.Item Progress toward a novel ortho-functionalized cyclic phenylalanine dipeptide(Texas Tech University, 1997-12) Neff, Bartholomew WayneSubstance P, a neuropeptide found in various mammalian tissues, is involved a variety of physiological processes including the regulation of blood pressure, smooth muscle contraction, and cell growth. Assays have shown that the phenylalanine residues (Phe7 and Phe8) of Substance P are particularly important for receptor binding. Modeling studies, based on NMR data and P-methyl substitiution, seem to indicate a preferred conformation for the phenyl sidechains. This preferred conformation for these sidechains can be approximated, without backbone distortion, through the use of a sidechain ortho 0-CH2-O-CH2-CH2-O-CH2-0 linkage between the two residues. We report progress toward the synthesis of an ortho-linked, cyclic phenylalanine dipeptide [cyclo(Boc-Phe-Phe-O-t-Bu)] for incorporation into a Substance P analog as described above. We also report the development of a synthetic method, based on the camphorsultam-derived synthesis of phenylalanine, for the formation phenylalanines containing novel sidechain functionality. These ortho-functionalized phenylalanines are then modified with the appropriate protecting groups, coupled to form the acyclic dipeptide, and cyclized via a crown ether-like SN2 coupling with ethylene glycol.