The work in this thesis aims to gain fundamental understanding of several important types of disordered systems, including liquids, supercritical fluids and amorphous solids on the basis of extensive molecular dynamics simulations. I begin with studying the diffusion in amorphous zirconolite, a potential waste form to encapsulate highly radioactive nuclear waste. I find that amorphization has a dramatic effect for diffusion. Interestingly and differently from previous understanding, diffusion increases as a result of amorphization at constant density. Another interesting insight is related to different response of diffusion of different atomic species to structural disorder. I calculate activation energies and diffusion pre-factors which can be used to predict long-term diffusion properties in this system. This improves our understanding of how waste forms operate and provides a quantitative tool to predict their performance. I subsequently study the effects of phase coexistence and phase decomposition in Y-stabilized zirconia, the system of interest in many industrial applications including in encapsulating nuclear waste due to its exceptional resistance to radiation damage. For the first time I show how the microstructure emerges and evolves in this system and demonstrate its importance for self-diffusion and other properties. This has not been observed before and is important for better understanding of existing experiments and planning the new ones. I subsequently address dynamical properties of subcritical liquids and supercritical fluids. I start with developing a new empirical potential for CO2 with improved performance. Using this and other potentials, I simulate the properties of supercritical H2O, CO2 and CH4 and map their Frenkel lines in the supercritical region of the phase diagram. I observe that the Frenkel line for CO2 coincides with experimentally found maxima of solubility and explain this finding by noting that the Frenkel line corresponds to the optimal combination of density and temperature where the density is maximal and the diffusion is still in the fast gas-like regime. This can serve as a guide in future applications of supercritical fluids and will result in their more efficient use in dissolving and extracting applications. I extend my study to collective modes in liquids. Here, my simulations provide first direct evidence that a gap emerges and evolves in the reciprocal space in transverse spectra of liquids. I show that the gap increases with temperature and is inversely proportional to liquid relaxation time. Interestingly, the gap emerges and evolves not only in subcritical liquids but also in supercritical fluids as long as they are below the Frenkel line. Given the importance of phonons in condensed matter physics and other areas of physics, I propose that the discovery of the gap represents a paradigm change. There is an active interest in the dynamics of liquids and supercritical fluids, and I therefore hope that my results will quickly stimulate high-temperature and high-pressure experiments aimed at detecting and studying the gap in several important systems.

Water-mediated interactions between non-polar moieties play a crucial role in driving self-assembly processes such as surfactant micellization, protein folding, and many other diverse phenomena. Among a variety of forces contributing to the self assembly, hydrophobic interactions play a dominant role. Historically, thermodynamic models describing hydrophobic effects have invariably relied on macroscopic thermodynamic properties to infer this molecular behavior. Experimental studies help to probe the spatial correlations between model hydrophobic solutes and to measure their waters of hydration in order to examine structural perturbations in the surrounding water induced by the solute, or to measure directly the attractive forces between hydrophobic surfaces. Further, molecular simulations can be used to derive entropic and enthalpic contributions to the free energy of hydrophobic hydration in terms of water structure surrounding simple, model hydrophobic solutes, such as methane. Based on the results for simple solutes, these methods can now be extended to investigate the hydrophobic hydration of more complex molecular solutes of arbitrary size and shape such as micelles. Atomistic simulations of chemical systems provide a new perspective towards testing the theories behind the ubiquitous phenomenon of hydrophobic effect, and probe the underlying thermodynamic signatures. In this context, my research work delves into the water-mediated interactions leading to the hydrophobic hydration of short chain alkanes, volumetric properties of unfolded polypeptides and self-assembly mechanism in polymer-surfactant systems. The first part of my research involves re-optimization of existing force field interaction parameters for the CHn alkane sites (n=0 to 4) to accurately reproduce the experimental hydration free energies of linear and branched chain alkanes over a range of temperatures. This Hydrophobic Hydration-Alkane (HH-Alkane) model accounts for polarization effects in the alkane hydration and can be extended to polypeptides in water. Subsequent discussions will focus on the results from extensive molecular simulations of tri- and tetrapeptides to quantify the accuracy of the simulation model in capturing the volumetric properties of unfolded polypeptides. Group additivity correlation was used to calculate the partial molar volumes of the neutral sidechains of amino acids, glycine backbone unit and both zwitterionic and N-acetyl/amide terminal units. The simulation results will be compared to the experimental results to validate these observations. In addition, the research explores the self-assembly and aggregation mechanism in anionic sodium dodecyl sulfate (SDS) surfactant- non-ionic Polyethylene Oxide (PEO) and Poly vinyl pyrrolidone (PVP) polymer systems. Potential of mean force calculations at multiple temperatures show an increasing trend in hydrophobic attractions within the polymer-micelle system. Also, these simulations provide interesting insights into the experimentally observed phenomena between the polymers and the micelles starting from pre-formed structure as well as random configurations. / 1 / Lalitanand N. Surampudi

There is a growing body of interest to understand the regulation of allosteric proteins. Allostery is a phenomenon of protein regulation whereby binding of an effector molecule at a remote site affects binding and activity at the protein‟s active site. Over the years, these sites have become popular drug targets as they provide advantages in terms of selectivity and saturability. Both experimental and computational methods are being used to study and identify allosteric sites. Although experimental methods provide us with detailed structures and have been relatively successful in identifying these sites, they are subject to time and cost limitations. In the present dissertation, Molecular Dynamics Simulations (MDS) and Principal Component Analysis (PCA) have been employed to enhance our understanding ofallostery and protein dynamics. MD simulations generated trajectories which were then qualitatively assessed using PCA. Both of these techniques were applied to two important trypanosomatid drug targets and controlling enzymes of the glycolytic pathway - pyruvate kinase (PYK) and phosphofructokinase (PFK). Molecular Dynamics simulations were first carried out on both the effector bound and unbound forms of the proteins. This provided a framework for direct comparison and inspection of the conformational changes at the atomic level. Following MD simulations, PCA was run to further analyse the motions. The principal components thus captured are in quantitative agreement with the previously published experimental data which increased our confidence in the reliability of our simulations. Also, the binding of FBP affects the allosteric mechanism of PYK in a very interesting way. The inspection of the vibrational modes reveals interesting patterns in the movement of the subunits which differ from the conventional symmetrical pattern. Also, lowering of B-factors on effector binding provides evidence that the effector is not only locking the R-state but is also acting as a general heat-sink to cool down the whole tetramer. This observation suggests that protein rigidity and intrinsic heat capacity are important factors in stabilizing allosteric proteins. Thus, this work also provides new and promising insights into the classical Monod-Wyman-Changeux model of allostery.

The aim of this thesis is to investigate the structural and thermodynamic properties of biologically and technological relevant macromolecules when placed at soft interfaces. In particular two amphiphilic macromolecules characterized by different topologies have been investigated namely amphiphilic dendrimers and linear block copolymers. This goal is achieved using a multiscale approach which includes all-atom, united atom and coarse grained models by means of molecular dynamic simulations.Amphiphilic dendrimers have shown to be promising building blocks for a range of interfacial materials and can be used in applications such as surface-base sensors or surface nanopatterning. In this part of the thesis by means of all-atom molecular dynamics simulations, we investigated the structure and stability of alkyl-modified polyamido-amide (PAMAM) dendrimers at the air/water interface as a function of the number and the relative position of the modified end groups. We found that the PAMAM dendrimer with all terminal groups functionalized is more stable at the interface than the Janus dendrimer, where only half the amine groups are modified. These results indicate that monolayers of fully functionalized molecules could be as stable as (or more stable than) those self-assembled from Janus molecules.The second part of the thesis is devoted to model a particular family of amphiphilic triblock copolymer sold as Pluronics, consisting of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) arranged as PEO–PPO–PEO. There is evidence that this class of amphiphilic materials can be used for different biological applications. A fuller understanding of the molecular mechanisms underpinning their interactions with living cells is essential for ensuring the polymers safety and efficacy in biomedical applications. Using united-atom molecular dynamics simulations and membrane lysis assays, we investigated the relationship between the molecular conformations of a subset of the Pluronic copolymers (L31, L61, L62 and L64) and their haemolytic activity. Our computational studies suggest that the hydrophilic blocks in these copolymers interact with the polar head groups of lipid molecules, resulting in a predicted modification of the structure of the membranes. Parallel membrane lysis assays in human erythrocytes indicate differences in the rates of haemolysis, as a result of incubation with these polymers, which correlate well with the predicted interactions from the atomistic simulations. The computational data thus provide a putative mechanism to rationalize the available experimental data on membrane lysis by these copolymers. The data quantitatively agree with haemoglobin release endpoints measured when copolymers with the same molecular weight and structure as of those modelled are incubated with erythrocytes. The data further suggest some new structure– function relationships at the nanoscale that are likely to be of importance in determining the biological activity of these otherwise inert copolymers.In order to visualise the effect of Pluronics at a length and time scale closer to the experimental one, in the third part of the thesis we developed a coarse-grained model for the amphiphilic copolymers within the framework of the MARTINI forcefield (Marrink et al., J. Phys. Chem. B, 2007, 111, 7812). The MARTINI force field is usually parameterized targeting thermodynamic properties. In addition to this, we further parameterized it based on atomistic simulations validating the parameters against structural properties of the copolymers. The ability of the model to predict several structural and thermodynamic properties of the atomistic system have been explored. The aim of this work is to be able to simulate the polymer/lipid interface at polymer concentration similar to the experimental one.

Determining the molecular mechanisms at the origin of protein function remains a challenge due to the complex non-covalent interactions that shape their structure. Since the non-covalent interactions arise from charge fluctuations, electric fields can be used as a tool to quantify the interactions between a target and its environment. The contribution of each component of the system is reflected in the direction and strength of the electric field exerted on the target, which can be calculated from molecular dynamics simulations. The interactions experienced by ligands in enzymatic active sites determine the catalytic activity of the enzyme. Ligands in synthetic enzymes lack interactions with the protein scaffold, which limit their efficiency. To substitute for the role of non-effective protein scaffold, we introduced a polar DNA fragment to the enzyme vicinity, inducing electrostatic interactions that will facilitate the reaction. We found that the introduction of a DNA fragment enhanced the original interactions between the residues in the active site and the ligand, without creating new interaction hot spots. Using electric fields, we calculated a reduction in activation energy of 2.0 kcal/mol when introducing the DNA fragment, indicating a promising avenue for catalytic improvement. Inspired by the success in using electric fields to understand enzyme catalysis in the context of electrostatic preorganization theory, we generalized these fundamental concepts to another type of proteins: voltage-gated ion channels. Our results indicate that electric fields also report on channel activity. We find an asymmetry in the number of active residues for channel function between the four domains and between the two gating motifs of the permeation pathway, with domain I being the major contributor in both cases. The importance of residues for channel activity is not a simple linear correlation of their distance with the functional motif, but a relationship dominated by non-covalent interactions. Finally, we investigate the effects of loop dynamics on enzyme product inhibition. We modify the chemical nature of the unstructured loops that obstruct the active site of DszB by glycosylating serine and threonine residues. We monitor the corresponding variations in loop dynamics and their effect on the interaction between the enzyme and the product. Overall, promising results were found using electric fields in the investigation of protein mechanisms that are mainly dominated by non-covalent interactions and provide insight into the role of the individual components in the system. / Doctor of Philosophy / Although weaker than covalent interactions, non-covalent interactions play a crucial role in molecular biological processes, especially in protein mechanisms. In order to modify the properties of proteins to our advantage, we need a metric with which we can map these interactions onto the protein structure. Different types of non-covalent interactions share one similarity: they originate from the change of electron distribution of interacting atoms, therefore can be captured by analyzing the protein- generated electric fields. Synthetic enzymes are designed to better adapt to varying environments and catalyze a broader reaction range. However, they are less effective than natural enzymes because the protein scaffold does not contribute to catalysis. Indeed, protein scaffolds in natural enzymes generate an electric field that lowers the reaction activation energy in the active site. Protein scaffolds in synthetic enzyme do not generate such electric fields. To address this issue, we modified the environment of synthetic enzyme KE15, introducing a polar DNA fragment to induce interactions in the active site. This modification strengthen the interactions between protein and ligand, leading to a decrease in the energy required for the reaction. While enzymes are famous for their generation of electric fields facilitating function, we demonstrated that this phenomenon also exist in voltage-gated ion channels Nav1.7. Residues were found to exert an electric field that can facilitate ion permeation. This is not simply because of their distance to the key regions, but a result of the non-covalent interactions regulating the mechanism, with different regions showing asymmetric importance in the process. Since the governing non-covalent interactions are relatively weak, proteins are flexible, especially protein loops. In enzyme DszB, this loop flexibility enables a conformational change when the ligand binds the active site. The change in loop conformation traps the product inside the active site, limiting enzymatic turnover. To prevent active site obstruction by these flexible loops, we attached glucose to a few loop residues to modify the hydrophobicity profile near the active site. The introduction of hydrophilic glucoses helps to pull the loops towards the solvent, rather than towards the active site, limiting product inhibition while preserving catalytic activity. Overall, our results show that electric field can be applied as a general method for protein studies, relating structure to function.

Yes / Molecular dynamics (MD) simulations contain considerable information with regard to the motions and fluctuations of a protein, the magnitude of which can be used to estimate conformational entropy. Here we survey conformational entropy across protein fold space using the Dynameomics database, which represents the largest existing dataset of protein MD simulations for representatives of essentially all known protein folds. We provide an overview of MD-derived entropies accounting for all possible degrees of dihedral freedom on an unprecedented scale. Although different side chains might be expected to impose varying restrictions on the conformational space that the backbone can sample, we found that the backbone entropy and side chain size are not strictly coupled. An outcome of these analyses is the Dynameomics Entropy Dictionary, the contents of which have been compared with entropies derived by other theoretical approaches and experiment. As might be expected, the conformational entropies scale linearly with the number of residues, demonstrating that conformational entropy is an extensive property of proteins. The calculated conformational entropies of folding agree well with previous estimates. Detailed analysis of specific cases identify deviations in conformational entropy from the average values that highlight how conformational entropy varies with sequence, secondary structure, and tertiary fold. Notably, alpha-helices have lower entropy on average than do beta-sheets, and both are lower than coil regions. / National Institutes of Health, US Department of Energy Office of Biological Research, National Energy Research Scientific Computing Center, Swedish Research Council, Knut and Alic Wallenberg Foundation

Fluoropolymers are employed in countless end-user applications across several industries. One such fluoropolymer is polytetrafluoroethylene. This research is concerned with studying and understanding the thermal behavior of polytetrafluoroethylene. Such understanding is critical to predict its behavior in diverse service environments as the polymer ages and for allowing bottom up design of improved polymers for specific applications. While a plethora of experiments have investigated the thermal properties of polytetrafluoroethylene, examining these properties using molecular dynamics simulations remains in its infancy. In particular, the current body of molecular dynamics research on polytetrafluoroethylene has primarily focused on studying polytetrafluoroethylene phases, its physical nature, and its helical conformational structure. The present study is the first molecular dynamics simulations research to study polytetrafluoroethylene behavior near the glassy transition temperature. Specifically, the current research utilizes molecular dynamics simulations to achieve the following objectives: (a) model and predict polytetrafluoroethylene glassy transition temperature at different molecular weights, (b) examine the impact of glassy transition temperature on the volume-temperature and thermal properties, (c) study the influence of molecular weight on polytetrafluoroethylene melt and glassy state, and (d) determine the governing forces at the molecular level that control polytetrafluoroethylene glassy transition temperature. Achieving the aforementioned objectives requires performing four major tasks. Motivated by the scarcity of polytetrafluoroethylene force fields research, the first task aims to generate and test polytetrafluoroethylene force fields. The parameters were produced based on the Optimized Potentials for Liquid Simulations All Atom model. The intramolecular parameters were generated using the automated frequency matching method while the torsional terms were fitted using the nonlinear least squares algorithm. The intermolecular partial atomic charges were obtained using Northwest Computational Chemistry software and fitted using the restrained electrostatic potential at (MP2/6-31G*) level of theory. The final set of parameter was tested by calculating polytetrafluoroethylene density using molecular dynamics simulations. The second task involves building polytetrafluoroethylene amorphous structure using molecular dynamics at periodic boundary conditions for polytetrafluoroethylene cell at different molecular weights. We use the amorphous structure in the molecular dynamics simulations in consistence with research evidence which reveals that polymer properties such as the specific volume will differ as the polymer passes the glassy transition when it is in the amorphous phase structure whereas no variation occurs when the polymer passes the glassy transition while it is in the crystalline structure. The third task includes testing polytetrafluoroethylene melt phase properties: density, specific heat, boiling point, and enthalpy of vaporization. In the fourth and final task, we performed molecular dynamics simulations using NAnoscale Molecular Dynamics program. This task involves the polymer relaxation process to predict polytetrafluoroethylene mechanical behavior around the glassy transition temperature. Properties that are affected by this transition such as density, heat capacity, volumetric thermal expansion, the specific volume, and the bulk modulus were examined and the simulated results were in good agreement with experimental findings.

This dissertation aims to establish a mathematical model to predict the steady-state (stationary) motion of a nano-particle that is suppressed between two parallel moving objects. The main purpose of this study intends to find an appropriate means to reduce surface damage caused by moving nano-paricle. This study will show that, via the molecular dynamics (MD) analysis, the surface will result in different sizes of damaged layer and surface roughness when a nano-particle moves in a distinct way on it. Therefore, it has a significant value in the applications of high precision polishing and surface cleaning to identify the dominant factors in affecting the motion of nano-particle. The proposed model is to find the steady-state motion by meeting the conditions of force and torque balances on a moving nano-particle. Several hypotheses are suggested to derive the interaction force occurred at the interface between particle and each object. The hypothesis starts from the energy point of view. It is claimed that the potential and kinetic energies of object atoms will increase when nano-particle moves relative to the object. Because of the relative motion, some of the object atoms will be pushed or driven away, depending on the manner of motion. The increment of potential or kinetic energies is assumed to be proportional to the number of pushed or driven atoms. The increase of energy is supplied from the works done by the normal stress and shear stress at the interface of particle. The interaction at the front end of particle is very different from that at the rear end when particle rolls on object surface. There is a pushing action at the front end while a pulling action occurs at the rear end. The magnitudes of both actions are dominated and proportional to the adhesive strength between particle and object. The computer simulations show that the particle motion is mainly affected by the relative adhesive strength among particle and two objects. If the adhesive strength between particle and one object increase, the particle will increase the sliding speed relative to another object. On the other hand, if the adhesive strength between particle and one object is close to that of another object, the particle tends to have significant rolling motion relative to two objects. The suppressed loading between particle and objects has little effect on the qualitative trend of particle motion. The validity of proposed model is evaluated by the molecular dynamics simulation. It indicates that the predicted behaviors of proposed model are consistent with that from the analysis of molecular dynamics simulations.

In this thesis, the folding process of the de novo designed polypeptide chignolin was elucidated through atomic-scale Molecular Dynamics (MD) computer simulations. In a series of long timescale and replica exchange MD simulations, chignolin’s folding and unfolding was observed numerous times and the native state was identified from the computed Gibbs free-energy landscape. The rate of the self-assembly process was predicted from the replica exchange data through a novel algorithm and the structural fluctuations of an enzyme, lysozyme, were analyzed. DNA’s structural flexibility was investigated through experimental structure determination methods in the liquid and gas phase. DNA nanostructures could be maintained in a flat geometry when attached to an electrostatically charged, atomically flat surface and imaged in solution with an Atomic Force Microscope. Free in solution under otherwise identical conditions, the origami exhibited substantial compaction, as revealed by small angle X-ray scattering. This condensation was even more extensive in the gas phase. Protein folding is highly reproducible. It can rapidly lead to a stable state, which undergoes moderate fluctuations, at least for small structures. DNA maintains extensive structural flexibility, even when folded into large DNA origami. One may reflect upon the functional roles of proteins and DNA as a consequence of their atomic-level structural flexibility. DNA, biology’s information carrier, is very flexible and malleable, adopting to ever new conformations. Proteins, nature’s machines, faithfully adopt highly reproducible shapes to perform life’s functions robotically.

In this thesis we employ computer simulations and statistical physics to understand the origin of liquid-liquid phase transitions and their relationship with anomalies typical of liquid water. Compared with other liquids, water has many anomalies. For example the density anomaly: when water is cooled below 4 C the density decreases rather than increases. This and other anomalies have also been found to occur in a few other one-component liquids, sometimes in conjunction with the existence of a liquid-liquid phase transition (LLPT) between a low-density liquid (LDL) and a high-density liquid (HDL). Using simple models we explain how these anomalies arise from the presence of two competing length scales. As a specific example we investigate the cut ramp potential, where we show the importance of "competition" in this context, and how one length scale can sometimes be zero. When there is a clear energetic preference for either LDL or HDL for all pressures and temperatures, then there is insufficient competition between the two liquid structures and no anomalies occur. From the simple models it also follows that anomalies can occur without the presence of a LLPT and vice versa. It remains therefore unclear if water has a LLPT that ends in a liquid-liquid critical point (LLCP), a hypothesis that was first proposed based on simulations of the ST2 water model. We confirm the existence of a LLCP in this model using finite size scaling and the Challa-Landau-Binder parameter, and show that the LLPT is not a liquid-crystal transition, as has recently been suggested. Previous research has indicated the possible existence of a LLCP in liquid silica. We perform a detailed analysis of two different silica models (WAC and BKS) at temperatures much lower than was previously simulated. Within the accessible temperature range we find no LLCP in either model, although in the case of WAC potential it is closely approached. We compare our results with those obtained for other tetrahedral liquids and conclude that insufficient "stiffness" in the Si-O-Si bond angle might be responsible for the absence of a LLCP.