Integrins are large heterodimeric (αβ) cell surface receptors that play a key role in the formation of focal adhesion complexes and are involved in various signal transduction pathways. They are ‘activated’ to a high affinity state by the formation of an intracellular complex between the membrane, the integrin β-subunit tail and talin, a process known as ‘inside-out activation’. The head domain of talin, a FERM domain homologue, plays a vital role in the formation of this complex. Recent studies also suggest that kindlins act in synergy with talin to induce integrin activation. Despite much available structural and functional data, details of how talin activates integrins remain elusive. In this thesis a multiscale simulation approach (using a combination of coarse-grained and atomistic molecular dynamics simulations) together with NMR experiments were employed to study talin-mediated integrin inside-out activation. A number of novel insights emerged from these studies including: (i) the crucial role of negatively charged lipids in talin/membrane association; (ii) a novel V-shape conformation of the talin head domain which optimizes its interactions with negatively charged lipids; (iii) that interactions of talin with negatively charged moieties in the membrane orient talin to optimize interactions with the β cytoplasmic tail; (iv) that binding of talin to the β cytoplasmic tail promotes rearrangement of the integrin TM helices and weakens the integrin α/β association; and (v) that an increase in the tilt angle of the β integrin TM helix initiates a scissoring movement of the two integrin TM helices. These results, combined with experimental data, provide new insights into the mechanism of integrin inside-out activation. The same multiscale approach was used to demonstrate the crucial role of the Gx3G motif in the packing of the integrin transmembrane helices. Using recent structural data the integrin/talin complex was modelled and inserted in bilayers which resemble the biological plasma membrane. The results demonstrate the dynamic nature of the integrin receptor and suggest that the integrin/talin complex alters the lipid organization and motion in the outer and inner bilayer leaflets in an asymmetric way and that diffusion of lipids in the vicinity of the protein is slowed down. The work in this thesis demonstrates that multiscale simulations have considerable strengths when applied to investigations of structure/function relationships in membrane proteins.

At the time of writing this thesis, the complete genomes of more than 180 organisms have been sequenced and more than 80000 biological macromolecular structures are available in the Protein Data Bank (PDB). While the number of sequenced genomes and solved three-dimensional structures are rapidly increasing, the functional annotation of protein sequences and structures is a much slower process, mostly because the experimental de-termination of protein function is expensive and time-consuming. A major class of in silico methods used for protein function prediction aim to transfer annotations between proteins based on sequence or structural similarities. These approaches rely on the assumption that homologous proteins of similar primary sequences and three-dimensional structures also have similar functions. While in most cases this assumption appears to be valid, an increasing number of examples show that proteins of highly similar sequences and/or structures can have different biochemical functions. Thus the relationship between the divergence of protein sequence, structure and function is more complex than previously anticipated. On the other hand, there is mounting evidence suggesting that minor changes of the sequences and structures of proteins can cause large differences in their conformational dynamics. As the intrinsic fluctuations of many proteins are key to their biochemical functions, the fact that very similar (almost identical) sequences or structures can have entirely different dynamics might be important for understanding the link between sequence, structure and function. In other words, the dynamic similarity of proteins could often serve as a better indicator of functional similarity than the similarity of their sequences or structures alone. Currently, little is known about how proteins are distributed in the 'dynamics space' and how protein motions depend on structure and sequence. These problems are relevant in the field of protein design, studying protein evolution and to better understand the functional differences of proteins. To address these questions, one needs a precise definition of dynamic similarity, which is not trivial given the complexity of protein motions. This thesis is intended to explore the possibilities of describing the similarity of proteins in the 'dynamics space'. To this end, novel methods of characterizing and comparing protein motions based on molecular dynamics simulation data were introduced. The generally applicable approach was tested on the family of PDZ domains; these small protein-protein interaction domains play key roles in many signalling pathways. The methodology was successfully used to characterize the dynamic dissimilarities of PDZ domains and helped to explain differences of their functional properties (e.g. binding promiscuity) also relevant for drug design studies. The software tools developed to implement the analysis are also introduced in the thesis. Finally, a network analysis study is presented to reveal dynamics-mediated intramolecular signalling pathways in an allosteric PDZ domain.

Structural and mechanical properties of nucleic acids play a key role in a wide range of biological processes, as well as in the field of nucleic acid nanotechnology. The thesis presents results of several studies focused on modelling these properties. Extensive unrestrained atomic-resolution molecular dynamics (MD) simulations are used to investigate structural dynamics of nucleic acids, and to parametrize their mechanical models. The deformation energy is assumed to be a general quadratic function of suitably chosen internal coordinates. Two types of models are employed which differ in the level of coarse- graining. The first one is based on the description of conformation at the level of individual bases and the second, coarser one is used to study global bending and twisting flexibility. The models are applied to explain mechanical properties of A-tracts in the context of DNA looping and nucleosome positioning, to characterize twist-stretch cou- pled deformations in DNA and RNA, and to predict changes in the properties of damaged DNA that are likely to be relevant for damage recognition and repair. Besides that, we propose a general model of DNA allostery, applied to study the effect of minor groove binding of small ligands and the allosteric coupling between proteins mediated by the DNA. A careful...

It is a well-known fact in the materials science community that the use of low-energy atom impacts during thin film deposition is an effective tool for altering the growth behavior and for increasing the crystallinity of the films. However, the manner in which the incident atoms affect the growth kinetics and surface morphology is quite complicated and still not fully understood. This provides a strong incentive for further investigations of the interaction among incident atoms and surface atoms on the atomic scale. These impact-induced energetic events are non-equilibrium, transient processes which complete in picoseconds. The only accessible technique today which permits direct observation of these events is molecular dynamics (MD) simulations. This thesis deals with MD simulations of low-energy atom impact phenomena on metal surfaces during crystal growth. Platinum is chosen as a model system given that it has seen extended use as a model surface over the past few decades, both in experiments and simulations. In MD, the classical equations of motion are solved numerically for a set of interacting atoms. The atomic interactions are calculated using the embedded atom method (EAM). The EAM is a semi-empirical, pair-functional interatomic potential based on density functional theory. This potential provides a physical picture that includes many-atom effects while retaining computational efficiency needed for larger systems. Single adatoms residing on a surface constitute the smallest possible clusters and are the fundamental components controlling nucleation kinetics. Small two-dimensional clusters on a surface are the result of nucleation and are present during the early stages of growth. These surface structures are chosen as targets in the simulations (papers I and II) to provide further knowledge of the atomistic processes which occur during deposition, to investigate at which impact energies the different kinetic pathways open up, and how they may affect growth behavior. Some of the events observed are adatom scattering, dimer formation, cluster disruption, formation of three-dimensional clusters, and residual vacancy formation. Given the knowledge obtained, papers III and IV deal with growth of several layers with the aim to study the underlying mechanisms responsible for altering growth behavior and how the overall intra- and interlayer atomic migration can be controlled by low-energy atom impacts. / <p>On the day of the defence date the status of article II was Accepted.</p>

The current thesis presents work on the structure and dynamics of oligosaccharides and polysaccharides as well as the free energetics of carbohydrate-protein interactions. By applying various computational tools such as molecular dynamics simulation, our in-house fast sugar structure prediction software, replica exchange molecular dynamics, homology modeling, umbrella sampling, steered molecular dynamics as well as the thermodynamic integration formalism, we have been able to study the role of water on the surface of homopolysaccharides as well as complex oligosachharides, we have been able to produce a prediction of the bound structure of triantennary oligosaccride on the asialoglycoprotein receptor, we have been able to estimate the free energy of binding of ManΑ1→2Man to the HIV-1 inactivating protein, Cyanovirin-N as well as the relative binding free energies of mutants of Cyanovirin-N to the same ligand.

Molecular dynamics simulations are an increasingly valuable tool to biochemical researchers: advances in computational power have expanded the range of biomolecules that can be simulated, and parameters describing these interactions are increasingly accurate. Despite substantial progress in force field parameterization, recent simulations of protein molecules using state-of-the-art, fixed-charge force fields revealed that the interactions among and within protein molecules can be too favorable, resulting in unrealistic aggregation or structural collapse of the proteins being simulated. To understand why these protein-protein interactions are so over-stabilized, I first assessed the ability of simulation force fields to represent accurately the interactions of individual amino acids, employing an osmotic pressure simulation apparatus that enabled direct comparison with experiment. Surprisingly, simulations of most of the amino acids resulted in behavior that was in strong agreement with experiment. A number of amino acids, however—notably those that contain hydroxyl groups and those that carry a formal charge—interacted in ways that were clearly inaccurate. Additionally, some commonly-used force fields failed to accurately represent the interactions of amino acids in a consistent manner. By further investigating the interactions of the functional groups of these amino acids, I was able not only to determine some of the root causes of individual amino acid inaccuracies, but also to implement simple modifications that brought the interactions of these small molecules and amino acids in stronger accord with experiment. These studies have highlighted some of the shortcomings in popular simulation force fields, and have proposed useful modifications to address them. Still, there is additional work that must be—and is being—conducted in order to correctly model the interaction behavior of proteins in simulation.

We conduct a comprehensive and systematic study of the Fermi-Pasta-Ulam (FPU) model using both equilibrium and non-equilibrium molecular dynamics simulations, with the aim being to explain the cause of the anomalous energy-transport behaviour in the model. In the equilibrium scenario, our motivation stems from the lack of a complete understanding of the effects of initial conditions on the energy dissipation among Fourier modes. We also critically reconsider the ????probes' that had been widely used to quantitatively describe the types of energy sharing in a system, and then decide on a preferred choice to be used in our equilibrium study. We establish, from strong numerical evidence, that there exists a critical energy density of approximately 0:1, above which the energy dissipation among the modes becomes independent of initial conditions and system parameters, and that the full equipartition of mode energy is never attained in the FPU model. We report, for the first time, the violation of particle positions in the FPU model at high energies, where the particles are found to pass through one another. In the non-equilibrium scenario, we critically review the Nos???Se-Hoover algorithm thermostatting method largely used by other works, and identify its weaknesses. We also review some other alternative methods and decide on the most appropriate one to be implemented throughout our work. We confirm the divergence of the thermal conductivity of the FPU model as the chain length increases, and that kfpu [symbol] No.41, in agreement with other works. Our study further shows that there exists an upper limit of the anharmonicity in the FPU model, and that any attempt to increase the strength of this anharmonicity will not succeed. We also introduce elastic collisions into the original FPU model and find that the Modified model (FPUC) still exhibits anomalous thermal conductivity. We conclude that a one-dimensional FPU-type model with ????only' nearest-neighbour interaction, regardless of being soft or hard, does not exhibit a finite thermal conductivity as the system size increases, due to the non-chaotic nature of its microscopic dynamics, the origin of which we are unable to account for. Finally, we briefly outline possible research directions.

We developed and implemented a first-principles based theory of the Landauer ballistic conductance, to determine the transport properties of nanostructures and molecular-electronics devices. Our approach starts from a quantum-mechanical description of the electronic structure of the system under consideration, performed at the density-functional theory level and using finite-temperature molecular dynamics simulations to obtain an ensemble of the most likely microscopic configurations. The extended Bloch states are then converted into maximally-localized Wannier functions to allow us to construct the Green's function of the conductor, from which we obtain the density of states (confirming the reliability of our microscopic calculations) and the Landauer conductance. A first application is presented to the case of pristine and functionalized carbon nanotubes. / Singapore-MIT Alliance (SMA)

Structural properties of pristine and defected graphene nanoribbons have been investigated by stretching them under 5 percent and 10 percent uniaxial strain until fragmentation. The stretching process has been carried out by performing molecular dynamics simulations (MDS) at 1 K and 300 K to determine the temperature effect on the structure of the graphene nanoribbons. Results of the simulations indicated that temperature, edge shape of graphene nanoribbons and stretching speed have a considerable effect on structural properties, however they have a slight effect on the strain value. The maximum strain at which fracture occurs is found to be 46.41 percent whereas minimum strain value is calculated as 21.00 percent. On the other hand, the defect formation energy is strongly affected from temperature and edge shape of graphene nanoribbons. Stone-Wales formation energy is calculated as -1.60 eV at 1 K whereas -30.13 eV at 300 K for armchair graphene nanoribbon.

The heterogeneous condensation of a vapour onto a substrate is a key step in a wide range of chemical and physical process that occur in both nature and technology. For example, dust and pollutant aerosol particles, ranging in size from several microns down to just a few nanometers, serve as cloud condensation nuclei in the atmosphere, and nanoscale structured surfaces provide templates for the controlled nucleation and growth of variety of complex materials. While much is known about the general features of heterogeneous nucleation onto macroscopic surfaces, much less is understood about both the dynamics and thermodynamics of nucleation involving nanoscale heterogeneities. The goal of this thesis is to understand the general features of condensation of vapours onto different types of nanoscale heterogeneity that range in degree of solubility from being insoluble, to partially miscible through to completely miscible. The heterogeneous condensation of the Lennard-Jones vapour onto an insoluble nanoscale seed particle is studied using a combination of molecular dynamics simulations and thermodynamic theory. The nucleation rate and free energy barrier are calculated from molecular dynamics using the mean first passage time method. These results show that the presence of a weakly interacting seed has no effect on the formation of small cluster embryos but accelerates the rate by lowering the free energy barrier of the larger clusters. A simple phenomenological model of film formation on a small seed is developed by extending the capillarity based liquid drop model. It captures the general features of heterogeneous nucleation, but a comparison with the simulation results show that the model significantly overestimates the height of the nucleation barrier while providing good estimates of the critical film size. A non-volatile liquid drop model that accounts for solution non-ideality is developed to describe the thermodynamics of partially miscible and fully miscible droplets in a solvent vapour. The model shows ideal solution drops dissolve always spontaneously, but partially miscible drops exhibit a free energy surface with two minima, associated with a partially dissolved drop and a fully dissolved drop, separated by a free energy barrier. The solubility transition between the two drops is shown to follow a hysteresis loop as a function of system volume similar to that observed in deliquescence. A simple lattice gas model describing the absorption of mono-layers of vapour onto the particle is also developed. Finally, molecular dynamics simulation of miscible and partially miscible binary Lennard-Jones mixtures are also used to study this system. For all cases studied, condensation onto the drop occurs spontaneously. Sub-monolayers of the solvent phase form when the system volume is large. At smaller system volumes, complete film formation is observed and the dynamics of film growth are dominated by cluster-cluster coalescence. Some degree of mixing into the core of the particle is observed for the miscible mixtures for all volumes. However, mixing of the solvent into the particle core only occurs below an onset volume for the partially miscible case, suggesting the presence of a solubility transition similar to the one described by the thermodynamic model.