Identifying and correcting non-Markov states in peptide conformational dynamics

Conformational transitions in proteins define their biological activity and can be investigated in detail using the Markov state model. The fundamental assumption on the transitions between the states, their Markov property, is critical in this framework. We test this assumption by analyzing the transitions obtained directly from the dynamics of a molecular dynamics simulated peptide valine-proline-alanine-leucine and states defined phenomenologically using clustering in dihedral space. We find that the transitions are Markovian at the time scale of ˜ 50 ps and longer. However, at the time scale of 30–40 ps the dynamics loses its Markov property. Our methodology reveals the mechanism that leads to non-Markov behavior. It also provides a way of regrouping the conformations into new states that now possess the required Markov property of their dynamics.

Hydrotalcite intercalated siRNA:computational characterization of the interlayer environment

Using molecular dynamics (MD) simulations, we explore the structural and dynamical properties of siRNA within the intercalated environment of a Mg:Al 2:1 Layered Double Hydroxide (LDH) nanoparticle. An ab initio force field (Condensed-phase Optimized Molecular Potentials for Atomistic Simulation Studies: COMPASS) is used for the MD simulations of the hybrid organic-inorganic systems. The structure, arrangement, mobility, close contacts and hydrogen bonds associated with the intercalated RNA are examined and contrasted with those of the isolated RNA. Computed powder X-ray diffraction patterns are also compared with related LDH-DNA experiments. As a method of probing whether the intercalated environment approximates the crystalline or rather the aqueous state, we explore the stability of the principle parameters (e.g., the major groove width) that differentiate both A- and A'- crystalline forms of siRNA and contrast this with recent findings for the same siRNA simulated in water. We find the crystalline forms remain structurally distinct when intercalated, whereas this is not the case in water. Implications for the stability of hybrid LDH-RNA systems are discussed.

Ion interactions with the carbon nanotube surface in aqueous solutions:understanding the molecular mechanisms

We study the molecular mechanisms of alkali halide ion interactions with the single-wall carbon nanotube surface in water by means of fully atomistic molecular dynamics simulations. We focus on the basic physical-chemical principles of ion–nanotube interactions in aqueous solutions and discuss them in light of recent experimental findings on selective ion effects on carbon nanotubes.

Dynamic complexity of chaotic transitions in high-dimensional classical dynamics:Leu-Enkephalin folding

Leu-Enkephalin in explicit water is simulated using classical molecular dynamics. A ß-turn transition is investigated by calculating the topological complexity (in the "computational mechanics" framework [J. P. Crutchfield and K. Young, Phys. Rev. Lett., 63, 105 (1989)]) of the dynamics of both the peptide and the neighbouring water molecules. The complexity of the atomic trajectories of the (relatively short) simulations used in this study reflect the degree of phase space mixing in the system. It is demonstrated that the dynamic complexity of the hydrogen atoms of the peptide and almost all of the hydrogens of the neighbouring waters exhibit a minimum precisely at the moment of the ß-turn transition. This indicates the appearance of simplified periodic patterns in the atomic motion, which could correspond to high-dimensional tori in the phase space. It is hypothesized that this behaviour is the manifestation of the effect described in the approach to molecular transitions by Komatsuzaki and Berry [T. Komatsuzaki and R.S. Berry, Adv. Chem. Phys., 123, 79 (2002)], where a "quasi-regular" dynamics at the transition is suggested. Therefore, for the first time, the less chaotic character of the folding transition in a realistic molecular system is demonstrated. © Springer-Verlag Berlin Heidelberg 2006.

Non-Markov state model of peptide dynamics

A hidden Markov state model has been applied to classical molecular dynamics simulated small peptide in explicit water. The methodology allows increasing the time resolution of the model and describe the dynamics with the precision of 0.3 ps (comparing to 6 ps for the standard methodology). It also permits the investigation of the mechanisms of transitions between the conformational states of the peptide. The detailed description of one of such transitions for the studied molecule is presented. © 2012 Elsevier B.V. All rights reserved.

Multiscale modelling:approaches and challenges

Multiscale systems that are characterized by a great range of spatial–temporal scales arise widely in many scientific domains. These range from the study of protein conformational dynamics to multiphase processes in, for example, granular media or haemodynamics, and from nuclear reactor physics to astrophysics. Despite the diversity in subject areas and terminology, there are many common challenges in multiscale modelling, including validation and design of tools for programming and executing multiscale simulations. This Theme Issue seeks to establish common frameworks for theoretical modelling, computing and validation, and to help practical applications to benefit from the modelling results. This Theme Issue has been inspired by discussions held during two recent workshops in 2013: ‘Multiscale modelling and simulation’ at the Lorentz Center, Leiden (http://www.lorentzcenter.nl/lc/web/2013/569/info.php3?wsid=569&venue=Snellius), and ‘Multiscale systems: linking quantum chemistry, molecular dynamics and microfluidic hydrodynamics’ at the Royal Society Kavli Centre. The objective of both meetings was to identify common approaches for dealing with multiscale problems across different applications in fluid and soft matter systems. This was achieved by bringing together experts from several diverse communities.

Molecular alignment relaxation in polymer optical fibers for sensing applications

A systematic study of annealing behavior of drawn PMMA fibers was performed. Annealing dynamics were investigated under different environmental conditions by fiber longitudinal shrinkage monitoring. The shrinkage process was found to follow a stretched exponential decay function revealing the heterogeneous nature of the underlying molecular dynamics. The complex dependence of the fiber shrinkage on initial degree of molecular alignment in the fiber, annealing time and temperature was investigated and interpreted. Moreover, humidity was shown to have a profound effect on the annealing process, which was not recognized previously. Annealing was also shown to have considerable effect on the fiber mechanical properties associated with the relaxation of molecular alignment in the fiber. The consequences of fiber annealing for the climatic stability of certain polymer optical fiber-based sensors are discussed, emphasizing the importance of fiber controlled pre-annealing with respect to the foreseeable operating conditions.

Stable algorithm for event detection in event-driven particle dynamics : logical states

Acknowledgments The authors gratefully acknowledge the support of the German Research Foundation (DFG) through the Cluster of Excellence ‘Engineering of Advanced Materials’ at the University of Erlangen-Nuremberg and through Grant Po 472/25.

A disappearing act performed by magnesium: the nucleotide exchange mechanism of Ran GTPase by Quantum mechanics/Molecular mechanics studies

The Ran GTPase protein is a guanine nucleotide-binding protein (GNBP) with an acknowledged profile in cancer onset, progression and metastases. The complex mechanism adopted by GNBPs in exchanging GDP for GTP is an intriguing process and crucial for Ran viability. The successful completion of the process is a fundamental aspect of propagating downstream signalling events. QM/MM molecular dynamics simulations were employed in this study to provide a deeper mechanistic understanding of the initiation of nucleotide exchange in Ran. Results indicate significant disruption of the metal-binding site upon interaction with RCC1 (the Ran guanine nucleotide exchange factor), overall culminating in the prominent shift of the divalent magnesium ion. The observed ion drifting is reasoned to occur as a consequence of the complex formation between Ran and RCC1 and is postulated to be a critical factor in the exchange process adopted by Ran. This is the first report to observe and detail such intricate dynamics for a protein in Ras superfamily.

How curvature-generating proteins build scaffolds on membrane nanotubes

Bin/Amphiphysin/Rvs (BAR) domain proteins control the curvature of lipid membranes in endocytosis, trafficking, cell motility, the formation of complex sub-cellular structures, and many other cellular phenomena. They form three-dimensional assemblies, which act as molecular scaffolds to reshape the membrane and alter its mechanical properties. It is unknown, however, how a protein scaffold forms and how BAR domains interact in these assemblies at protein densities relevant for a cell. In this work, we employ various experimental, theoretical and simulation approaches to explore how BAR proteins organize to form a scaffold on a membrane nanotube. By combining quantitative microscopy with analytical modeling, we demonstrate that a highly curving BAR protein endophilin nucleates its scaffolds at the ends of a membrane tube, contrary to a weaker curving protein centaurin, which binds evenly along the tube’s length. Our work implies that the nature of local protein-membrane interactions can affect the specific localization of proteins on membrane-remodeling sites. Furthermore, we show that amphipathic helices are dispensable in forming protein scaffolds. Finally, we explore a possible molecular structure of a BAR-domain scaffold using coarse-grained molecular dynamics simulations. Together with fluorescence microscopy, the simulations show that proteins need only to cover 30–40% of a tube’s surface to form a rigid assembly. Our work provides mechanical and structural insights into the way BAR proteins may sculpt the membrane as a high-order cooperative assembly in important biological processes. 

X-Ray Absorption Spectroscopy and Computer Modelling Study of Nanocrystalline Binary Alkaline Earth Fluorides

Nanocrystalline samples of Ba1-xCaxF2 prepared by high-energy milling show an unusually high F-ion conductivity, which exhibit a maximum in the magnitude and a minimum in the activation energy at x = 0.5. Here, we report an X-ray absorption spectroscopy (XAS) at the Ca and Sr K edges and the Ba L-3 edge and a molecular dynamics (MD) simulation study of the pure and mixed fluorides. The XAS measurements on the pure binary fluorides, CaF2, SrF2 and BaF2 show that high-energy ball-milling produces very little amorphous material, in contrast to the results for ball milled oxides. XAS measurements of Ba1-xCaxF2 reveal that for 0 < x < 1 there is considerable disorder in the local environments of the cations which is highest for x = 0.5. Hence the maximum in the conductivity corresponds to the composition with the maximum level of local disorder. The MD calculations also show a highly disordered structure consistent with the XAS results and similarly showing maximum disorder at x = 0.5.

A study of electrochemical transport and diffuse charge dynamics using a Langevin equation

This thesis aims to develop new numerical and computational tools to study electrochemical transport and diffuse charge dynamics at small scales. Previous efforts at modeling electrokinetic phenomena at scales where the noncontinuum effects become significant have included continuum models based on the Poisson-Nernst-Planck equations and atomic simulations using molecular dynamics algorithms. Neither of them is easy to use or conducive to electrokinetic transport modeling in strong confinement or over long time scales. This work introduces a new approach based on a Langevin equation for diffuse charge dynamics in nanofluidic devices, which incorporates features from both continuum and atomistic methods. The model is then extended to include steric effects resulting from finite ion size, and applied to the phenomenon of double layer charging in a symmetric binary electrolyte between parallel-plate blocking electrodes, between which a voltage is applied. Finally, the results of this approach are compared to those of the continuum model based on the Poisson-Nernst-Planck equations.

Heat dissipation from carbon nano-electronics

The incorporation of graphitic compounds such as carbon nanotubes (CNTs) and graphene into nano-electronic device packaging holds much promise for waste heat management given their high thermal conductivities. However, as these graphitic materials must be used in together with other semiconductor/insulator materials, it is not known how thermal transport is affected by the interaction. Using different simulation techniques, in this thesis, we evaluate the thermal transport properties - thermal boundary conductance (TBC) and thermal conductivity - of CNTs and single-layer graphene in contact with an amorphous SiO2 (a-SiO2) substrate. First, the theoretical methodologies and concepts used in our simulations are presented. In particular, two concepts are described in detail as they are necessary for the understanding of the subsequent chapters. The first is the linear response Green-Kubo (GK) theory of thermal boundary conductance (TBC), which we develop in this thesis, and the second is the spectral energy density method, which we use to directly compute the phonon lifetimes and thermal transport coefficients. After we set the conceptual foundations, the TBC of the CNT-SiO2 interface is computed using non- equilibrium molecular dynamics (MD) simulations and the new Green-Kubo method that we have developed. Its dependence on temperature, the strength of the interaction with the substrate, and tube diameter are evaluated. To gain further insight into the phonon dynamics in supported CNTs, the scattering rates are computed using the spectral energy density (SED) method. With this method, we are able to distinguish the different scattering mechanisms (boundary and CNT-substrate phonon-phonon) and rates. The phonon lifetimes in supported CNTs are found to be reduced by contact with the substrate and we use that lifetime reduction to determine the change in CNT thermal conductivity. Next, we examine thermal transport in graphene supported on SiO2. The phonon contribution to the TBC of the graphene-SiO2 interface is computed from MD simulations and found to agree well with experimentally measured values. We derive the theory of remote phonon scattering of graphene electrons and compute the heat transfer coefficient dependence on doping level and temperature. The thermal boundary conductance from remote phonon scattering is found to be an order of magnitude smaller than that of the phonon contribution. The in-plane thermal conductivity of supported graphene is calculated from MD simulations. The experimentally measured order of magnitude reduction in thermal conductivity is reproduced in our simulations. We show that this reduction is due to the damping of the flexural (ZA) modes. By varying the interaction between graphene and the substrate, the ZA modes hybridize with the substrate Rayleigh modes and the dispersion of the hybridized modes is found to linearize in the strong coupling limit, leading to an increased thermal conductance in the composite structure.

A influência da incorporação de ácido α-eleosteárico, purificado e isolado do óleo de tungue, na dinâmica molecular de lipossomos

Este trabalho descreve o isolamento e purificação do ácido α-eleosteárico (α-ESA) a partir do óleo de tungue e sua caracterização por espectroscopia de infravermelho com transformada de Fourier (FTIR), cromatografia gasosa acoplada com espectrometria de massas (GC-MS) e espectroscopia de ressonância magnética nuclear (RMN) de 1H e 13C. O α-ESA apresenta atividades biológicas (antitumorais, anti-inflamatórias e antioxidantes), tornando-se importante compreender sua interação com membranas lipídicas. Assim, este trabalho também descreve resultados referentes ao efeito da incorporação de α-ESA na dinâmica molecular de lipossomos compostos por fosfatidilcolina. O sistema lipossomal puro e contendo α-ESA foi caracterizado através do uso de espectroscopia de UV-visível, FTIR, RMN e calorimetria de varredura diferencial (DSC). Como resultados da purificação do α-ESA, obtivemos uma pureza de 95,9% utilizando acetona como solvente de recristalização em detrimento dos 92,2% em solução etanólica. Na incorporação em lipossomos, observou-se uma maior interação do α-ESA com a parte polar, de interface e os primeiros metilenos da região apolar da fosfatidilcolina. Além disso, α-ESA apresentou um efeito de redução da fluidez de lipossomos. Os resultados contribuem para a geração de conhecimento para o desenvolvimento de novos sistemas farmacológicos.

Host-guest system of 4-nerolidylcatechol in 2-hydroxypropyl-beta-cyclodextrin: preparation, characterization and molecular modeling

The interaction of 4-nerolidylcatechol (4-NRC), a potent antioxidant agent, and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was investigated by the solubility method using Fourier transform infrared (FTIR) methods in addition to UV-Vis, (1)H-nuclear magnetic resonance (NMR) spectroscopy and molecular modeling. The inclusion complexes were prepared using grinding, kneading and freeze-drying methods. According to phase solubility studies in water a B(S)-type diagram was found, displaying a stoichiometry complexation of 2:1 (drug:host) and stability constant of 6494 +/- A 837 M(-1). Stoichiometry was established by the UV spectrophotometer using Job's plot method and, also confirmed by molecular modeling. Data from (1)H-NMR, and FTIR, experiments also provided formation evidence of an inclusion complex between 4-NRC and HP-beta-CD. 4-NRC complexation indeed led to higher drug solubility and stability which could probably be useful to improve its biological properties and make it available to oral administration and topical formulations.