Dinucleotides as simple models of the base stacking-unstacking component of DNA 'breathing' mechanisms

14 pagesRegulatory protein access to the DNA duplex 'interior' depends on local DNA 'breathing' fluctuations, and the most fundamental of these are thermally-driven base stacking-unstacking interactions. The smallest DNA unit that can undergo such transitions is the dinucleotide, whose structural and dynamic properties are dominated by stacking, while the ion condensation, cooperative stacking and inter-base hydrogen-bonding present in duplex DNA are not involved. We use dApdA to study stacking-unstacking at the dinucleotide level because the fluctuations observed are likely to resemble those of larger DNA molecules, but in the absence of constraints introduced by cooperativity are likely to be more pronounced, and thus more accessible to measurement. We study these fluctuations with a combination of Molecular Dynamics simulations on the microsecond timescale and Markov State Model analyses, and validate our results by calculations of circular dichroism (CD) spectra, with results that agree well with the experimental spectra. Our analyses show that the CD spectrum of dApdA is defined by two distinct chiral conformations that correspond, respectively, to a Watson-Crick form and a hybrid form with one base in a Hoogsteen configuration. We find also that ionic structure and water orientation around dApdA play important roles in controlling its breathing fluctuations.This research was supported by a grant from the National Institute of Child Health and Human Development (5R01HD081 362-05) awarded to L.S. and N.B.A. The funding sources had no role in the study design, data collection and analysis, or submission process

Advancements in multi scale modeling: Adaptive resolution simulations and related issues

Adaptive resolution methods are becoming increasingly important in the study of complex systems by multi scale modeling. In this paper we present a brief overview of the method and highlight some questions that in our opinion are relevant for the future development of the method, and more in general of the field of multiscale modeling

Anomalous Dynamics in Macromolecular Liquids

Macromolecular liquids display short-time anomalous behaviors in disagreement with conventional single-molecule mean-field theories. In this study, we analyze the behavior of the simplest but most realistic macromolecular system that displays anomalous dynamics, i.e., a melt of short homopolymer chains, starting from molecular dynamics simulation trajectories. Our study sheds some light on the microscopic molecular mechanisms responsible for the observed anomalous behavior. The relevance of the correlation hole, a unique property of polymer liquids, in relation to the observed subdiffusive dynamics, naturally emerges from the analysis of the van Hove distribution functions and other properties

On the Density Dependence of the Integral Equation Coarse-Graining Effective Potential

Coarse-graining (CG) procedures provide computationally efficient methods for investigating the corresponding long time- and length-scale processes. In the bottom-up approaches, the effective interactions between the CG sites are obtained using the information from the atomistic simulations, but reliable CG procedures are required to preserve the structure and thermodynamics. In this regard, the integral equation coarse-graining (IECG) method is a promising approach that uses the first-principles Ornstein–Zernike equation in liquid state theory to determine the effective potential between CG sites. In this work, we present the details of the IECG method while treating the density as an intrinsic property and active variable of the CG system. Performing extensive simulations of polymer melts, we show that the IECG theory/simulation and atomistic simulation results are consistent in structural properties such as the pair-correlation functions and form factors, and also thermodynamic properties such as pressure. The atomistic simulations of the liquids show that the structure is largely sensitive to the repulsive part of the potential. Similarly, the IECG simulations of polymeric liquids show that the structure can be determined by the relatively short-range CG repulsive interactions, but the pressure is only accurately determined once the long-range, weak CG attractive interactions are included. This is in agreement with the seminal work by Widom on the influence of the potential on the phase diagram of the liquid [Widom, B. Science 1967, 157, 375–382]. Other aspects of the IECG theory/simulations are also discussed

Polymer-mode-coupling theory of the slow dynamics of entangled macromolecular fluids

A microscopic statistical dynamical theory of the slow dynamics of entangled macromolecular fluids has been formulated at the level of effective generalized Langevin equations- of-motion of a tagged polymer. A novel macromolecular version of mode-coupling theory is employed to approximately capture the cooperative motions of entangled polymers induced by the long range, self-similiar interchain correlations. Polymer integral equation methods are used to determine the required equilibrium structural input. Entanglements arise due to time and space correlations of the excluded volume forces exerted by the surrounding matrix on a tagged macromolecule. A spatially resolved description of entanglement constraint amplitudes relates the fluctuating forces to fluid structure. Constraint relaxation proceeds via three parallel processes: probe center-of-mass translation and shape fluctuations, and collective matrix relaxation. Asymptotic scaling law predictions for the molecular weight and concentration dependences of transport coefficients and relaxation times of chain polymer solutions and melts are in qualitative agreement with the phenomenological reptation theory. Predictions for finite frequency properties such as anomalous diffusion, and shear stress and dielectric relaxation, are derived. Enhanced, power law dissipation for properties controlled by conformational relaxation is predicted, with the corresponding frequency scaling exponents in good agreement with experiments but differing from reptation behavior. For experimentally accessible chain lengths strong finite size corrections for the transport coefficients arise due to entanglement constraint porosity and constraint release. Successful quantitative applications to many experimental data sets suggest the theory provides a unified microscopic understanding of the non-asymptotic scaling laws observed for the viscosity, dielectric relaxation time, and solution self and tracer diffusion constants. Generalization to fractal macromolecular architectures allows semi-quantitative treatment of ring and spherical microgel melts, and tracer diffusion in gels. A theory for the influence of concentration fluctuations in entangled polymer blends and diblock copolymers has also been developed. Self-diffusion in blends is quantitatively suppressed due to dynamical constraints associated with domain formation. Much stronger suppression of diffusion and chain relaxation is predicted near and well below the order-disorder transition of diblock copolymer melts due to microdomain formation. New dynamical scaling laws are predicted, and quantitative agreement of the theory with recent measurements on polyolefin diblocks is demonstrated. Limitations of the theory, open problems, and possible future directions are discussed

A Theory of Protein Dynamics to Predict NMR Relaxation

We present a theoretical, site-specific, approach to predict protein subunit correlation times, as measured by NMR experiments of 1H-15N nuclear Overhauser effect, spin-lattice relaxation, and spin-spin relaxation. Molecular dynamics simulations are input to our equation of motion for protein dynamics, which is solved analytically to produce the eigenvalues and the eigenvectors that specify the NMR parameters. We directly compare our theoretical predictions to experiments and to simulation data for the signal transduction chemotaxis protein Y (CheY), which regulates the swimming response of motile bacteria. Our theoretical results are in good agreement with both simulations and experiments, without recourse to adjustable parameters. The theory is general, since it allows calculations of any dynamical property of interest. As an example, we present theoretical calculations of NMR order parameters and x-ray Debye-Waller temperature factors; both quantities show good agreement with experimental data