Complex Macromolecular Systems Research Articles

Hybrid Approaches to Structural Characterization of Conformational Ensembles of Complex Macromolecular Systems Combining NMR Residual Dipolar Couplings and Solution X-ray Scattering.

Solving structures or structural ensembles of large macromolecular systems in solution poses a challenging problem. While NMR provides structural information at atomic resolution, increased spectral complexity, chemical shift overlap, and short transverse relaxation times (associated with slow tumbling) render application of the usual techniques that have been so successful for medium sized systems (<50 kDa) difficult. Solution X-ray scattering, on the other hand, is not limited by molecular weight but only provides low resolution structural information related to the overall shape and size of the system under investigation. Here we review how combining atomic resolution structures of smaller domains with sparse experimental data afforded by NMR residual dipolar couplings (which yield both orientational and shape information) and solution X-ray scattering data in rigid-body simulated annealing calculations provides a powerful approach for investigating the structural aspects of conformational dynamics in large multidomain proteins. The application of this hybrid methodology is illustrated for the 128 kDa dimer of bacterial Enzyme I which exists in a variety of open and closed states that are sampled at various points in the catalytic cycles, and for the capsid protein of the human immunodeficiency virus.

25 years of Macromolecular Theory and Simulations!

It's hard to believe that already an entire quarter century has passed since Macromolecular Theory and Simulations (MTS) was launched in 1992. As can be also seen from its initial title “Makromolekulare Chemie, Theory and Simulations”, the journal was the first topical spin-off from the established mother journal Macromolecular Chemistry and Physics - at that time still published multilingual and under the German name “Makromolekulare Chemie”. While the topical focus of MTS always has been rather specialized in comparison with more general research areas (e.g., materials science), the fields of macromolecular theory, mathematical methods, computer simulations, and modeling proved to be a small but essential part of polymer science. As written by the founding editors H. Höcker and B. Jung back in 1992: “The investigation of complex macromolecular systems […] more and more call for the development and application of theories and for the use of computer simulation.” and “… [we] hope that the new journal “Theory and Simulations” will be well accepted by the scientific community.” 25 years later it seems fair to state that these expectations have been more than met: Macromolecular Theory and Simulations has long reached an established position as the only high-quality polymer science journal dedicated exclusively to theory and simulations. Its present ISI impact factor is 1.67 (2015 Journal Citation Reports), and the numbers of submissions and article accesses remain stable in a challenging market situation. To celebrate the anniversary of Macromolecular Theory and Simulations a special issue is in preparation for publication later in 2016; more details will be communicated in due course. The 25 year anniversary is also a good occasion to look at what the most influential papers published in MTS have been. As can be seen from Table 1, and using the total number of citations as the criterion for “influence”, the clear lead is Michael Wulkow's seminal paper on a new concept for the modeling and dynamic simulation of macromolecular processes and a related software package (PREDICI). Without being able to cover all the scientific details in the limited space for this editorial, it can be easily seen that many of the most-cited papers listed here cover topics that are still in the focus of present research interest. Furthermore, some of the authors of these papers are still very active and even more prestigious today than they were when publishing their earlier work. More recent trends in the field of theory and simulation of polymers and polymeric materials are visible from Table 2, summarizing those articles published in 2014/2015 that received the highest number of downloads. The list displays the diversity of scientific areas and authors, who are all leading experts in their respective disciplines. The topics covered range from improving different modeling and simulation techniques to applying such approaches to practical aspects including colloidal systems, creep or thermosets - but also fundamental questions like the mechanisms of surface-initiated ATRP. The most downloaded paper in the timeframe documented here is work on the modeling of polyelectrolyte systems by Yaroslava G. Yingling et al., incidentally also featured on the cover of issue 2015/1. Some of you may already be aware of the present editorial team - but in light of recent changes, I would like to cite from the according statement of Kirsten Severing, Editor-in-Chief of the Macromolecular Journals family: “… the journals are run by a dedicated team of full time editors. Mara Staffilani is doing a great job as the main responsible editor for Macromolecular Chemistry and Physics, as is Anne Pfisterer for Macromolecular Bioscience and Macromolecular Materials and Engineering. Although Stefan Spiegel became the editor-in-chief of the Journal of Applied Polymer Science in 2014, he is still in full charge of his babies Macromolecular Theory and Simulations and Macromolecular Reaction Engineering. That leaves enough time for me to work on my two main journals, Macromolecular Rapid Communications and Advanced Science. The whole team benefits tremendously from the support of our new colleague David Huesmann, who joined the team in August last year. We are also grateful to our Beijing-based colleague Emily Hu for her editorial contribution to Macromolecular Materials and Engineering.” Last but most definitely not least it is my obligation and pleasure to thank those people indispensable for Macromolecular Theory and Simulations: our authors for their fascinating research and interest in the journal, our reviewers for helping us to identify the best articles, and the members of the advisory boards for their encouraging support. It is an ongoing pleasure collaborating with all of you, and we look forward to an even brighter future! Stefan Spiegel Editor

DIRECT-ID: An automated method to identify and quantify conformational variations--application to β2 -adrenergic GPCR.

The conformational dynamics of a macromolecule can be modulated by a number of factors, including changes in environment, ligand binding, and interactions with other macromolecules, among others. We present a method that quantifies the differences in macromolecular conformational dynamics and automatically extracts the structural features responsible for these changes. Given a set of molecular dynamics (MD) simulations of a macromolecule, the norms of the differences in covariance matrices are calculated for each pair of trajectories. A matrix of these norms thus quantifies the differences in conformational dynamics across the set of simulations. For each pair of trajectories, covariance difference matrices are parsed to extract structural elements that undergo changes in conformational properties. As a demonstration of its applicability to biomacromolecular systems, the method, referred to as DIRECT-ID, was used to identify relevant ligand-modulated structural variations in the β2 -adrenergic (β2 AR) G-protein coupled receptor. Micro-second MD simulations of the β2 AR in an explicit lipid bilayer were run in the apo state and complexed with the ligands: BI-167107 (agonist), epinephrine (agonist), salbutamol (long-acting partial agonist), or carazolol (inverse agonist). Each ligand modulated the conformational dynamics of β2 AR differently and DIRECT-ID analysis of the inverse-agonist vs. agonist-modulated β2 AR identified residues known through previous studies to selectively propagate deactivation/activation information, along with some previously unidentified ligand-specific microswitches across the GPCR. This study demonstrates the utility of DIRECT-ID to rapidly extract functionally relevant conformational dynamics information from extended MD simulations of large and complex macromolecular systems.

The Theory of Ultra-Coarse-Graining. 2. Numerical Implementation.

The increasing interest in the modeling of complex macromolecular systems in recent years has spurred the development of numerous coarse-graining (CG) techniques. However, many of the CG models are constructed assuming that all details beneath the resolution of CG degrees of freedom are fast and average out, which sets limits on the resolution of feasible coarse-grainings and on the range of applications of the CG models. Ultra-coarse-graining (UCG) makes it possible to construct models at any desired resolution while accounting for discrete conformational or chemical changes within the CG sites that can modulate the interactions between them. Here, we discuss the UCG methodology and its numerical implementation. We pay particular attention to the numerical mechanism for including state transitions between different conformations within CG sites because this has not been discussed previously. Using a simple example of 1,2-dichloroethane, we demonstrate the ability of the UCG model to reproduce the multiconfigurational behavior of this molecular liquid, even when each molecule is modeled with only one CG site. The methodology can also be applied to other molecular liquids and macromolecular systems with time scale separation between conformational transitions and other intramolecular motions and rotations.

Investigating increasingly complex macromolecular systems with small-angle X-ray scattering.

The biological solution small-angle X-ray scattering (BioSAXS) field has undergone tremendous development over recent decades. This means that increasingly complex biological questions can be addressed by the method. An intricate synergy between advances in hardware and software development, data collection and evaluation strategies and implementations that readily allow integration with complementary techniques result in significant results and a rapidly growing user community with ever increasing ambitions. Here, a review of these developments, by including a selection of novel BioSAXS method-ologies and recent results, is given.

Biological applications of classical electrostatics methods

Continuum electrostatics modeling of solvation based on the Poisson–Boltzmann (PB) equation has gained wide acceptance in biomolecular applications such as energetic analysis and structural visualization. Successful application of the PB solvent models requires careful calibration of the solvation parameters. Extensive testing and validation is also important to ensure accuracy in their applications. Limitation in the continuum modeling of solvation is also a known issue in certain biomolecular applications. Growing interest in membrane systems has further spurred developmental efforts to allow inclusion of membrane in the PB solvent models. Despite their past successes due to careful parameterization, algorithm development and parallel implementation, there is still much to be done to improve their transferability from the small molecular systems upon which they were developed and validated to complex macromolecular systems as advances in technology continue to push forward, providing ever greater computational resources to researchers to study more interesting biological systems of higher complexity.

ChemInform Abstract: Solid‐State NMR for Bacterial Biofilms

AbstractReview: 67 refs.

A review of Innovative Chemical Drawing and Spectra Prediction Computer Software

In recent years there has been an increasing research emphasis on complex macromolecular systems. These include polymers and coordination compounds with precise control of structures, multicomponent systems with higher degrees of organization, they involved in confined environments, nanochemistry and nanostructures, biopolymers and bio-inspired chemistry. Successful Spectroscopic studies of these complexes require judicious applications of existing techniques and development of new or improved strategies and methodologies. In this article various Chemical drawing and Spectra prediction computer software are compared and analyzed for their role in research in complex macromolecular systems. We have compared various software like Accelrys (Symyx) Draw, ChemDraw (ChemBioDraw), DrawIt, ChemSketch, ChemDoodle, Chemistry 4-D Draw, MarvinSketch and MestreNova NMR Predict.

Quantitative study of equilibrium and non-equilibrium polymer dynamics through systematic hierarchical coarse-graining simulations

Study of complex macromolecular systems through molecular simulations is a very intense research area. Here we present an overview concerning the development and application of hierarchical particle coarsegraining molecular dynamics simulations on the quantitative prediction of the dynamics and the rheology of polymers. Through a systematic time mapping approach that involves data from detailed atomistic dynamic simulations the coarse-grained polymer model can be used to quantitatively predict the dynamics and the rheology of the polymeric chains in a very broad range of characteristic length and time scales. Data from the application of these approaches on the dynamics of polystyrene melts under equilibrium and under shear flow conditions are presented.

Solid-state NMR for bacterial biofilms

Bacteria associate with surfaces and one another by elaborating an extracellular matrix to encapsulate cells, creating communities termed biofilms. Biofilms are beneficial in some ecological niches, but also contribute to the pathogenesis of serious and chronic infectious diseases. New approaches and quantitative measurements are needed to define the composition and architecture of bacterial biofilms to help drive the development of strategies to interfere with biofilm assembly. Solid-state nuclear magnetic resonance (NMR) is uniquely suited to the examination of insoluble and complex macromolecular and whole-cell systems. This article highlights three examples that implement solid-state NMR to deliver insights into bacterial biofilm composition and changes in cell-wall composition as cells transition to the biofilm lifestyle. Most recently, solid-state NMR measurements provided a total accounting of the protein and polysaccharide components in the extracellular matrix of an Escherichia coli biofilm and transformed our qualitative descriptions of matrix composition into chemical parameters that permit quantitative comparisons among samples. We present additional data for whole biofilm samples (cells plus the extracellular matrix) that complement matrix-only analyses. The study of bacterial biofilms by solid-state NMR is an exciting avenue ripe with many opportunities and we close the article by articulating some outstanding questions and future directions in this area.

Water-Driven Cavity-Ligand Binding: Comparison of Thermodynamic Signatures from Coarse-Grained and Atomic-Level Simulations.

The role of water (thermo)dynamics is crucial in molecular recognition and self-assembly. Here, we study a prototype cavity-ligand system as a model for hydrophobic noncovalent binding. Two alternative molecular dynamics simulation resolutions are employed and the resulting structural, dynamic, and thermodynamic properties compared: first, a coarse-grained (CG) resolution based on the previously reported and validated methane-like M solute and mW water models; second, an atomic-level (AL) resolution based on the popular OPLS united atom methane and the TIP4P water models. The CG model reproduces, as a function of the cavity-ligand distance, (1) the water occupancy of the cavity, (2) the cavity-ligand potential of mean force (free energy) and its temperature dependence, and (3) some of the major qualitative features of the thermodynamic signatures (free energy, enthalpy, and entropy) for cavity-ligand association of the AL model. The limits of the CG and AL models in this context are also discussed with comparison to experimental data. Our study suggests that CG simulation with models that include the translational contribution of water and anisotropic "hydrogen-bond"-like interactions could reproduce the thermodynamics of molecular recognition and water-driven assembly in complex macromolecular systems and nanoscale processes with convenient computational time savings.

Ion Binding Sites and Their Representations by Reduced Models

The binding of small metal ions to complex macromolecular structures is typically dominated by strong local interactions of the ion with its nearest ligands. Progress in understanding the molecular determinants of ion selectivity can often be achieved by considering simplified reduced models comprised of only the most important ion-coordinating ligands. Although the main ingredients underlying simplified reduced models are intuitively clear, a formal statistical mechanical treatment is nonetheless necessary in order to draw meaningful conclusions about complex macromolecular systems. By construction, reduced models only treat the ion and the nearest coordinating ligands explicitly. The influence of the missing atoms from the protein or the solvent is incorporated indirectly. Quasi-chemical theory offers one example of how to carry out such a separation in the case of ion solvation in bulk liquids, and in several ways, a statistical mechanical formulation of reduced binding site models for macromolecules is expected to follow a similar route. However, there are also important differences when the ion-coordinating moieties are not solvent molecules from a bulk phase but are molecular ligands covalently bonded to a macromolecular structure. Here, a statistical mechanical formulation of reduced binding site models is elaborated to address these issues. The formulation provides a useful framework to construct reduced binding site models, and define the average effect from the surroundings on the ion and the nearest coordinating ligands.

GMCT : A Monte Carlo simulation package for macromolecular receptors

Generalized Monte Carlo titration (GMCT) is a versatile suite of computer programs for the efficient simulation of complex macromolecular receptor systems as for example proteins. The computational model of the system is based on a microstate description of the receptor and an average description of its surroundings in terms of chemical potentials. The receptor can be modeled in great detail including conformational flexibility and many binding sites with multiple different forms that can bind different ligand types. Membrane embedded systems can be modeled including electrochemical potential gradients. Overall properties of the receptor as well as properties of individual sites can be studied with a variety of different Monte Carlo (MC) simulation methods. Metropolis MC, Wang-Landau MC and efficient free energy calculation methods are included. GMCT is distributed as free open source software at www.bisb.uni-bayreuth.de under the terms of the GNU Affero General Public License.

Highly Efficient Fluorescence Quenching with Graphene

Fluorescence quenching is a powerful technique used to obtain information about the dynamic changes of proteins in complex macromolecular systems. In this work, graphene is shown to be a very efficient quencher of fluorescence molecules where the quenching effect was one order of magnitude higher than that of gold. The fluorescence intensity was distance-dependent where increasing the distance between the fluorescence molecule and the graphene surface from 4 to 7 nm increased the fluorescence intensity by a factor of 7.5. This type of distance dependence suggests a nonradiative nature in the energy transfer between the graphene and the fluorophore due to the excitation of an exciton.

Molecular friction dissipation and mode coupling in organic monolayers and polymer films

The impact of thermally active molecular rotational and translational relaxation modes on the friction dissipation process involving smooth nano-asperity contacts has been studied by atomic force microscopy, using the widely known Eyring analysis and a recently introduced method, dubbed intrinsic friction analysis. Two distinctly different model systems, i.e., monolayers of octadecyl-phosphonic acid (ODPA) and thin films of poly(tert-butyl acrylate) (PtBA) were investigated regarding shear-rate critical dissipation phenomena originating from diverging mode coupling behaviors between the external shear perturbation and the internal molecular modes of relaxation. Rapidly (ODPA) versus slowly (PtBA) relaxing systems, in comparison to the sliding rate, revealed monotonous logarithmic and nonmonotonous spectral shear rate dependences, respectively. Shear coupled, enthalpic activation energies of 46 kJ∕mol for ODPA and of 35 and ∼65 kJ∕mol for PtBA (below and above the glass transition) were found that could be attributed to intrinsic modes of relaxations. Also, entropic energies involved in the cooperative backbone mobility of PtBA could be quantified, dwarfing the activation energy by more than a factor of five. This study provides (i) a material specific understanding of the molecular scale dissipation process in shear compliant substances, (ii) analyses of material intrinsic shear-rate mode coupling, shear coordination and energetics, (iii) a verification of Eyring's model applied to tribological systems toward material intrinsic specificity, and (iv) a valuable extension of the Eyring analysis for complex macromolecular systems that are slowly relaxing, and thus, exhibit shear-rate mode coupling.

Thermal characterization of HCN polymers by TG–MS, TG, DTA and DSC methods

This paper presents a thermogravimetry (TG) study of hydrogen cyanide polymers, synthesized from the reaction of equimolar aqueous solutions of sodium cyanide and ammonium chloride. Differential thermal analysis (DTA) and differential scanning calorimetry (DSC) were also used to evaluate the thermal behaviour of these black polymers, which play an important role in prebiotic chemistry. A coupled TG–mass spectrometer (MS) system allowed us to analyze the principal volatile thermal decomposition and fragmentation products of the isolated HCN polymers under dynamic conditions and an inert atmosphere. After dehydration, a multi-step decomposition occurred in this particular polymeric system, due to the release of ammonia, hydrogen cyanide (depolymerization reaction), isocyanic acid (or cyanic acid) and formamide; these two latter species allow us identify bond connectivities. Finally, data collected from TG experiments in an oxidative atmosphere showed significant differences at higher temperatures, above 400 °C. According to these results, the different techniques of thermal analysis here applied have demonstrated to be an adequate methodology for the study and characterization of this complex macromolecular system, whose structure remains controversial even today.

20 Years of Macromolecular Theory and Simulations

Dear Readers, Back in January 1992, the founding editors of Macromolecular Theory and Simulations, Hartwig Höcker and Bernd Jung, wrote: “The investigation of complex macromolecular systems […] more and more call for the development and application of theories and for the use of computer simulation.” and “… [we] hope that the new journal 'Theory and Simulations' will be well accepted by the scientific community.” Now that we are celebrating the 20th year of Macromolecular Theory and Simulations (MTS) in 2011, it seems fair to state that these expectations have been more than met: MTS has long reached an established position as the only high-quality polymer science journal dedicated exclusively to theory and simulations. Its most recent 2009 ISI impact factor is 1.68, and the numbers of submissions and article accesses (full-text downloads) are continuously growing. There is, however, a certain downside to the growing interest and increasing number of submissions to Macromolecular Theory and Simulations: Editorial pre-selection and the criteria for external peer-reviewing need to be even stricter than they have been before. A rejection rate that has already reached a value well above 50% inevitably results in the fact that we have to disappoint some of the submitting authors competing for the limited space. Nevertheless, we trust that our readers appreciate that research results considered suitable for publication in MTS need to be of upmost quality and interest to our readers. More recent trends in the field of theory and simulation of polymers and polymeric materials are visible from the table, which summarizes the MTS articles published in 2008-2009 that received the highest number of citations in 2010. The list displays the diversity of topics and authors, who are all leading experts in their respective disciplines. The topics include theoretical investigations of nanocomposites as well as several studies on the kinetics and mechanism of radical polymerizations, and technical approaches ranging from quantum-chemical modeling to Monte Carlo simulations. In addition to unsolicited submissions, MTS highlights fields of special interest by topical issues and an ongoing special article series dedicated to “Modeling for Polymer Design”, the latter being guest-edited by Christopher Barner-Kowollik. A special issue “Novel Simulation Approaches to Polymeric and Soft Matter Systems” (guest-edited by Christian Holm, Kurt Kremer, and J. J. Cerda) will be published in 2011, and later in the year I look forward especially to our special “Anniversary Issue” with contributions authored exclusively by members of the advisory board of Macromolecular Theory and Simulations. For updated information on these activities, please refer to the journal's homepage (www.mts-journal.de). Visibility and discoverability of the scientific content of Macromolecular Theory and Simulations is ensured primarily via Wiley's new online presence, Wiley Online Library, which was launched in summer 2010, but also by special landing pages presenting the content of the special article series. Contributions considered ‘very important’ by our referees (and us) are additionally featured on MaterialsViews.com, our news website that presents the best news from the materials science world everyday - another additional service highly appreciated by the authors whose work is highlighted there. Last but certainly not least, it is our obligation and pleasure to thank those people indispensable for Macromolecular Theory and Simulations: our authors for their fascinating research and interest in the journal, our referees for helping us to identify the best articles, and the members of the advisory boards for their encouraging support. It is an ongoing pleasure collaborating with all of you, and we look forward to an even brighter future!

Fast Mapping of Global Protein Folding States by Multivariate NMR: A GPS for Proteins

To obtain insight into the functions of proteins and their specific roles, it is important to establish efficient procedures for exploring the states that encapsulate their conformational space. Global Protein folding State mapping by multivariate NMR (GPS NMR) is a powerful high-throughput method that provides such an overview. GPS NMR exploits the unique ability of NMR to simultaneously record signals from individual hydrogen atoms in complex macromolecular systems and of multivariate analysis to describe spectral variations from these by a few variables for establishment of, and positioning in, protein-folding state maps. The method is fast, sensitive, and robust, and it works without isotope-labelling. The unique capabilities of GPS NMR to identify different folding states and to compare different unfolding processes are demonstrated by mapping of the equilibrium folding space of bovine α-lactalbumin in the presence of the anionic surfactant sodium dodecyl sulfate, SDS, and compare these with other surfactants, acid, denaturants and heat.

Differential geometry based multiscale models.

Large chemical and biological systems such as fuel cells, ion channels, molecular motors, and viruses are of great importance to the scientific community and public health. Typically, these complex systems in conjunction with their aquatic environment pose a fabulous challenge to theoretical description, simulation, and prediction. In this work, we propose a differential geometry based multiscale paradigm to model complex macromolecular systems, and to put macroscopic and microscopic descriptions on an equal footing. In our approach, the differential geometry theory of surfaces and geometric measure theory are employed as a natural means to couple the macroscopic continuum mechanical description of the aquatic environment with the microscopic discrete atomistic description of the macromolecule. Multiscale free energy functionals, or multiscale action functionals are constructed as a unified framework to derive the governing equations for the dynamics of different scales and different descriptions. Two types of aqueous macromolecular complexes, ones that are near equilibrium and others that are far from equilibrium, are considered in our formulations. We show that generalized Navier-Stokes equations for the fluid dynamics, generalized Poisson equations or generalized Poisson-Boltzmann equations for electrostatic interactions, and Newton's equation for the molecular dynamics can be derived by the least action principle. These equations are coupled through the continuum-discrete interface whose dynamics is governed by potential driven geometric flows. Comparison is given to classical descriptions of the fluid and electrostatic interactions without geometric flow based micro-macro interfaces. The detailed balance of forces is emphasized in the present work. We further extend the proposed multiscale paradigm to micro-macro analysis of electrohydrodynamics, electrophoresis, fuel cells, and ion channels. We derive generalized Poisson-Nernst-Planck equations that are coupled to generalized Navier-Stokes equations for fluid dynamics, Newton's equation for molecular dynamics, and potential and surface driving geometric flows for the micro-macro interface. For excessively large aqueous macromolecular complexes in chemistry and biology, we further develop differential geometry based multiscale fluid-electro-elastic models to replace the expensive molecular dynamics description with an alternative elasticity formulation.

Extracting Thermodynamic Parameters from Site-Specific Observables: Chi-Value Analysis

Interactions between different structural domains are important determinants of the function and regulation of allosteric proteins. Prevalent theories to understand the thermodynamic basis of cooperativity have frequently constrained the interactions between the different domains to come up with a mathematical model which can reproduce the complex behavior of a global thermodynamic observable such as ligand binding or enzyme activity. Such simple phenomenological models, in general, are not amenable to molecular description of cooperative interactions. Here, we provide the theoretical framework of a method, the chi-value analysis, which can elucidate the thermodynamic effect of molecular level perturbations. The chi value analysis involves extracting a site-specific parameter (chi value) associated with a structural domain and observing how the chi value is altered by a mutation. Through this formalism, based on classical statistical mechanics, we show that the chi value analysis can be used to deconstruct and quantify the energetic effects of mutations even in a complex macromolecular system consisting of a large number of structural units interacting via a complex network of interactions. Using models of the multi-domain voltage-dependent sodium and large-conductance calcium activated potassium channels, we have performed extensive numerical simulations to probe the validity of the chi value analysis. Our theory may provide a general approach to understand the detailed energetics underlying cooperative behavior of multi-domain proteins.