Rotamer decomposition and protein dynamics: Efficiently analyzing dihedral populations from molecular dynamics

Molecular mechanics methods have matured into powerful methods to understand the dynamics and flexibility of macromolecules and especially proteins. As multinanosecond to microsecond length molecular dynamics (MD) simulations become commonplace, advanced analysis tools are required to generate scientifically useful information from large amounts of data. Some of the key degrees of freedom to understand protein flexibility and dynamics are the amino acid residue side chain dihedral angles. In this work, we present an easily automated way to summarize and understand the relevant dihedral populations. A tremendous reduction in complexity is achieved by describing dihedral timeseries in terms of histograms decomposed into Gaussians. Using the familiar and widely studied protein lysozyme, it is demonstrated that our approach captures essential properties of protein structure and dynamics. A simple classification scheme is proposed that indicates the rotational state population for each dihedral angle of interest and allows a decision if a given side chain or peptide backbone fragment remains rigid during the course of an MD simulation, adopts a converged distribution between conformational substates or has not reached convergence yet. © 2012 Wiley Periodicals, Inc.     

Affinity Matrices of Cratylia mollis Seed Lectins for Isolation of Glycoproteins from Complex Protein Mixtures

This work reports the use of matrices containing Cratylia mollis lectins (Cramoll 1,2,3-Sepharose and Cramoll 3-Sepharose) for isolation of glycoproteins from fetal bovine serum, human colostrum, hen egg white, and human blood plasma. Cramoll 1,2,3-Sepharose was able to bind a glycoprotein from fetal bovine serum which showed the same fetuin electrophoretic profile. The data indicate that this protein adsorbed to the matrix by interaction with Cramoll 3. Cramoll 1,2,3-Sepharose was not efficient to retain glycoproteins from human colostrum or commercial ovalbumin. Cramoll 3-Sepharose bound ovalbumin, and the support retained protein from hen egg white. Protein peaks eluted from the column with 1.0 M NaCl or 0.3 M galactose showed apparent molecular mass of ovalbumin. Two main proteins from blood plasma with apparent molecular mass 67 (similar to albumin) and 50 kDa (similar to fetuin) adsorbed on Cramoll 3-Sepharose and were eluted with 1.0 M NaCl as a single peak. Elution of adsorbed plasma proteins with 0.3 M galactose was less selective than with 1.0 M NaCl as revealed by SDS-PAGE. In conclusion, the Cramoll 1,2,3-Sepharose and Cramoll 3-Sepharose matrices were useful to separate glycoproteins from complex protein mixtures, and the adsorption phenomena was a carbohydrate-dependent event.     

Development of 7TM receptor-ligand complex models using ligand-biased, semi-empirical helix-bundle repacking in torsion space: application to the agonist interaction of the human dopamine D2 receptor

Prediction of 3D structures of membrane proteins, and of G-protein coupled receptors (GPCRs) in particular, is motivated by their importance in biological systems and the difficulties associated with experimental structure determination. In the present study, a novel method for the prediction of 3D structures of the membrane-embedded region of helical membrane proteins is presented. A large pool of candidate models are produced by repacking of the helices of a homology model using Monte Carlo sampling in torsion space, followed by ranking based on their geometric and ligand-binding properties. The trajectory is directed by weak initial restraints to orient helices towards the original model to improve computation efficiency, and by a ligand to guide the receptor towards a chosen conformational state. The method was validated by construction of the β₁ adrenergic receptor model in complex with (S)-cyanopindolol using bovine rhodopsin as template. In addition, models of the dopamine D₂ receptor were produced with the selective and rigid agonist (R)-N-propylapomorphine ((R)-NPA) present. A second quality assessment was implemented by evaluating the results from docking of a library of 29 ligands with known activity, which further discriminated between receptor models. Agonist binding and recognition by the dopamine D₂ receptor is interpreted using the 3D structure model resulting from the approach. This method has a potential for modeling of all types of helical transmembrane proteins for which a structural template with sequence homology sufficient for homology modeling is not available or is in an incorrect conformational state, but for which sufficient empirical information is accessible.     

A Hybrid Ring‐Opening Metathesis Polymerization Catalyst Based on an Engineered Variant of the β‐Barrel Protein FhuA

A β‐barrel protein hybrid catalyst was prepared by covalently anchoring a Grubbs–Hoveyda type olefin metathesis catalyst at a single accessible cysteine amino acid in the barrel interior of a variant of β‐barrel transmembrane protein ferric hydroxamate uptake protein component A (FhuA). Activity of this hybrid catalyst type was demonstrated by ring‐opening metathesis polymerization of a 7‐oxanorbornene derivative in aqueous solution.     

Deformations of Charged Axially Symmetric Initial Data and the Mass–Angular Momentum–Charge Inequality

We show how to reduce the general formulation of the mass–angular momentum–charge inequality, for axisymmetric initial data of the Einstein–Maxwell equations, to the known maximal case whenever a geometrically motivated system of equations admits a solution. It is also shown that the same reduction argument applies to the basic inequality yielding a lower bound for the area of black holes in terms of mass, angular momentum, and charge. This extends previous work by the authors (Cha and Khuri, Ann Henri Poincaré, doi: 10.1007/s00023-014-0332-6, arXiv:1401.3384, 2014), in which the role of charge was omitted. Lastly, we improve upon the hypotheses required for the mass–angular momentum–charge inequality in the maximal case.     

Loading characteristics and chemical stability of headgroup‐functionalized poly(ethylene glycol)‐lipid ligand tethers on polypropylene capillary‐channeled polymer fibers

Polypropylene capillary‐channeled polymer fibers have been modified by adsorption of headgroup‐functionalized poly(ethylene glycol)‐lipids to generate a species‐specific stationary phase. In order to study ligand binding characteristics, a fluorescein‐labeled poly(ethylene glycol)‐lipid was used as a model system. Breakthrough curves and frontal analysis were employed to characterize the surface loading characteristics across a range of lipid concentrations and mobile phase flow rates. Efficient mass transfer and fluid transport yield a linear adsorption isotherm up to the maximum loading concentration of 3 mg/mL, at a linear velocity of 57.1 mm/s. Under these conditions, the dynamic binding capacity was found to be 1.52 mg/g of fiber support. Variation of the linear velocity from 8.6 to 57.1 mm/s showed only small changes in breakthrough volume. The maximum capacity of 1.8 mg/g is found under conditions of a load velocity of 34.2 mm/s and a concentration of 3 mg/mL lipid. Exposure of the lipid modified fibers to several challenge solvents reveals a chemically robust system, with only 50% acetonitrile and hexanes able to disrupt the lipid adsorption. The straightforward capillary‐channeled polymer fiber surface modification with headgroup‐functionalized lipids provides both a diverse yet practically robust ligand tethering system.     

Parallel simulation of large scale multibody systems

Virtual prototyping plays an ever increasing role in the engineering disciplines. Nowadays, engineers can rely on powerful tools like object oriented modeling languages, e.g., Modelica. Models written in this language can be simulated by open source software as well as commercial tools. The advantage of this approach is that the engineers can concentrate themselves on modeling, whereas the numerical intricacies of the simulation are handled by the software. On the other hand the simulations are usually slower than implementations which are parallelized and optimized manually. This can lead to computation times which are infeasible in practice, e.g., when a real time simulation is necessary for a hardware-in-the-loop simulation. In this contribution we are concerned with speeding up such automated simulations by parallelization (on desktop hardware as well as HPC systems). We examine the parallelism across the system approaches. Additionally, the influence of the problem formulation on the simulation time is discussed. The implemented methods are demonstrated on engineering examples. (© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Liquid–Liquid Phase Equilibrium and Ion-Exchange Exploration for Aqueous Two-Phase Systems of ([C4mim]Cl + K2CO3 or K3C6H5O7 + water) at Different Temperatures

Journal of Solution Chemistry - Liquid–liquid equilibrium (LLE) data and phase diagrams for new aqueous two-phase systems (ATPSs) containing 1-butyl-3-methylimidazolium chloride...