Molecular modelling studies of binding of DACD derivatives into G-Quadruplex DNA: comparison of force field and quantum polarized ligand docking methods

The DNA G-qadruplexes are one of the targets being actively explored for anti-cancer therapy by inhibiting them through small molecules. This computational study was conducted to predict the binding strengths and orientations of a set of novel dimethyl-amino-ethyl-acridine (DACA) analogues that are designed and synthesized in our laboratory, but did not diffract in Synchrotron light.Thecrystal structure of DNA G-Quadruplex(TGGGGT)4(PDB: 1O0K) was used as target for their binding properties in our studies.We used both the force field (FF) and QM/MM derived atomic charge schemes simultaneously for comparing the predictions of drug binding modes and their energetics. This study evaluates the comparative performance of fixed point charge based Glide XP docking and the quantum polarized ligand docking schemes. These results will provide insights on the effects of including or ignoring the drug-receptor interfacial polarization events in molecular docking simulations, which in turn, will aid the rational selection of computational methods at different levels of theory in future drug design programs. Plenty of molecular modelling tools and methods currently exist for modelling drug-receptor or protein-protein, or DNA-protein interactionssat different levels of complexities.Yet, the capasity of such tools to describevarious physico-chemical propertiesmore accuratelyis the next step ahead in currentresearch.Especially, the usage of most accurate methods in quantum mechanics(QM) is severely restricted by theirtedious nature. Though the usage of massively parallel super computing environments resulted in a tremendous improvement in molecular mechanics (MM) calculations like molecular dynamics,they are still capable of dealing with only a couple of tens to hundreds of atoms for QM methods. One such efficient strategy that utilizes thepowers of both MM and QM are the QM/MM hybrid methods. Lately, attempts have been directed towards the goal of deploying several different QM methods for betterment of force field based simulations, but with practical restrictions in place. One of such methods utilizes the inclusion of charge polarization events at the drug-receptor interface, that is not explicitly present in the MM FF.

A complete atomistic model of molten polyethylene from neutron scattering data: a new methodology for polymer structure

A new approach to the study of the local organization in amorphous polymer materials is presented. The method couples neutron diffraction experiments that explore the structure on the spatial scale 1–20 Å with the reverse Monte Carlo fitting procedure to predict structures that accurately represent the experimental scattering results over the whole momentum transfer range explored. Molecular mechanics and molecular dynamics techniques are also used to produce atomistic models independently from any experimental input, thereby providing a test of the viability of the reverse Monte Carlo method in generating realistic models for amorphous polymeric systems. An analysis of the obtained models in terms of single chain properties and of orientational correlations between chain segments is presented. We show the viability of the method with data from molten polyethylene. The analysis derives a model with average C-C and C-H bond lengths of 1.55 Å and 1.1 Å respectively, average backbone valence angle of 112, a torsional angle distribution characterized by a fraction of trans conformers of 0.67 and, finally, a weak interchain orientational correlation at around 4 Å.

Segmental dynamics in entangled linear polymer melts

We present molecular dynamics (MD) and slip-springs model simulations of the chain segmental dynamics in entangled linear polymer melts. The time-dependent behavior of the segmental orientation autocorrelation functions and mean-square segmental displacements are analyzed for both flexible and semiflexible chains, with particular attention paid to the scaling relations among these dynamic quantities. Effective combination of the two simulation methods at different coarse-graining levels allows us to explore the chain dynamics for chain lengths ranging from Z ≈ 2 to 90 entanglements. For a given chain length of Z ≈ 15, the time scales accessed span for more than 10 decades, covering all of the interesting relaxation regimes. The obtained time dependence of the monomer mean square displacements, g1(t), is in good agreement with the tube theory predictions. Results on the first- and second-order segmental orientation autocorrelation functions, C1(t) and C2(t), demonstrate a clear power law relationship of C2(t) C1(t)m with m = 3, 2, and 1 in the initial, free Rouse, and entangled (constrained Rouse) regimes, respectively. The return-to-origin hypothesis, which leads to inverse proportionality between the segmental orientation autocorrelation functions and g1(t) in the entangled regime, is convincingly verified by the simulation result of C1(t) g1(t)−1 t–1/4 in the constrained Rouse regime, where for well-entangled chains both C1(t) and g1(t) are rather insensitive to the constraint release effects. However, the second-order correlation function, C2(t), shows much stronger sensitivity to the constraint release effects and experiences a protracted crossover from the free Rouse to entangled regime. This crossover region extends for at least one decade in time longer than that of C1(t). The predicted time scaling behavior of C2(t) t–1/4 is observed in slip-springs simulations only at chain length of 90 entanglements, whereas shorter chains show higher scaling exponents. The reported simulation work can be applied to understand the observations of the NMR experiments.

Molecular insights into aggregates made of amphiphilic Fmoc-tetrapeptides

Pre-assembled aggregates made of Fmoc-conjugated RGDS and GRDS peptides, where Fmoc refers to fluorenylmethoxycarbonyl, have been investigated using atomistic molecular dynamics simulations. The structural characteristics of twelve different models involving two sheets packed with the Fmoc-aligned or with the charged side groups oriented face-to-face, each one containing seven explicit peptide molecules arranged in parallel or antiparallel, have been evaluated for each Fmoc-tetrapeptide. Structural criteria have been used to select the preferred assembly for each Fmoc-tetrapeptide. The two peptides have been found to prefer b-sheet assemblies with a parallel configuration under simulated low concentration conditions. Furthermore, the assembly is dominated by the interactions among Fmoc units. The overall results provide a complete atomistic view of the interactions between Fmoc-peptide molecules comprised within the same sheet or in different sheets that was not achieved experimentally.

Lattice dynamics study of microstructures of electrorheological fluids

The lattice dynamics method is used to study the stability of the chain structures formed in electrorheological (ER) fluids. The appearance of the soft modes in the phonon dispersion of the structures indicates that the chains tend to distort and aggregate into thicker columns due to the electrostatic attractive forces and thermal generated forces between them. The results show that the stability of the chains relies on their width and the separation between them. The complete chain structures are more stable than the chains with defects. The results can be used to elucidate the densification phenomenon of the chains in the structuring process of ER fluids in the quiescent state.

Structure and viscoelasticity of an electrorheological fluid in oscillatory shear: computer simulation investigation

The three-dimensional molecular dynamics simulation method has been used to study the dynamic responses of an electrorheological (ER) fluid in oscillatory shear. The structure and related viscoelastic behaviour of the fluid are found to be sensitive to the amplitude of the strain. With the increase of the strain amplitude, the structure formed by the particles changes from isolated columns to sheet-like structures which may be perpendicular or parallel to the oscillating direction. Along with the structure evolution, the field-induced moduli decrease significantly with an increase in strain amplitude. The viscoelastic behaviour of the structures obtained in the cases of different strain amplitudes was examined in the linear response regime and an evident structure dependence of the moduli was found. The reason for this lies in the anisotropy of the arrangement of the particles in these structures. Short-range interactions between the particles cannot be neglected in determining the viscoelastic behaviour of ER fluids at small strain amplitude, especially for parallel sheets. The simulation results were compared with available experimental data and good agreement was reached for most of them.

Rerum cognoscere causas: part II - opportunities generated by the agency/structure debate and suggestions for clarifying the social theoretic position of system dynamics

This is the second half of a two-part paper dealing with the social theoretic assumptions underlying system dynamics. In the first half it was concluded that analysing system dynamics using traditional, paradigm-based social theories is highly problematic. An innovative and potentially fruitful resolution is now proposed to these problems. In the first section it is argued that in order to find an appropriate social theoretic home for system dynamics it is necessary to look to a key exchange in contemporary social science: the agency/structure debate. This debate aims to move beyond both the theories based only on the actions of individual human agents, and those theories that emphasise only structural influences. Emerging from this debate are various theories that instead aim to unite the human agent view of the social realm with views that concentrate solely on system structure. It is argued that system dynamics is best viewed as being implicitly grounded in such theories. The main conclusion is therefore that system dynamics can contribute to an important part of social thinking by providing a formal approach for explicating social mechanisms. This conclusion is of general significance for system dynamics. However, the over-arching aim of the two-part paper is to increase the understanding of system dynamics in related disciplines. Four suggestions are therefore offered for how the system dynamics method might be extended further into the social sciences. It is argued that, presented in the right way, the formal yet contingent feedback causality thinking of system dynamics should diffuse widely in the social sciences and make a distinctive and important contribution to them. Felix qui potuit rerum cognoscere causas Happy is he who comes to know the causes of things Virgil - Georgics, Book II, line 490. 29 BCE

Structure-based energetics of protein interfaces guides foot-and-mouth disease virus vaccine design

Virus capsids are primed for disassembly, yet capsid integrity is key to generating a protective immune response. Foot-and-mouth disease virus (FMDV) capsids comprise identical pentameric protein subunits held together by tenuous noncovalent interactions and are often unstable. Chemically inactivated or recombinant empty capsids, which could form the basis of future vaccines, are even less stable than live virus. Here we devised a computational method to assess the relative stability of protein-protein interfaces and used it to design improved candidate vaccines for two poorly stable, but globally important, serotypes of FMDV: O and SAT2. We used a restrained molecular dynamics strategy to rank mutations predicted to strengthen the pentamer interfaces and applied the results to produce stabilized capsids. Structural analyses and stability assays confirmed the predictions, and vaccinated animals generated improved neutralizing-antibody responses to stabilized particles compared to parental viruses and wild-type capsids.

Significance of cross correlations in the stress relaxation of polymer melts

According to linear response theory, all relaxation functions in the linear regime can be obtained using time correlation functions calculated under equilibrium. In this paper, we demonstrate that the cross correlations make a significant contribution to the partial stress relaxation functions in polymer melts. We present two illustrations in the context of polymer rheology using (1) Brownian dynamics simulations of a single chain model for entangled polymers, the slip-spring model, and (2) molecular dynamics simulations of a multichain model. Using the single chain model, we analyze the contribution of the confining potential to the stress relaxation and the plateau modulus. Although the idea is illustrated with a particular model, it applies to any single chain model that uses a potential to confine the motion of the chains. This leads us to question some of the assumptions behind the tube theory, especially the meaning of the entanglement molecular weight obtained from the plateau modulus. To shed some light on this issue, we study the contribution of the nonbonded excluded-volume interactions to the stress relaxation using the multichain model. The proportionality of the bonded/nonbonded contributions to the total stress relaxation (after a density dependent "colloidal" relaxation time) provides some insight into the success of the tube theory in spite of using questionable assumptions. The proportionality indicates that the shape of the relaxation spectrum can indeed be reproduced using the tube theory and the problem is reduced to that of finding the correct prefactor. (c) 2007 American Institute of Physics

Hierarchical modeling of entangled polymers

We demonstrate that it is possible to link multi-chain molecular dynamics simulations with the tube model using a single chain slip-links model as a bridge. This hierarchical approach allows significant speed up of simulations, permitting us to span the time scales relevant for a comparison with the tube theory. Fitting the mean-square displacement of individual monomers in molecular dynamics simulations with the slip-spring model, we show that it is possible to predict the stress relaxation. Then, we analyze the stress relaxation from slip-spring simulations in the framework of the tube theory. In the absence of constraint release, we establish that the relaxation modulus can be decomposed as the sum of contributions from fast and longitudinal Rouse modes, and tube survival. Finally, we discuss some open questions regarding possible future directions that could be profitable in rendering the tube model quantitative, even for mildly entangled polymers

Deforming glassy polystyrene: Influence of pressure, thermal history, and deformation mode on yielding and hardening

The toughness of a polymer glass is determined by the interplay of yielding, strain softening, and strain hardening. Molecular-dynamics simulations of a typical polymer glass, atactic polystyrene, under the influence of active deformation have been carried out to enlighten these processes. It is observed that the dominant interaction for the yield peak is of interchain nature and for the strain hardening of intrachain nature. A connection is made with the microscopic cage-to-cage motion. It is found that the deformation does not lead to complete erasure of the thermal history but that differences persist at large length scales. Also we find that the strain-hardening modulus increases with increasing external pressure. This new observation cannot be explained by current theories such as the one based on the entanglement picture and the inclusion of this effect will lead to an improvement in constitutive modeling.

Microscopic Mechanisms of Strain Hardening in Glassy Polymers

The mechanisms underlying the increase in stress for large mechanical strains of a polymer glass, quantified by the strain-hardening modulus, are still poorly understood. In the present paper we aim to elucidate this matter and present new mechanisms. Molecular-dynamics simulations of two polymers with very different strain-hardening moduli (polycarbonate and polystyrene) have been carried out. Nonaffine displacements occur because of steric hindrances and connectivity constraints. We argue that it is not necessary to introduce the concept of entanglements to understand strain hardening, but that hardening is rather coupled with the increase in the rate of nonaffine particle displacements. This rate increases faster for polycarbonate, which has the higher strain-hardening modulus. Also more nonaffine chain stretching is present for polycarbonate. It is shown that the inner distances of such a nonaffinely deformed chain can be well described by the inner distances of the worm-like chain, but with an effective stiffness length (equal to the Kuhn length for an infinite worm-like chain) that increases during deformation. It originates from the finite extensibility of the chain. In this way the increase in nonaffine particle displacement can be understood as resulting from an increase in the effective stiffness length of the perturbed chain during deformation, so that at larger strains a higher rate of plastic events in terms of nonaffine displacement is necessary, causing in turn the observed strain hardening in polymer glasses.

Developments in near infrared spectroscopy

Vibrational spectroscopy at high excitation is an important research frontier for two reasons. Firstly, the near infrared is proving to be an important area for the analytical applications of spectroscopy, and we would therefore like to understand how the spectra we observe relate to the molecular structure of the absorbing species. Secondly, there is a fundamental interest in understanding molecular dynamics and energy flow within a polyatomic molecule at high excitation, because this is the boundary between spectroscopy and chemistry through which we try to understand the details of a chemical reaction. In this presentation I shall survey recent progress in this field.

Dinuclear copper and zinc complexes of a hexaazamacrocycle containing p-xylyl spacers and bridging anions: theoretical and spectroscopic studies

The hexaazamacrocycle 7,22-dimethyl-3,7,11,18,22,26-hexaazatricyclo[26.2.2.2(13,16)] tetratriaconta-1(30), 13,15,28,31,33- hexaene (Me-2[30] pbz(2)N(6)) was synthesized and characterised by single crystal X-ray diffraction. The macrocycle adopts a conformation with the two aromatic rings almost parallel at a distance of ca. 4.24 Angstrom, but displaced relative to each other by ca. 1.51 Angstrom. The protonation constants of this compound and the stability constants of its complexes with Cu2+ and Zn2+, were determined in water - methanol (9 : 1 v/v) at 25 degreesC with ionic strength 0.10 mol dm(-3) in KCl. The potentiometric and spectroscopic studies (NMR of zinc, cadmium and lead complexes, and EPR of the copper complexes) indicate the formation of only dinuclear complexes. The association constants of the dinuclear copper complex with anions ( thiocyanate, terephthalate and glyphosate) and neutral molecules (1,4-benzenedimethanol, p-xylylenediamine and terephthalic acid) were determined at 20 degreesC in methanol. The structural preferences of this ligand and of its dinuclear copper(II) complex with a variety of bridging ligands were evaluated theoretically by molecular mechanics calculations (MM) and molecular dynamics (MD) using quenching techniques.

Binding studies of a protonated dioxatetraazamacrocycle with carboxylate substrates

The tetraprotonated form of the dioxatetraazamacrocycle, 6,19-dioxa-3,9,16,22-tetraaza[22.2.2.2(11,14)]-triaconta-1(26),11,13,24, 27,29-hexaene, (H4L1)(4+), was used as the receptor for binding studies with carboxylate anionic substrates of different shapes, sizes, and charges [succinate (suc(2-)), cyclo- hexanetricarboxylate (cta(3-)), phthalate (ph(2-)), isophthalate (iph(2-)), terephthalate (tph(2-)), and benezenetricarboxylate (btc(3-))]. Association constants were determined by potentiometry in aqueous solution at 298.2 K and 0.10 M KCl and by H-1 NMR titration in D2O. The strongest association was found for the btc3- anion at 5-7 pH region. From both techniques it was possible to establish the binding preference trend of the receptor for the different substrates, and the H-1 NMR spectroscopy gave important suggestions about the type of interactions between partners and the location of the substrates in the supramolecular entities formed. The effective binding constants at pH 6 follow the order: btc(3-)>iph(2-)>cta(3-) =ph(2-)>tph(2-)>suc(2-). All the studies suggest that the anionic substrates bind to the receptor via N-H center dot center dot center dot O = C hydrogen bonds and electrostatic interactions, and the aromatic substrates can also establish pi-pi stacking interactions. The crystal structures of (H4L1)(4+) and its supramolecular assemblies with ph(2-) and tph(2-) were determined by X-ray diffraction. The last two structures showed that the association process in solid state occurs via multiple N-H center dot center dot center dot O = C hydrogen bonds with the anionic substrate located outside the macrocyclic cavity of the receptor. Molecular dynamics simulations carried out for the association of (H4L1)(4+) with tph(2-) and btC(3-) in water solution established at atomic level the existence of all interactions suggested by the experimental studies, which act cooperatively in the binding process. Furthermore, the binding free energies were estimated and the values are in agreement with the experimental ones, indicating that the binding of these two anionic substrates occurs into the receptor cavity. However, the tph(2-) has also propensity to leave the macrocyclic cavity and its molecular recognition can also happen at the top of the receptor. (C) 2008 Elsevier Ltd. All rights reserved.