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

The structural effect of Methyl substitution on the binding of Polypyridyl Ru-dppz Complexes to DNA

ABSTRACT: Polypyridyl ruthenium complexes have been intensively studied and possess photophysical properties which are both interesting and useful. They can act as probes for DNA, with a substantial enhancement in emission when bound, and can induce DNA damage upon photoirradiation and therefore, the synthesis and characterization of DNA binding of new complexes is an area of intense research activity. Whilst knowledge of how the binding of derivatives compares to the parent compound is highly desirable, this information can be difficult to obtain. Here we report the synthesis of three new methylated complexes, [Ru(TAP)2(dppz-10-Me).2Cl, [Ru(TAP)2(dppz-10,12-Me2)].2Cl and [Ru(TAP)2(dppz-11-Me)].2Cl, and examine the consequences for DNA binding through the use of atomic resolution X-ray crystallography. We find that the methyl groups are located in discrete positions with a complete directional preference. This may help to explain the quenching behavior which is found in solution for analogous [Ru(phen)2(dppz)]2+ derivatives

Conformational modulation of sequence recognition in synthetic macromolecules

The different triplet sequences in high molecular weight aromatic copolyimides comprising pyromellitimide units ("I") flanked by either ether-ketone ("K") or ether-sulfone residues ("S") show different binding strengths for pyrene-based tweezer-molecules. Such molecules bind primarily to the diimide unit through complementary π-π-stacking and hydrogen bonding. However, as shown by the magnitudes of 1H NMR complexation shifts and tweezer-polymer binding constants, the triplet "SIS" binds tweezer-molecules more strongly than "KIS" which in turn bind such molecules more strongly than "KIK". Computational models for tweezer-polymer binding, together with single-crystal X-ray analyses of tweezer-complexes with macrocyclic ether-imides, reveal that the variations in binding strength between the different triplet sequences arise from the different conformational preferences of aromatic rings at diarylketone and diarylsulfone linkages. These preferences determine whether or not chain-folding and secondary π−π-stacking occurs between the arms of the tweezermolecule and the 4,4'-biphenylene units which flank the central diimide residue

Selective and highly efficient dye scavenging by a pH-responsive molecular hydrogelator

A structurally simple low molecular weight hydrogelator derived from isophthalic acid forms robust pH-responsive hydrogels capable of highly efficient and selective dye adsorption

Economic evaluation of flexible IGCC plants with integrated membrane reactor modules

Integrated Gasification Combined Cycle with embedded membrane reactor modules (IGCC-MR) represents a new technology option for the co-production of electricity and pure hydrogen endowed with enhanced environmental performance capacity. It is an alternative to conventional coaland gas-fired power generation technologies. As a new technology, the IGCC-MR power plant needs to be evaluated in the presence of irreducible regulatory and fuel market uncertainties for the potential deployment of an initial fleet of demonstration plants at the commercial scale. This paper presents the development of a systematic and comprehensive three-step methodological framework to assess the economic value of flexible alternatives in the design and operations of an IGCC-MR plant under the aforementioned sources of uncertainty. The main objective is to demonstrate the potential value enhancements stemming to the long-term economic performance of flexible IGCC-MR project investments, by managing the uncertainty associated with future environmental regulations and fuel costs. The paper provides an overview of promising design flexibility concepts for IGCC-MR power plants and focuses on operational and constructional flexibility. The operational flexibility is realized through the option of a temporary shutdown of the plant with considerations of regulatory and market uncertainties. This option reduces the probability of loss and the downside risk compared to the base case. The constructional flexibility considers installation of a Carbon Capture and Storage (CCS) unit in the plant under three different alternatives: 1) installing CCS in the initial construction phase, 2) retrofitting CCS at a later stage and 3) retrofitting CCS with pre-investment at a later stage. Monte Carlo simulations and financial analysis are used to demonstrate that the most economically advantageous flexibility option is to install CCS in the initial IGCC-MR construction phase

Experimental study of super-rotation in a magnetostrophic spherical Couette flow

We report measurements of electric potentials at the surface of a spherical container of liquid sodium in which a magnetized inner core is differentially rotating. The azimuthal angular velocities inferred from these potentials reveal a strong super-rotation of the liquid sodium in the equatorial region, for small differential rotation. Super-rotation was observed in numerical simulations by Dormy et al. [1]. We find that the latitudinal variation of the electric potentials in our experiments differs markedly from the predictions of a similar numerical model, suggesting that some of the assumptions used in the model - steadiness, equatorial symmetry, and linear treatment for the evolution of both the magnetic and velocity fields - are violated in the experiments. In addition, radial velocity measurements, using ultrasonic Doppler velocimetry, provide evidence of oscillatory motion near the outer sphere at low latitude: it is viewed as the signature of an instability of the super-rotating region

Zonal shear and super-rotation in a magnetized spherical Couette flow experiment

We present measurements performed in a spherical shell filled with liquid sodium, where a 74 mm-radius inner sphere is rotated while a 210 mm-radius outer sphere is at rest. The inner sphere holds a dipolar magnetic field and acts as a magnetic propeller when rotated. In this experimental set-up called DTS, direct measurements of the velocity are performed by ultrasonic Doppler velocimetry. Differences in electric potential and the induced magnetic field are also measured to characterize the magnetohydrodynamic flow. Rotation frequencies of the inner sphere are varied between -30 Hz and +30 Hz, the magnetic Reynolds number based on measured sodium velocities and on the shell radius reaching to about 33. We have investigated the mean axisymmetric part of the flow, which consists of differential rotation. Strong super-rotation of the fluid with respect to the rotating inner sphere is directly measured. It is found that the organization of the mean flow does not change much throughout the entire range of parameters covered by our experiment. The direct measurements of zonal velocity give a nice illustration of Ferraro's law of isorotation in the vicinity of the inner sphere where magnetic forces dominate inertial ones. The transition from a Ferraro regime in the interior to a geostrophic regime, where inertial forces predominate, in the outer regions has been well documented. It takes place where the local Elsasser number is about 1. A quantitative agreement with non-linear numerical simulations is obtained when keeping the same Elsasser number. The experiments also reveal a region that violates Ferraro's law just above the inner sphere.Comment: Phys Rev E, in pres

Strategic Real Option and Flexibility Analysis for Nuclear Power Plants Considering Uncertainty in Electricity Demand and Public Acceptance

Nuclear power is an important energy source especially in consideration of CO2 emissions and global warming. Deploying nuclear power plants, however, may be challenging when uncertainty in long-term electricity demand and more importantly public acceptance are considered. This is true especially for emerging economies (e.g., India, China) concerned with reducing their carbon footprint in the context of growing economic development, while accommodating a growing population and significantly changing demographics, as well as recent events that may affect the public's perception of nuclear technology. In the aftermath of the Fukushima Daiichi disaster, public acceptance has come to play a central role in continued operations and deployment of new nuclear power systems worldwide. In countries seeing important long-term demographic changes, it may be difficult to determine the future capacity needed, when and where to deploy it over time, and in the most economic manner. Existing studies on capacity deployment typically do not consider such uncertainty drivers in long-term capacity deployment analyses (e.g., + 40 years). To address these issues, this paper introduces a novel approach to nuclear power systems design and capacity deployment under uncertainty that exploits the idea of strategic flexibility and managerial decision rules. The approach enables dealing more pro-actively with uncertainty and helps identify the most economic deployment paths for new nuclear capacity deployment over multiple sites. One novelty of the study lies in the explicit recognition of public acceptance as an important uncertainty driver affecting economic performance, along with long-term electricity demand. Another novelty is in how the concept of flexibility is exploited to deal with uncertainty and improve expected lifecycle performance (e.g. cost). New design and deployment strategies are developed and analyzed through a multistage stochastic programming framework where decision rules are represented as non-anticipative constraints. This approach provides a new way to devise and analyze adaptation strategies in view of long-term uncertainty fluctuations that is more intuitive and readily usable by system operators than typical solutions obtained from standard real options analysis techniques, which are typically used to analyze flexibility in large-scale, irreversible investment projects. The study considers three flexibility strategies subject to uncertainty in electricity demand and public acceptance: 1) phasing (or staging) capacity deployment over time and space, 2) on-site capacity expansion, and 3) life extension. Numerical analysis shows that flexible designs perform better than rigid optimal design deployment strategies, and the most flexible design combining the above strategies outperforms both more rigid and less flexible design alternatives. It is also demonstrated that a flexible design benefits from the strategies of phasing and capacity expansion most significantly across all three strategies studied. The results provide useful insights for policy and decision-making in countries that are considering new nuclear facility deployment, in light of ongoing challenges surrounding new nuclear builds worldwide