Computational studies of darunavir into HIV-1 protease and DMPC bilayer: necessary conditions for effective binding and the role of the flaps

Human immunodeficiency virus type 1 protease (HIV-1 PR) is one of the main targets toward AIDS therapy. We have selected the potent drug darunavir and a weak inhibitor (fullerene analog) as HIV-1 PR substrates to compare protease's conformational features upon binding. Molecular dynamics (MD), molecular mechanics Poisson-Boltzmann surface area (MM-PBSA), and quantum-mechanical (QM) calculations indicated the importance of the stability of HIV-1 PR flaps toward effective binding: a weak inhibitor may induce flexibility to the flaps, which convert between closed and semiopen states. A water molecule in the darunavir-HIV-1 PR complex bridged the two flap tips of the protease through hydrogen bonding (HB) interactions in a stable structure, a feature that was not observed for the fullerene-HIV-1 PR complex. Additionally, despite that van der Waals interactions and nonpolar contribution to solvation favored permanent fullerene entrapment into the cavity, these interactions alone were not sufficient for effective binding; enhanced electrostatic interactions as observed in the darunavir-complex were the crucial component of the binding energy. An alternative pathway to the usual way of a ligand to access the cavity was also observed for both compounds. Each ligand entered the binding cavity through an opening between the one flap of the protease and a neighboring loop. This suggested that access to the cavity is not necessarily regulated by flap opening. Darunavir exerts its biological action inside the cell, after crossing the membrane barrier. Thus, we also initiated a study on the interactions between darunavir and the DMPC bilayer to reveal that the drug was accommodated inside the bilayer in conformations that resembled its structure into HIV-1 PR, being stabilized via HBs with the lipids and water molecules.     

Total synthesis of enantiopure 1,3-dimethylpyranonaphthoquinones including ventiloquinones E, G, L and eleutherin

A new synthetic approach to enantiopure pyranonaphthoquinones is described. (S)-Mellein 10, prepared in 6 steps from (S)-propylene oxide 16, is converted stereospecifically to the (1R,3S)-dimethylpyran 15. The pyran 15 is then converted to the benzoquinone 14, which undergoes regiospecific Diels-Alder reactions with a variety of oxygenated butadienes to give pyranonaphthoquinones including ventiloquinones E, G, L, eleutherin and ent-deoxyquinone A.     

Singular Ricci Solitons and Their Stability under the Ricci Flow

We introduce certain spherically symmetric singular Ricci solitons and study their stability under the Ricci flow from a dynamical PDE point of view. The solitons in question exist for all dimensions n + 1 ≥ 3, and all have a point singularity where the curvature blows up; their evolution under the Ricci flow is in sharp contrast to the evolution of their smooth counterparts. In particular, the family of diffeomorphisms associated with the Ricci flow “pushes away” from the singularity causing the evolving soliton to open up immediately becoming an incomplete (but non-singular) metric. The main objective of this paper is to study the local-in time stability of this dynamical evolution, under spherically symmetric perturbations of the singular initial metric. We prove a local well-posedness result for the Ricci flow in suitably weighted Sobolev spaces, which in particular implies that the “opening up” of the singularity persists for the perturbations as well.     

Combining evolutionary and stochastic gradient techniques for system identification

In the present contribution, a novel method combining evolutionary and stochastic gradient techniques for system identification is presented. The method attempts to solve the AutoRegressive Moving Average (ARMA) system identification problem using a hybrid evolutionary algorithm which combines Genetic Algorithms (GAs) and the Least Mean Squares LMS algorithm. More precisely, LMS is used in the step of the evaluation of the fitness function in order to enhance the chromosomes produced by the GA. Experimental results demonstrate that the proposed method manages to identify unknown systems, even in cases with high additive noise. Furthermore, it is observed that, in most cases, the proposed method finds the correct order of the unknown system without using a lot of a priori information, compared to other system identification methods presented in the literature. So, the proposed hybrid evolutionary algorithm builds models that not only have small MSE, but also are very similar to the real systems. Except for that, all models derived from the proposed algorithm are stable.     

Lumina: an adaptive,automated and extensible prototype for exploring,enriching and visualizing data

Journal of Visualization - Given a tabular dataset which should be graphically represented, how could the current complex visualization pipeline be improved? Could we produce a more visually...     

A time–frequency technique for the stability analysis of impulse responses from nonlinear aeroelastic systems

A time–frequency method is proposed for the analysis of response time histories from nonlinear aeroelastic systems. The approach is based on a time-varying curve-fit of the short time Fourier transform of the impulse response. It is shown that the method can be used in order to obtain a clear picture of the sub-critical stability of a number of aeroelastic systems with a variety of structural and aerodynamic nonlinearities. Additionally, frequency and amplitude information can be obtained for both the linear and nonlinear signatures of the response signals in the sub- and post-critical regions. Finally, it is shown that, given certain types of nonlinear functions, sub-critical damping trends can be extrapolated to predict bifurcation airspeeds.     

Styrene synthesis over iron oxide catalysts: from single crystal model system to real catalysts

Surface science methods originating from analysis of noble metal catalysts are increasingly applied to metal oxides. These methods provide direct access to fundamental structural properties and phase equilibria governing the catalytic properties of metal oxide surfaces. However, no systematic way existed so far for transferring this knowledge to technical catalysts. The aim of this paper is to combine surface science with chemical engineering methods to bridge this gap. Styrene synthesis over pure and K-doped iron oxides is used as an example to develop and to explain the methodology. Single crystal films (SCF), grown epitaxially on a Pt-carrier are considered as ideal model surfaces. Comprehensive UHV analyses yield the structural properties of SCF as well as their interaction with relevant components of the reaction mixture. Their results are combined with conversion experiments to derive a mechanistic catalyst model along with quantitative information on the reaction rates. The activity of SCF as well as their phase transitions under reactive conditions can be described with a continuum model depending on the macroscopic properties of the system. This model forms the crucial link towards technical catalysts. It is shown that the behaviour of a powder catalyst can be described as a superposition of the above kinetic model and an appropriate porous model. In this paper we review the developed methodology and conclude with the evaluation of the concept.     

Studies Related to Biological Detoxification of Kraft Pulp Mill Effluent. III. The Biodegradation of Abietic Acid with Mortierella isabellina

A study relating to the biological detoxification of resin acids is described. Abietic acid was transformed into a number of non-toxic hydroxylated derivatives by Mortierella isabellina. The biotransformation products have been identified and shown to be less toxic than abietic acid.     

Effective transport properties for flashing ratchets using homogenization theory

We study effective transport properties of Brownian motor models of molecular motors. The effective drift and diffusivity can be calculated by solving cell problems, given explicitly by homogenization theory. We briefly describe how this approach is equivalent to theWang-Peskin-Elston (WPE) [3] numerical algorithm for calculating effective transport properties of flashing ratchets. For an on-off flashing ratchet we examine the optimization of the Peclet number as a function of the free parameters of the system. We also present a numerical method for solving the cell equations for a flashing ratchet with Gaussian multiplicative noise. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)