Attracting cavities for docking. Replacing the rough energy landscape of the protein by a smooth attracting landscape

Molecular docking is a computational approach for predicting the most probable position of ligands in the binding sites of macromolecules and constitutes the cornerstone of structure‐based computer‐aided drug design. Here, we present a new algorithm called Attracting Cavities that allows molecular docking to be performed by simple energy minimizations only. The approach consists in transiently replacing the rough potential energy hypersurface of the protein by a smooth attracting potential driving the ligands into protein cavities. The actual protein energy landscape is reintroduced in a second step to refine the ligand position. The scoring function of Attracting Cavities is based on the CHARMM force field and the FACTS solvation model. The approach was tested on the 85 experimental ligand–protein structures included in the Astex diverse set and achieved a success rate of 80% in reproducing the experimental binding mode starting from a completely randomized ligand conformer. The algorithm thus compares favorably with current state‐of‐the‐art docking programs. © 2015 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.     

Scalable improvement of SPME multipolar electrostatics in anisotropic polarizable molecular mechanics using a general short‐range penetration correction up to quadrupoles

We propose a general coupling of the Smooth Particle Mesh Ewald SPME approach for distributed multipoles to a short‐range charge penetration correction modifying the charge‐charge, charge‐dipole and charge‐quadrupole energies. Such an approach significantly improves electrostatics when compared to ab initio values and has been calibrated on Symmetry‐Adapted Perturbation Theory reference data. Various neutral molecular dimers have been tested and results on the complexes of mono‐ and divalent cations with a water ligand are also provided. Transferability of the correction is adressed in the context of the implementation of the AMOEBA and SIBFA polarizable force fields in the TINKER‐HP software. As the choices of the multipolar distribution are discussed, conclusions are drawn for the future penetration‐corrected polarizable force fields highlighting the mandatory need of non‐spurious procedures for the obtention of well balanced and physically meaningful distributed moments. Finally, scalability and parallelism of the short‐range corrected SPME approach are addressed, demonstrating that the damping function is computationally affordable and accurate for molecular dynamics simulations of complex bio‐ or bioinorganic systems in periodic boundary conditions. © 2016 Wiley Periodicals, Inc.     

Stoichiometries and thermodynamic stabilities for aqueous sulfate complexes of U(VI)

The formation constants of UO2SO4 (aq), UO2(SO4)2(2-), and UO2(SO4)3(4-) were measured in aqueous solutions from 10 to 75 degrees C by time-resolved laser-induced fluorescence spectroscopy (TRLFS). A constant enthalpy of reaction approach was satisfactorily used to fit the thermodynamic parameters of stepwise complex formation reactions in a 0.1 M Na(+) ionic medium: log 10 K 1(25 degrees C) = 2.45 +/- 0.05, Delta r H1 = 29.1 +/- 4.0 kJ x mol(-1), log10 K2(25 degrees C) = 1.03 +/- 0.04, and Delta r H2 = 16.6 +/- 4.5 kJ x mol(-1). While the enthalpy of the UO2(SO4)2(2-) formation reaction is in good agreement with calorimetric data, that for UO2SO4 (aq) is higher than other values by a few kilojoules per mole. Incomplete knowledge of the speciation may have led to an underestimation of Delta r H1 in previous calorimetric studies. In fact, one of the published calorimetric determinations of Delta r H1 is here supported by the TRLFS results only when reinterpreted with a more correct equilibrium constant value, which shifts the fitted Delta r H1 value up by 9 kJ x mol(-1). UO2(SO 4) 3 (4-) was evidenced in a 3 M Na (+) ionic medium: log10 K3(25 degrees C) = 0.76 +/- 0.20 and Delta r H3 = 11 +/- 8 kJ x mol(-1) were obtained. The fluorescence features of the sulfate complexes were observed to depend on the ionic conditions. Changes in the coordination mode (mono- and bidentate) of the sulfate ligands may explain these observations, in line with recent structural data.     

Ruthenium-SYNPHOS-catalyzed asymmetric hydrogenations: an entry to highly stereoselective synthesis of the C15-C30 subunit of dolabelide A

An efficient construction of the C15-C30 segment of the cytotoxic macrolide dolabelide A is described. The synthesis relies on ruthenium-SYNPHOS-mediated asymmetric hydrogenation reactions of beta-keto esters to generate the C19, C21, and C27 hydroxyl-bearing stereocenters with very high levels of enantio- and diastereoselectivity.     

Solvation of UCl6(2-) anionic complex by MeBu3N(+), BuMe2Im(+), and BuMeIm(+) cations

The complexes [MeBu 3N] 2[UCl 6] and [BuMe 2Im] 2[UCl 6] were characterized in the solid state and in solution of [MeBu 3N][Tf 2N], [BuMe 2Im][Tf 2N], and [BuMeIm][Tf 2N] room-temperature ionic liquids using single-crystal XRD, EXAFS, electrochemistry, UV-visible absorption spectroscopy, and NMR. In the solid state and in solution, the existence of hydrogen bonding between the UCl 6 (2-) complex and the ionic liquid cations was revealed by these techniques. The MeBu 3N (+) cation interacts with UCl 6 (2-) via the protons on the alpha-carbon atoms of nitrogen. The protons of the imidazolium ring account for the interaction between the BuMe 2Im (+) cation and the UCl 6 (2-) anion. For the BuMeIm (+) cation the major interaction was confirmed between the most acidic proton on C(2) and the chlorides of UCl 6 (2-). The experimental results also show that the intensity of the interaction between the UCl 6 (2-) anion and the cation varies with the ionic liquid cation in the following order: MeBu 3N (+) approximately BuMe 2Im (+) < BuMeIm (+).     

Möbius inversion formula for monoids with zero

The Möbius inversion formula, introduced during the 19th century in number theory, was generalized to a wide class of monoids called locally finite such as the free partially commutative, plactic and hypoplactic monoids for instance. In this contribution are developed and used some topological and algebraic notions for monoids with zero, similar to ordinary objects such as the (total) algebra of a monoid, the augmentation ideal or the star operation on proper series. The main concern is to extend the study of the Möbius function to some monoids with zero, i.e., with an absorbing element, in particular the so-called Rees quotients of locally finite monoids. Some relations between the Möbius functions of a monoid and its Rees quotient are also provided.     

Transport-equilibrium schemes for computing nonclassical shocks

This Note presents a very efficient numerical strategy for computing weak solutions of a scalar conservation law which fails to be genuinely nonlinear. In such a situation, the dynamics of shock solutions turns out to be mainly driven by a prescribed kinetic function that imposes the speed of propagation of the discontinuities. We show how to enforce the validity of the kinetic criterion at the discrete level. The resulting scheme provides, in addition, sharp profiles. Numerical evidence are included. To cite this article: C. Chalons, C. R. Acad. Sci. Paris, Ser. I 342 (2006).     

Weak consistency of the Support Vector Machine Quantile Regression approach when covariates are functions

This paper deals with a nonparametric estimation of conditional quantile regression when the explanatory variable X takes its values in a bounded subspace of a functional space X and the response Y takes its values in a compact of the space Y?R. The functional observations, X₁,…,X_n, are projected onto a finite dimensional subspace having a suitable orthonormal system. The X_i’s will be characterized by their coordinates in this basis. We perform the Support Vector Machine Quantile Regression approach in finite dimension with the selected coefficients. Then we establish weak consistency of this estimator. The various parameters needed for the construction of this estimator are automatically selected by data-splitting and by penalized empirical risk minimization.     

Multivariate skewing mechanisms: A unified perspective based on the transformation approach

In recent years, models for (possibly multivariate) skewed distributions have become more and more popular. In the univariate case, Ferreira and Steel (2006) [Ferreira, J.T.A.S., Steel, M.F.J., 2006. A constructive representation of univariate skewed distributions. J. Amer. Statist. Assoc. 101, 823–829] introduced general skewing mechanisms in order to compare existing skewing methods in a common framework and to ease construction of new such methods according to the needs in given situations. In this paper, we make use of the classical transformation approach to define alternative skewing mechanisms for the same purpose. While keeping all the nice features of Ferreira and Steel’s skewing mechanisms (flexibility, surjectivity, the possibility of retaining prespecified characteristics of the original symmetric distribution, etc.), our skewing mechanisms, unlike theirs, can easily be extended to the multivariate case. We describe our skewing schemes, investigate their main properties, and illustrate their effects on standard (multi)normal distributions by means of a few examples. Finally, we briefly discuss their relevance in the context of optimal symmetry testing.     

Influence Function and Efficiency of the Minimum Covariance Determinant Scatter Matrix Estimator

The minimum covariance determinant (MCD) scatter estimator is a highly robust estimator for the dispersion matrix of a multivariate, elliptically symmetric distribution. It is relatively fast to compute and intuitively appealing. In this note we derive its influence function and compute the asymptotic variances of its elements. A comparison with the one step reweighted MCD and with S-estimators is made. Also finite-sample results are reported.