mCSM-AB: a web server for predicting antibody-antigen affinity changes upon mutation with graph-based signatures.

Computational methods have traditionally struggled to predict the effect of mutations in antibody-antigen complexes on binding affinity. This has limited their usefulness during antibody engineering and development, and their ability to predict biologically relevant escape mutations. Here we present mCSM-AB, a user-friendly web server for accurately predicting antibody-antigen affinity changes upon mutation which relies on graph-based signatures. We show that mCSM-AB performs better than comparable methods that have been previously used for antibody engineering. mCSM-AB web server is available at http://structure.bioc.cam.ac.uk/mcsm_ab.This is the final published version. It first appeared at http://nar.oxfordjournals.org/content/early/2016/05/23/nar.gkw458.full

pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures.

Drug development has a high attrition rate, with poor pharmacokinetic and safety properties a significant hurdle. Computational approaches may help minimize these risks. We have developed a novel approach (pkCSM) which uses graph-based signatures to develop predictive models of central ADMET properties for drug development. pkCSM performs as well or better than current methods. A freely accessible web server (http://structure.bioc.cam.ac.uk/pkcsm), which retains no information submitted to it, provides an integrated platform to rapidly evaluate pharmacokinetic and toxicity properties.Newton Fund RCUK-CONFAP grant awarded by The Medical Research Council (MRC) and Fundac a o de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) [to D.E.V.P., T.L.B,. and D.B.A.]; Conselho Nacional de Desenvolvimento Cienti fi co e Tecnolo gico (CNPq), and Centro de Pesquisas Rene Rachou (CPqRR/FIOCRUZ Minas), Brazil [to D.E.V.P.]; NHMRC CJ Martin Fellowship [APP1072476 to D.B.A.]; University of Cambridge and The Wellcome Trust for facilities and support [to T.L.B.]. Funding for open access charge: The Wellcome Trust.This is the final version. It was first published by ACS at http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b00104

In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity.

Despite interest in associating polymorphisms with clinical or experimental phenotypes, functional interpretation of mutation data has lagged behind generation of data from modern high-throughput techniques and the accurate prediction of the molecular impact of a mutation remains a non-trivial task. We present here an integrated knowledge-driven computational workflow designed to evaluate the effects of experimental and disease missense mutations on protein structure and interactions. We exemplify its application with analyses of saturation mutagenesis of DBR1 and Gal4 and show that the experimental phenotypes for over 80% of the mutations correlate well with predicted effects of mutations on protein stability and RNA binding affinity. We also show that analysis of mutations in VHL using our workflow provides valuable insights into the effects of mutations, and their links to the risk of developing renal carcinoma. Taken together the analyses of the three examples demonstrate that structural bioinformatics tools, when applied in a systematic, integrated way, can rapidly analyse a given system to provide a powerful approach for predicting structural and functional effects of thousands of mutations in order to reveal molecular mechanisms leading to a phenotype. Missense or non-synonymous mutations are nucleotide substitutions that alter the amino acid sequence of a protein. Their effects can range from modifying transcription, translation, processing and splicing, localization, changing stability of the protein, altering its dynamics or interactions with other proteins, nucleic acids and ligands, including small molecules and metal ions. The advent of high-throughput techniques including sequencing and saturation mutagenesis has provided large amounts of phenotypic data linked to mutations. However, one of the hurdles has been understanding and quantifying the effects of a particular mutation, and how they translate into a given phenotype. One approach to overcome this is to use robust, accurate and scalable computational methods to understand and correlate structural effects of mutations with disease.Newton Fund RCUK-CONFAP Grant awarded by The Medical Research Council (MRC) and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) [to D.E.V.P, T.L.B. and D.B.A.]. Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and René Rachou Research Center (CPqRR/FIOCRUZ Minas), Brazil [to D.E.V.P.]; NHMRC CJ Martin Fellowship [APP1072476 to D.B.A.]; University of Cambridge and The Wellcome Trust for facilities and support [to T.L.B.]. Funding for open access charge: The Wellcome Trust.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/srep1984

Modeling planar degenerate wetting and anchoring in nematic liquid crystals

We propose a simple surface potential favoring the planar degenerate anchoring of nematic liquid crystals, i.e., the tendency of the molecules to align parallel to one another along any direction parallel to the surface. We show that, at lowest order in the tensorial Landau-de Gennes order-parameter, fourth-order terms must be included. We analyze the anchoring and wetting properties of this surface potential. In the nematic phase, we find the desired degenerate planar anchoring, with positive scalar order-parameter and some surface biaxiality. In the isotropic phase, we find, in agreement with experiments, that the wetting layer may exhibit a uniaxial ordering with negative scalar order-parameter. For large enough anchoring strength, this negative ordering transits towards the planar degenerate state

mCSM-lig: quantifying the effects of mutations on protein-small molecule affinity in genetic disease and emergence of drug resistance.

The ability to predict how a mutation affects ligand binding is an essential step in understanding, anticipating and improving the design of new treatments for drug resistance, and in understanding genetic diseases. Here we present mCSM-lig, a structure-guided computational approach for quantifying the effects of single-point missense mutations on affinities of small molecules for proteins. mCSM-lig uses graph-based signatures to represent the wild-type environment of mutations, and small-molecule chemical features and changes in protein stability as evidence to train a predictive model using a representative set of protein-ligand complexes from the Platinum database. We show our method provides a very good correlation with experimental data (up to ρ = 0.67) and is effective in predicting a range of chemotherapeutic, antiviral and antibiotic resistance mutations, providing useful insights for genotypic screening and to guide drug development. mCSM-lig also provides insights into understanding Mendelian disease mutations and as a tool for guiding protein design. mCSM-lig is freely available as a web server at http://structure.bioc.cam.ac.uk/mcsm_lig.Newton Fund RCUK-CONFAP Grant awarded by The Medical Research Council (MRC) and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) [MR/M026302/1 to D.E.V.P, T.L.B. and D.B.A.]. René Rachou Research Center (CPqRR/FIOCRUZ Minas), Brazil [to D.E.V.P.]; NHMRC CJ Martin Fellowship [APP1072476 to D.B.A.]; University of Cambridge and The Wellcome Trust for facilities and support [to T.L.B.].This is the final version of the article. It first appeared from Nature Publishing Group at http://dx.doi.org/10.1038/srep29575

Long-time behaviour of discretizations of the simple pendulum equation

We compare the performance of several discretizations of the simple pendulum equation in a series of numerical experiments. The stress is put on the long-time behaviour. We choose for the comparison numerical schemes which preserve the qualitative features of solutions (like periodicity). All these schemes are either symplectic maps or integrable (preserving the energy integral) maps, or both. We describe and explain systematic errors (produced by any method) in numerical computations of the period and the amplitude of oscillations. We propose a new numerical scheme which is a modification of the discrete gradient method. This discretization preserves (almost exactly) the period of small oscillations for any time step.Comment: 41 pages, including 18 figures and 4 table

Spherically symmetric Yang-Mills solutions in a (4+n)- dimensional space-time

We consider the Einstein-Yang-Mills Lagrangian in a (4+n)-dimensional space-time. Assuming the matter and metric fields to be independent of the n extra coordinates, a spherical symmetric Ansatz for the fields leads to a set of coupled ordinary differential equations. We find that for n > 1 only solutions with either one non-zero Higgs field or with all Higgs fields constant exist. We construct the analytic solutions which fulfill this conditions for arbitrary n, namely the Einstein-Maxwell-dilaton solutions. We also present generic solutions of the effective 4-dimensional Einstein-Yang-Mills-Higgs-dilaton model, which possesses n Higgs triplets coupled in a specific way to n independent dilaton fields. These solutions are the abelian Einstein-Maxwell- dilaton solutions and analytic non-abelian solutions, which have diverging Higgs fields. In addition, we construct numerically asymptotically flat and finite energy solutions for n=2.Comment: 15 Latex pages, 4 eps figures; v2: discussion of results revisite

High density QCD on a Lefschetz thimble?

It is sometimes speculated that the sign problem that afflicts many quantum field theories might be reduced or even eliminated by choosing an alternative domain of integration within a complexified extension of the path integral (in the spirit of the stationary phase integration method). In this paper we start to explore this possibility somewhat systematically. A first inspection reveals the presence of many difficulties but - quite surprisingly - most of them have an interesting solution. In particular, it is possible to regularize the lattice theory on a Lefschetz thimble, where the imaginary part of the action is constant and disappears from all observables. This regularization can be justified in terms of symmetries and perturbation theory. Moreover, it is possible to design a Monte Carlo algorithm that samples the configurations in the thimble. This is done by simulating, effectively, a five dimensional system. We describe the algorithm in detail and analyze its expected cost and stability. Unfortunately, the measure term also produces a phase which is not constant and it is currently very expensive to compute. This residual sign problem is expected to be much milder, as the dominant part of the integral is not affected, but we have still no convincing evidence of this. However, the main goal of this paper is to introduce a new approach to the sign problem, that seems to offer much room for improvements. An appealing feature of this approach is its generality. It is illustrated first in the simple case of a scalar field theory with chemical potential, and then extended to the more challenging case of QCD at finite baryonic density.Comment: Misleading footnote 1 corrected: locality deserves better investigations. Formula (31) corrected (we thank Giovanni Eruzzi for this observation). Note different title in journal versio

Effect of Cattail (Typha domingensis) Extracts, Leachates, and Selected Phenolic Compounds on Rates of Oxygen Production by Salvinia (Salvinia minima)

Salvinia (Salvinia minima Willd.) is a water fern found in Florida waters, usually associated with Lemna and other small free-floating species. Due to its buoyancy and mat-forming abilities, it is spread by moving waters. In 1994, salvinia was reported to be present in 247 water bodies in the state (out of 451 surveyed public waters, Schardt 1997). It is a small, rapidly growing species that can become a nuisance due to its explosive growth rates and its ability to shade underwater life (Oliver 1993). Any efforts toward management of salvinia populations must consider that, in reasonable amounts, its presence is desirable since it plays an important role in the overall ecosystem balance. New management alternatives need to be explored besides the conventional herbicide treatments; for example, it has been shown that the growth of S. molesta can be inhibited by extracts of the tropical weed parthenium (Parthenium hysterophorus) and its purified toxin parthenin (Pande 1994, 1996). We believe that cattail, Typha spp. may be a candidate for control of S. minima infestations. Cattail is an aggressive aquatic plant, and has the ability to expand over areas that weren't previously occupied by other species (Gallardo et al. 1998a and references cited there). In South Florida, T. domingensis is a natural component of the Everglades ecosystem, but in many cases it has become the dominant marsh species, outcompeting other native plants. In Florida public waters, this cattail species is the most dominant emergent species of aquatic plants (Schardt 1997). Several factors enable it to accomplish opportunistic expansion, including size, growth habits, adaptability to changes in the surroundings, and the release of compounds that can prevent the growth and development of other species. We have been concerned in the past with the inhibitory effects of the T. domingensis extracts, and the phenolic compounds mentioned before, towards the growth and propagation of S. minima (Gallardo et al. 1998b). This investigation deals with the impact of cattail materials on the rates of oxygen production of salvinia, as determined through a series of Warburg experiments (Martin et al. 1987, Prindle and Martin 1996)

Geodesic motion in the space-time of a cosmic string

We study the geodesic equation in the space-time of an Abelian-Higgs string and discuss the motion of massless and massive test particles. The geodesics can be classified according to the particles energy, angular momentum and linear momentum along the string axis. We observe that bound orbits of massive particles are only possible if the Higgs boson mass is smaller than the gauge boson mass, while massless particles always move on escape orbits. Moreover, neither massive nor massless particles can ever reach the string axis for non-vanishing angular momentum. We also discuss the dependence of light deflection by a cosmic string as well as the perihelion shift of bound orbits of massive particles on the ratio between Higgs and gauge boson mass and the ratio between symmetry breaking scale and Planck mass, respectively.Comment: 20 pages including 14 figures; v2: references added, discussion on null geodesics extended, numerical results adde