Efficient minimization of multipole electrostatic potentials in torsion space

The development of models of macromolecular electrostatics capable of delivering improved fidelity to quantum mechanical calculations is an active field of research in computational chemistry. Most molecular force field development takes place in the context of models with full Cartesian coordinate degrees of freedom. Nevertheless, a number of macromolecular modeling programs use a reduced set of conformational variables limited to rotatable bonds. Efficient algorithms for minimizing the energies of macromolecular systems with torsional degrees of freedom have been developed with the assumption that all atom-atom interaction potentials are isotropic. We describe novel modifications to address the anisotropy of higher order multipole terms while retaining the efficiency of these approaches. In addition, we present a treatment for obtaining derivatives of atom-centered tensors with respect to torsional degrees of freedom. We apply these results to enable minimization of the Amoeba multipole electrostatics potential in a system with torsional degrees of freedom, and validate the correctness of the gradients by comparison to finite difference approximations. In the interest of enabling a complete model of electrostatics with implicit treatment of solvent-mediated effects, we also derive expressions for the derivative of solvent accessible surface area with respect to torsional degrees of freedom

Identification of the growth factor-binding sequence in the extracellular matrix protein MAGP-1

Editorial Análisis de casos Reforma agraria y lucha por la tierra en América Latina La Reforma Agraria en América Latina: una revolución frustrada Plinio Arruda Sampaio A Nova Questão Agrária e a Reinvenção do Campesinato: o caso do MST Carlos Walter Porto-Gonçalves El movimiento campesino en el Paraguay: conflictos, planteamientos y desafíos Tomás Palau Viladesau Movimientos campesinos e indígenas en México: la lucha por la tierra Luciano Concheiro Bórquez y Sergio Grajales Ventura Las luchas campesinas en Colombia en los albores del siglo XXI: de la frustración a la esperanza Isaías Tobasura Acuña Documentos O que precisa ser feito para mudar a vida do povo! Comunicado del Frente Nacional Campesino Ezequiel Zamora de Venezuela Cronología del conflicto La geografía política del conflicto social en América Latina José Seoane y Clara Algranati Región Sur Los sindicatos uruguayos ante el primer gobierno de izquierda Luis Senatore y Jaime Yaffé • Argentina • Brasil • Chile • Paraguay • Uruguay Región Andina Quito en abril: los forajidos derrotan al coronel Mario Unda • Bolivia • Colombia • Ecuador • Perú • Venezuela Región Norte La Guatemala de la resistencia y de la esperanza: las jornadas de lucha contra el CAFTA Simona Violetta Yagenova • Costa Rica • El Salvador • Guatemala • Honduras • México • Nicaragua • Panamá • Puerto Rico • República Dominicana Debates Territorio y movimientos sociales O retorno do território Apresentação por Maria Adélia Aparecida de Souza Milton Santos Outros territórios, outros mapas Ana Clara Torres Ribeiro Movimentos socioterritoriais e movimentos socioespaciais Bernardo Mançano Fernandes Territorios en disputa: iniciativas productivas y acción política en Mosconi, Argentina Norma Giarracca y Juan Wahren Sarjam [Vocablo en lengua aymara que significa ándate] Jorge A. Sainz Cardon

Hierarchical Generalized Linear Models for Multiple Groups of Rare and Common Variants: Jointly Estimating Group and Individual-Variant Effects

Complex diseases and traits are likely influenced by many common and rare genetic variants and environmental factors. Detecting disease susceptibility variants is a challenging task, especially when their frequencies are low and/or their effects are small or moderate. We propose here a comprehensive hierarchical generalized linear model framework for simultaneously analyzing multiple groups of rare and common variants and relevant covariates. The proposed hierarchical generalized linear models introduce a group effect and a genetic score (i.e., a linear combination of main-effect predictors for genetic variants) for each group of variants, and jointly they estimate the group effects and the weights of the genetic scores. This framework includes various previous methods as special cases, and it can effectively deal with both risk and protective variants in a group and can simultaneously estimate the cumulative contribution of multiple variants and their relative importance. Our computational strategy is based on extending the standard procedure for fitting generalized linear models in the statistical software R to the proposed hierarchical models, leading to the development of stable and flexible tools. The methods are illustrated with sequence data in gene ANGPTL4 from the Dallas Heart Study. The performance of the proposed procedures is further assessed via simulation studies. The methods are implemented in a freely available R package BhGLM (http://www.ssg.uab.edu/bhglm/)

Rediscovering the value of families for psychiatric genetics research

As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full range of the allelic frequency distribution should be utilized to dissect the genetic influences on mental illness. The rate limiting factor for inferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in the studied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals are necessary to unambiguously associate a locus with an illness. Unfortunately, such large samples are often cost prohibitive. However, by using alternative analytic strategies and studying related individuals, particularly those from large multiplex families, it is possible to reduce the required sample size while maintaining statistical power. We contend that using whole genome sequence (WGS) in extended pedigrees provides a cost-effective strategy for psychiatric gene mapping that complements common variant approaches and WGS in unrelated individuals. This was our impetus for forming the “Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders” consortium. In this review, we provide a rationale for the use of WGS with pedigrees in modern psychiatric genetics research. We begin with a focused review of the current literature, followed by a short history of family-based research in psychiatry. Next, we describe several advantages of pedigrees for WGS research, including power estimates, methods for studying the environment, and endophenotypes. We conclude with a brief description of our consortium and its goals.This research was supported by National Institute of Mental Health grants U01 MH105630 (DCG), U01 MH105634 (REG), U01 MH105632 (JB), R01 MH078143 (DCG), R01 MH083824 (DCG & JB), R01 MH078111 (JB), R01 MH061622 (LA), R01 MH042191 (REG), and R01 MH063480 (VLN).UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Biología Celular y Molecular (CIBCM)UCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Biologí

Evaluating SASA derivatives from intersectional information.

<p>Expressions for the derivative of SASA of a molecule with respect to its torsional degrees of freedom can be deduced from the arcs that define the intersections of spherical overlaps, without differentiating the full expression for each atomic SASA. <b>A.</b> An atom is shown rendered as a grey sphere with a patch buried by a neighboring atom colored in white. The unit vector <b><i>e</i></b> shows the direction from the atom under consideration to the neighboring atom responsible for the overlap. The first contribution to the SASA derivative comes from motions that change the distance between two atoms. In the absence of other atoms, the rotation of the neighboring atom about the atom of interest serves only to relocate the buried patch without changing the SASA. <b>B.</b> The change in the size of the buried patch due to another atom with respect to interatomic separation can be determined by applying the law of cosines to the intersectional geometry for the spheres. <b>C.</b> When multiple patches overlap, the surface of the sphere that is occluded is described by a set of arcs. In this case, there are two arcs. One arc goes clockwise from <b><i>v</i></b>_<b>1</b> to <b><i>v</i></b>_<b>2</b>, and a second arc completes the cycle clockwise from <b><i>v</i></b>_<b>2</b> to <b><i>v</i></b>_<b>1</b>. The contribution to the change in SASA due to altered distance to a neighboring atom is modified relative to the two atom case in that only a fraction of the buried patch is independent of other atoms. In this example, the change in patch size with respect to interatomic separation in panel A is scaled by . In addition, a second contribution to the SASA derivative results from distance-preserving rotations of intersecting atoms about the atom under consideration. Infinitesimal rotations perpendicular to the line between the points that define each arc (<b><i>v</i></b>_<b>1</b> and <b><i>v</i></b>_<b>2</b> in panel C) sweep out an infinitesimal slice of surface area (shown as a grey box).</p

Multipole energy term derivatives for Gō framework in vector form.

<p>Multipole energy term derivatives for Gō framework in vector form.</p

The split coordinate frame problem.

<p><b>A.</b> Cycles in molecular topology complicate a tree-based description of molecular topology. Proline residues contain a cycle, as the side chain emanating from the <i>C</i>_<i>α</i> atom forms a closed ring, reentering the main chain at the N atom. Because of the requirement for ring closure, the torsion values (indicated by gray arrows) are not independent. <b>B.</b> The strategy for handling cycles in the Rosetta program is to create an artificial break in the ring, restoring a tree-like topology. The requirement for closure is enforced with the introduction of a ‘virtual’ N atom (denoted by the hollow typeface). Supplemental constraints are added to the energy potential to ensure that the virtual atom overlays its real atom counterpart. <b>C.</b> Interaction between ring breakage and local coordinate definitions complicate gradient calculation. A coordinate system is defined for each atom to properly orient its dipole and quadrupole moments in the global frame. This local frame is defined for each atom in terms of its bonded neighbors. For the N atom of proline, the z-axis is defined to lie along its bond with the <i>C</i>_<i>α</i> atom, and the x-axis lies in the plane formed by the z-axis and the direction towards the <i>C</i>_<i>δ</i> atom. When the bond between the N and <i>C</i>_<i>δ</i> atoms is artificially broken to reestablish a tree-like topology, rotations such as that about the torsion indicated by the star can lead to alteration of the local coordinate frame at the N atom (the two configurations of the <i>C</i>_<i>δ</i> atom give rise to the two local coordinate frames shown inside the proline ring). This change in local frame effects the interactions between the N atom and every other atom in the molecule, resulting in an energy gradient between atoms that are on the same side of a rotatable bond. Strong constraints to enforce the overlap between the ‘real’ and ‘virtual’ copies of the N atom can minimize the value of this gradient. However, this effect represents a violation of the original assumption of Noguti and Gō that energy potentials depend only on interatomic distances [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0195578#pone.0195578.ref031" target="_blank">31</a>].</p

The frame rotation problem.

<p>Rotation about a torsion bond (for example, the bond colored green in the figure) changes the distances between atoms upstream and downstream of the bond. It also causes a rotation of the coordinate frame centered on the atom at the downstream end of the bond (atom 2 in the figure). This frame rotation results in a change in the dipole (denoted by the orange lobes) and quadrupole moments for the atom in the global frame. Thus, the energetic interaction between atoms 1 and 2 has a derivative with respect to the torsion angle even though the distance between the atoms remains constant.</p