Comparison of tertiary structures of proteins in protein-protein complexes with unbound forms suggests prevalence of allostery in signalling proteins

Abstract: Background: Most signalling and regulatory proteins participate in transient protein-protein interactions during biological processes. They usually serve as key regulators of various cellular processes and are often stable in both protein-bound and unbound forms. Availability of high-resolution structures of their unbound and bound forms provides an opportunity to understand the molecular mechanisms involved. In this work, we have addressed the question "What is the nature, extent, location and functional significance of structural changes which are associated with formation of protein-protein complexes?" Results: A database of 76 non-redundant sets of high resolution 3-D structures of protein-protein complexes, representing diverse functions, and corresponding unbound forms, has been used in this analysis. Structural changes associated with protein-protein complexation have been investigated using structural measures and Protein Blocks description. Our study highlights that significant structural rearrangement occurs on binding at the interface as well as at regions away from the interface to form a highly specific, stable and functional complex. Notably, predominantly unaltered interfaces interact mainly with interfaces undergoing substantial structural alterations, revealing the presence of at least one structural regulatory component in every complex. Interestingly, about one-half of the number of complexes, comprising largely of signalling proteins, show substantial localized structural change at surfaces away from the interface. Normal mode analysis and available information on functions on some of these complexes suggests that many of these changes are allosteric. This change is largely manifest in the proteins whose interfaces are altered upon binding, implicating structural change as the possible trigger of allosteric effect. Although large-scale studies of allostery induced by small-molecule effectors are available in literature, this is, to our knowledge, the first study indicating the prevalence of allostery induced by protein effectors. Conclusions: The enrichment of allosteric sites in signalling proteins, whose mutations commonly lead to diseases such as cancer, provides support for the usage of allosteric modulators in combating these diseases.

Computing Reeb Graphs as a Union of Contour Trees

The Reeb graph of a scalar function tracks the evolution of the topology of its level sets. This paper describes a fast algorithm to compute the Reeb graph of a piecewise-linear (PL) function defined over manifolds and non-manifolds. The key idea in the proposed approach is to maximally leverage the efficient contour tree algorithm to compute the Reeb graph. The algorithm proceeds by dividing the input into a set of subvolumes that have loop-free Reeb graphs using the join tree of the scalar function and computes the Reeb graph by combining the contour trees of all the subvolumes. Since the key ingredient of this method is a series of union-find operations, the algorithm is fast in practice. Experimental results demonstrate that it outperforms current generic algorithms by a factor of up to two orders of magnitude, and has a performance on par with algorithms that are catered to restricted classes of input. The algorithm also extends to handle large data that do not fit in memory.

Effective Q Criterion for Disk Stability in an External Potential

The standard Q criterion (with Q > 1) describes the stability against local, axisymmetric perturbations in a disk supported by rotation and random motion. Most astrophysical disks, however, are under the influence of an external gravitational potential, which can significantly affect their stability. A typical example is a galactic disk embedded in a dark matter halo. Here, we do a linear perturbation analysis for a disk in an external potential and obtain a generalized dispersion relation and the effective stability criterion. An external potential, such as that due to the dark matter halo concentric with the disk, contributes to the unperturbed rotational field and significantly increases its stability. We obtain the values for the effective Q parameter for the Milky Way and for a low surface brightness galaxy, UGC 7321. We find that in each case the stellar disk by itself is barely stable and it is the dark matter halo that stabilizes the disk against local, axisymmetric gravitational instabilities. Thus, the dark matter halo is necessary to ensure local disk stability. This result has been largely missed so far because in practice the Q parameter for a galactic disk is obtained using the observed rotational field that already includes the effect of the halo

EFFECTIVE Q CRITERION FOR DISK STABILITY IN AN EXTERNAL POTENTIAL

standard Q criterion (with Q > 1) describes the stability against local, axisymmetric perturbations in a disk supported by rotation and random motion. Most astrophysical disks, however, are under the influence of an external gravitational potential, which can significantly affect their stability. A typical example is a galactic disk embedded in a dark matter halo. Here, we do a linear perturbation analysis for a disk in an external potential and obtain a generalized dispersion relation and the effective stability criterion. An external potential, such as that due to the dark matter halo concentric with the disk, contributes to the unperturbed rotational field and significantly increases its stability. We obtain the values for the effective Q parameter for the Milky Way and for a low surface brightness galaxy, UGC 7321. We find that in each case the stellar disk by itself is barely stable and it is the dark matter halo that stabilizes the disk against local, axisymmetric gravitational instabilities. Thus, the dark matter halo is necessary to ensure local disk stability. This result has been largely missed so far because in practice the Q parameter for a galactic disk is obtained using the observed rotational field that already includes the effect of the halo.

Organocatalytic Enantioselective Formal C(sp(2))-H Alkylation

An organocatalytic enantioselective formal C(sp(2))-H alkylation is reported. This alkylative desymmetrization of prochiral 2,2-disubstituted cyclopentene-1,3-dione is catalyzed by a bifunctional tertiary aminourea derivative, utilizes air-stable and inexpensive nitroalkanes as the alkylating agents, and delivers synthetically versatile five-membered carbocycles containing an all-carbon quaternary stereogenic center remote from the reaction site in excellent enantioselectivity.

A Full Body Steerable Wind Display for a Locomotion Interface

This paper presents the Treadport Active Wind Tunnel (TPAWT)-a full-body immersive virtual environment for the Treadport locomotion interface designed for generating wind on a user from any frontal direction at speeds up to 20 kph. The goal is to simulate the experience of realistic wind while walking in an outdoor virtual environment. A recirculating-type wind tunnel was created around the pre-existing Treadport installation by adding a large fan, ducting, and enclosure walls. Two sheets of air in a non-intrusive design flow along the side screens of the back-projection CAVE-like visual display, where they impinge and mix at the front screen to redirect towards the user in a full-body cross-section. By varying the flow conditions of the air sheets, the direction and speed of wind at the user are controlled. Design challenges to fit the wind tunnel in the pre-existing facility, and to manage turbulence to achieve stable and steerable flow, were overcome. The controller performance for wind speed and direction is demonstrated experimentally.

Controlled release kinetics of p-aminosalicylic acid from biodegradable crosslinked polyesters for enhanced anti-mycobacterial activity

Unlike conventional polymeric drug delivery systems, where drugs are entrapped in polymers, this study focuses on the incorporation of the drug into the polymer backbone to achieve higher loading and sustained release. Crosslinked, biodegradable, xylitol based polyesters have been synthesized in this study. The bioactive drug moiety, p-aminosalicylic acid (PAS), was incorporated in xylitol based polyesters to impart its anti-mycobacterial activity. To understand the influence of the monomer chemistry on the incorporation of PAS and its subsequent release from the polymer, different diacids have been used. Controlled release profiles of the drug from these polyesters were studied under normal physiological conditions. The degradation of the polyesters varied from 48% to 76% and the release of PAS ranged from 54% to 65% of its initial loading in 7 days. A new model was developed to explain the release kinetics of PAS from the polymer that accounted for the polymer degradation and drug concentration. The thermal, mechanical, drug release and cytocompatibility properties of the polymers indicate their suitability in biomedical applications. The released products from these polymers were observed to be pharmacologically active against Mycobacteria. The high drug loading and sustained release also ensured enhanced efficacy. These polymers form biocompatible, biodegradable polyesters where the sustained release of PAS may be tailored for potential treatment of mycobacterial infections. Statement of significance In the present work, we report on novel polyesters with p-aminosalicylic acid (PAS) incorporated in the polymer backbone. The current work aims to achieve controlled release of PAS and ensures the delivered PAS is stable and pharmacologically active. The novelty of this work primarily involves the synthetic chemistry of polymerization and detailed analysis and efficacy of active PAS delivery. A new kinetic model has been developed to explain the PAS release profiles. These polymers are biodegradable, cytocompatible and anti-mycobacterial in nature. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.