Dataset Information

FlexOracle: predicting flexible hinges by identification of stable domains.

ABSTRACT: Protein motions play an essential role in catalysis and protein-ligand interactions, but are difficult to observe directly. A substantial fraction of protein motions involve hinge bending. For these proteins, the accurate identification of flexible hinges connecting rigid domains would provide significant insight into motion. Programs such as GNM and FIRST have made global flexibility predictions available at low computational cost, but are not designed specifically for finding hinge points.Here we present the novel FlexOracle hinge prediction approach based on the ideas that energetic interactions are stronger within structural domains than between them, and that fragments generated by cleaving the protein at the hinge site are independently stable. We implement this as a tool within the Database of Macromolecular Motions, MolMovDB.org. For a given structure, we generate pairs of fragments based on scanning all possible cleavage points on the protein chain, compute the energy of the fragments compared with the undivided protein, and predict hinges where this quantity is minimal. We present three specific implementations of this approach. In the first, we consider only pairs of fragments generated by cutting at a single location on the protein chain and then use a standard molecular mechanics force field to calculate the enthalpies of the two fragments. In the second, we generate fragments in the same way but instead compute their free energies using a knowledge based force field. In the third, we generate fragment pairs by cutting at two points on the protein chain and then calculate their free energies.Quantitative results demonstrate our method's ability to predict known hinges from the Database of Macromolecular Motions.

SUBMITTER: Flores SC

PROVIDER: S-EPMC1933439 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

FlexOracle: predicting flexible hinges by identification of stable domains.

Flores Samuel C SC Gerstein Mark B MB

BMC bioinformatics 20070622

<h4>Background</h4>Protein motions play an essential role in catalysis and protein-ligand interactions, but are difficult to observe directly. A substantial fraction of protein motions involve hinge bending. For these proteins, the accurate identification of flexible hinges connecting rigid domains would provide significant insight into motion. Programs such as GNM and FIRST have made global flexibility predictions available at low computational cost, but are not designed specifically for findin ...[more]

PMID: 17587456

Similar Datasets

Project description:Transmembrane bacterial chemoreceptors are extended, rod-shaped homodimers with ligand-binding sites at one end and interaction sites for signaling complex formation and histidine kinase control at the other. There are atomic-resolution structures of chemoreceptor fragments but not of intact, membrane-inserted receptors. Electron tomography of in vivo signaling complex arrays lack distinct densities for chemoreceptor rods away from the well-ordered base plate region, implying structural heterogeneity. We used negative staining, transmission electron microscopy, and image analysis to characterize the molecular shapes of intact homodimers of the Escherichia coli aspartate receptor Tar rendered functional by insertion into nanodisc-provided E. coli lipid bilayers. Single-particle analysis plus tomography of particles in a three-dimensional matrix revealed two bend loci in the chemoreceptor cytoplasmic domain, (i) a short, two-strand gap between the membrane-proximal, four-helix-bundle HAMP (histidine kinases, adenylyl cyclases, methyl-accepting chemoreceptors, and phosphatases) domain and the membrane-distal, four-helix coiled coil and (ii) aligned glycines in the extended, four-helix coiled coil, the position of a bend noted in the previous X-ray structure of a receptor fragment. Our images showed HAMP bends from 0° to ?13° and glycine bends from 0° to ?20°, suggesting that the loci are flexible hinges. Variable hinge bending explains indistinct densities for receptor rods outside the base plate region in subvolume averages of chemotaxis arrays. Bending at flexible hinges was not correlated with the chemoreceptor signaling state. However, our analyses showed that chemoreceptor bending avoided what would otherwise be steric clashes between neighboring receptors that would block the formation of core signaling complexes and chemoreceptor arrays.IMPORTANCE This work provides new information about the shape of transmembrane bacterial chemoreceptors, crucial components in the molecular machinery of bacterial chemotaxis. We found that intact, lipid-bilayer-inserted, and thus functional homodimers of the Escherichia coli chemoreceptor Tar exhibited bends at two flexible hinges along their ?200-Å, rod-like, cytoplasmic domains. One hinge was at the short, two-strand gap between the membrane-proximal, four-helix-bundle HAMP (histidine kinases, adenylyl cyclases, methyl-accepting chemoreceptors, and phosphatases) domain and the membrane-distal, four-helix coiled coil. The other hinge was at aligned glycines in the extended, four-helix coiled coil, where a bend had been identified in the X-ray structure of a chemoreceptor fragment. Our analyses showed that flexible hinge bending avoided structural clashes in chemotaxis core complexes and their arrays.

Dataset Information

FlexOracle: predicting flexible hinges by identification of stable domains.

Publications

FlexOracle: predicting flexible hinges by identification of stable domains.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets