Jens M. H. Thomas

Crystal structure of the Nipah virus phosphoprotein tetramerization domain

ABSTRACT The Nipah virus phosphoprotein (P) is multimeric and tethers the viral polymerase to the nucleocapsid. We present the crystal structure of the multimerization domain of Nipah virus P: a long, parallel, tetrameric, coiled coil with a small, α-helical cap structure. Across the paramyxoviruses, these domains share little sequence identity yet are similar in length and structural organization, suggesting a common requirement for scaffolding or spatial organization of the functions of P in the virus life cycle.

Routine phasing of coiled-coil protein crystal structures with AMPLE

AMPLE solved 80% of a large set of coiled-coil protein targets of diverse architectures by molecular replacement with ab initio structure predictions. Successes included targets of up to 253 residues, cases of diffraction to only 2.9 Å resolution and macromolecular complexes containing proteins with other folds or DNA.

Residue contacts predicted by evolutionary covariance extend the application of ab initio molecular replacement to larger and more challenging protein folds

Residue-contact predictions extend the range of ab initio molecular replacement.

Exploring the speed and performance of molecular replacement with AMPLE using QUARK ab initio protein models

Two ab initio modelling programs solve complementary sets of targets, enhancing the success of AMPLE with small proteins.

Novel self-assembled 2D networks based on zinc metal ion co-ordination: synthesis and comparative study with 3D networks

The synthesis of linear and trigonal terpyridine bearing molecules (tpys) and their self-assembly to form novel extended self-assembled 2D networks of trigonal tpys with linear tpys through zinc metal ion (Zn2+) co-ordination is reported. The resulting Zn2+ co-ordination networks have been characterized by means of X-ray photoelectron spectroscopy (XPS), small angle X-ray scattering (SAXS), BET, and photophysical methods. The presence of some short range order in these networks has been shown by the SAXS results and these results have been analyzed with the help of molecular modelling studies. These metallo-supramolecular Zn2+ networks revealed the influence of the metal ion on the thermal and optical properties of the synthesized metallo-supramolecular assemblies, similar to the results previously reported for 1D and 3D self-assembled metallo-supramolecular materials. Moreover, these networks have shown high luminescence with a long fluorescence lifetime and good thermal stabilities. The monolayer of such ordered networks can be used as a template to build hierarchical nanostructures. These hierarchical nanostructures could be used as active components in electronic devices and as templates for the formation of hybrid organic–inorganic nanomaterials.

SIMBAD: a sequence-independent molecular-replacement pipeline

SIMBAD is a sequence-independent molecular-replacement pipeline for solving difficult molecular-replacement cases where contaminants have been crystallized. It can also be used to find structurally related search models where no obvious homologue can be found through sequence-based searching.

ConKit: a python interface to contact predictions

Summary: Recent advances in protein residue contact prediction algorithms have led to the emergence of many new methods and a variety of file formats. We present ConKit, an open source, modular and extensible Python interface which allows facile conversion between formats and provides an interface to analyses of sequence alignments and sets of contact predictions. Availability and Implementation: ConKit is available via the Python Package Index. The documentation can be found at http://www.conkit.org. ConKit is licensed under the BSD 3‐Clause. Contact: hlfsimko@liverpool.ac.uk or drigden@liverpool.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.

AMPLE- usingde novoprotein structure modelling techniques to create and enhance search models for use in molecular replacement

The prediction of protein folds through de novo/ ab initio modelling is a rapidly developing field. Recent years have seen advances in the techniques used to the point where the conformations of smaller proteins or protein domains (120 residues or less) can now be reliably predicted in a significant fraction of test cases. It has been shown that these models can be good enough for use as search models in the molecular replacement technique of protein structure solution by X-ray diffraction methods. [1,2] This can be particularly useful in cases where no homologous structure is available. It has also been shown to be effective in preparing low sequence identity homologues for molecular replacement where these homologues have proven insufficient as search models when prepared using more traditional methods. Here we present AMPLE [3], a new software tool jointly developed by the University of Liverpool and CCP4 which is designed to make this technique available to users in an automated way and requiring only limited computational hardware resources. It calls upon Rosetta [4-6] for the generation of de novo template models, these are then put through an intricate processing procedure to optimize their suitability for molecular replacement. Our initial tests on a set of 296 cases drawn from the PDB have shown that the techniques employed in AMPLE can result in solutions in approximately 40% of the trials. AMPLE has already proven its worth in novel protein structure solution and a beta release version is included in the latest release of the CCP4 software suite [7].

Large scale ab initio modeling of structurally uncharacterized antimicrobial peptides reveals known and novel folds

Antimicrobial resistance within a wide range of infectious agents is a severe and growing public health threat. Antimicrobial peptides (AMPs) are among the leading alternatives to current antibiotics, exhibiting broad spectrum activity. Their activity is determined by numerous properties such as cationic charge, amphipathicity, size, and amino acid composition. Currently, only around 10% of known AMP sequences have experimentally solved structures. To improve our understanding of the AMP structural universe we have carried out large scale ab initio 3D modeling of structurally uncharacterized AMPs that revealed similarities between predicted folds of the modeled sequences and structures of characterized AMPs. Two of the peptides whose models matched known folds are Lebocin Peptide 1A (LP1A) and Odorranain M, predicted to form β‐hairpins but, interestingly, to lack the intramolecular disulfide bonds, cation‐π or aromatic interactions that generally stabilize such AMP structures. Other examples include Ponericin Q42, Latarcin 4a, Kassinatuerin 1, Ceratotoxin D, and CPF‐B1 peptide, which have α‐helical folds, as well as mixed αβ folds of human Histatin 2 peptide and Garvicin A which are, to the best of our knowledge, the first linear αββ fold AMPs lacking intramolecular disulfide bonds. In addition to fold matches to experimentally derived structures, unique folds were also obtained, namely for Microcin M and Ipomicin. These results help in understanding the range of protein scaffolds that naturally bear antimicrobial activity and may facilitate protein design efforts towards better AMPs.

Ensembles generated from crystal structures of single distant homologues solve challenging molecular-replacement cases in AMPLE

Novel ways to produce search models from distant homologues for molecular replacement are presented.