Biomedical subjects

Jens Kleinjung

Publications and source records attributed to Jens Kleinjung.

10 recordsLinked to original sources

PubMed2007

Interaction of malaria parasite-inhibitory antibodies with the merozoite surface protein MSP1(19) by computational docking.

Merozoite surface protein 1 (MSP1) of the malaria parasite Plasmodium falciparum is an important vaccine candidate antigen. Antibodies specific for the C-terminal maturation product, MSP1(19), have been shown to inhibit erythrocyte invasion and parasite growth. Specific monoclonal antibodies react with conformational epitopes contained within the two EGF-like domains that constitute the antigen MSP1(19). To gain greater insight into the inhibitory process, the authors selected two strongly inhibitory antibodies (designated 12.8 and 12.10) and modeled their structures by homology. Computational docking was used to generate antigen-antibody complexes and a selection filter based on NMR data was applied to obtain plausible models. Molecular Dynamics simulations of the selected complexes were performed to evaluate the role of specific side chains in the binding. Favorable complexes were obtained that complement the NMR data in defining specific binding sites. These models can provide valuable guidelines for future experimental work that is devoted to the understanding of the action mechanism of invasion-inhibitory antibodies.

Amino Acid Sequence↗

PubMed2007

MinSet: a general approach to derive maximally representative database subsets by using fragment dictionaries and its application to the SCOP database.

MOTIVATION: The size of current protein databases is a challenge for many Bioinformatics applications, both in terms of processing speed and information redundancy. It may be therefore desirable to efficiently reduce the database of interest to a maximally representative subset. RESULTS: The MinSet method employs a combination of a Suffix Tree and a Genetic Algorithm for the generation, selection and assessment of database subsets. The approach is generally applicable to any type of string-encoded data, allowing for a drastic reduction of the database size whilst retaining most of the information contained in the original set. We demonstrate the performance of the method on a database of protein domain structures encoded as strings. We used the SCOP40 domain database by translating protein structures into character strings by means of a structural alphabet and by extracting optimized subsets according to an entropy score that is based on a constant-length fragment dictionary. Therefore, optimized subsets are maximally representative for the distribution and range of local structures. Subsets containing only 10% of the SCOP structure classes show a coverage of >90% for fragments of length 1-4. AVAILABILITY: http://mathbio.nimr.mrc.ac.uk/~jkleinj/MinSet. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Algorithms↗

PubMed2005

POPSCOMP: an automated interaction analysis of biomolecular complexes.

Large-scale analysis of biomolecular complexes reveals the functional network within the cell. Computational methods are required to extract the essential information from the available data. The POPSCOMP server is designed to calculate the interaction surface between all components of a given complex structure consisting of proteins, DNA or RNA molecules. The server returns matrices and graphs of surface area burial that can be used to automatically annotate components and residues that are involved in complex formation, to pinpoint conformational changes and to estimate molecular interaction energies. The analysis can be performed on a per-atom level or alternatively on a per-residue level for low-resolution structures. Here, we present an analysis of ribosomal structures in complex with various antibiotics to exemplify the potential and limitations of automated complex analysis. The POPSCOMP server is accessible at http://ibivu.cs.vu.nl/programs/popscompwww/.

Anti-Bacterial Agents↗

PubMed2004

Plasticity of influenza haemagglutinin fusion peptides and their interaction with lipid bilayers.

A detailed molecular dynamics study of the haemagglutinin fusion peptide (N-terminal 20 residues of the HA2 subunits) in a model bilayer has yielded useful information about the molecular interactions leading to insertion into the lipids. Simulations were performed on the native sequence, as well as a number of mutant sequences, which are either fusogenic or nonfusogenic. For the native sequence and fusogenic mutants, the N-terminal 11 residues of the fusion peptides are helical and insert with a tilt angle of approximately 30 degrees with respect to the membrane normal, in very good agreement with experimental data. The tilted insertion of the native sequence peptide leads to membrane bilayer thinning and the calculated order parameters show larger disorder of the alkyl chains. These results indicate that the lipid packing is perturbed by the fusion peptide and could be used to explain membrane fusion. For the nonfusogenic sequences investigated, it was found that most of them equilibrate parallel to the interface plane and do not adopt a tilted conformation. The presence of a charged residue at the beginning of the sequence (G1E mutant) resulted in a more difficult case, and the outcomes do not fall straightforwardly into the general picture. Sequence searches have revealed similarities of the fusion peptide of influenza haemagglutinin with peptide sequences such as segments of porin, amyloid alpha eta peptide, and a peptide from the prion sequence. These results confirm that the sequence can adopt different folds in different environments. The plasticity and the conformational dependence on the local environment could be used to better understand the function of fusion peptides.

Amino Acid Sequence↗

PubMed2004

Effect of thyroid hormone binding proteins on insulin receptor binding of B1-thyronine-insulin analogues.

Certain thyronine-insulin analogues, which form non-covalent complexes with plasma proteins, have been shown to act preferentially in the liver. We hypothesized that this property may be dependent on the ability of the analogue to bind to the insulin receptor without prior dissociation from the binding protein. NaB1-L-thyroxyl-insulin, NaB1-3,3',5'-triiodothyronine-insulin, NaB1-D-thyroxyl-insulin and NaB1-L-thyroxyl-aminolauroyl-insulin were compared with insulin for their capacity to inhibit the binding of [125I]TyrA14-insulin to rat liver plasma membrane in albumin-free buffer. Effective doses at 50% maximum inhibition of binding (ED50) were calculated with and without addition of the thyroid hormone binding proteins transthyretin, thyroxine binding globulin and human serum albumin. The binding of thyronine-insulin analogues to insulin receptors was inhibited in a dose-dependent manner by the addition of thyroid hormone binding proteins at concentrations in the physiological range. Complexes of thyronine-insulin analogues with thyroid hormone binding proteins exhibit impaired insulin receptor binding affinities compared with those of the analogues in their free form. Hepatoselectivity in vivo may not depend on binding of the intact complexes to hepatocytes. These results have implications for the physiological role of hormone binding proteins and the in vivo properties of other insulin analogues which bind to plasma proteins.

Animals↗

PubMed2004

Contact-based sequence alignment.

This paper introduces the novel method of contact-based protein sequence alignment, where structural information in the form of contact mutation probabilities is incorporated into an alignment routine using contact-mutation matrices (CAO: Contact Accepted mutatiOn). The contact-based alignment routine optimizes the score of matched contacts, which involves four (two per contact) instead of two residues per match in pairwise alignments. The first contact refers to a real side-chain contact in a template sequence with known structure, and the second contact is the equivalent putative contact of a homologous query sequence with unknown structure. An algorithm has been devised to perform a pairwise sequence alignment based on contact information. The contact scores were combined with PAM-type (Point Accepted Mutation) substitution scores after parameterization of gap penalties and score weights by means of a genetic algorithm. We show that owing to the structural information contained in the CAO matrices, significantly improved alignments of distantly related sequences can be obtained. This has allowed us to annotate eight putative Drosophila IGF sequences. Contact-based sequence alignment should therefore prove useful in comparative modelling and fold recognition.

Algorithms↗

PubMed2003

POPS: A fast algorithm for solvent accessible surface areas at atomic and residue level.

POPS (Parameter OPtimsed Surfaces) is a new method to calculate solvent accessible surface areas, which is based on an empirically parameterisable analytical formula and fast to compute. Atomic and residue areas (the latter represented by a single sphere centered on the C(alpha) atom of amino acids and at the P atom of nucleotides) have been optimised versus accurate all-atom methods. The parameterisation has been derived from a selected dataset of proteins and nucleic acids of different sizes and topologies. The residue based approach POPS-R, has been devised as a useful tool for the analysis of large macromolecular assemblies like the ribosome and it is specially suited for the refinement of low resolution structures. POPS-R also allows for estimates of the loss of free energy of solvation upon complex formation, which should be particularly useful for the design of new protein-protein and protein-nucleic acid complexes. The program POPS is available at http://mathbio.nimr.mrc.ac.uk/~ffranca/POPS and at the mirror site http://www.cs.vu.nl/~ibivu/programs/popswww.

Algorithms↗

PubMed2003

Thermal unfolding simulations of apo-calmodulin using leap-dynamics.

The simulation method leap-dynamics (LD) has been applied to protein thermal unfolding simulations to investigate domain-specific unfolding behavior. Thermal unfolding simulations of the 148-residue protein apo-calmodulin with implicit solvent were performed at temperatures 290 K, 325 K, and 360 K and compared with the corresponding molecular dynamics trajectories in terms of a number of calculated conformational parameters. The main experimental results of unfolding are reproduced in showing the lower stability of the C-domain: at 290 K, both the N- and C-domains are essentially stable; at 325 K, the C-domain unfolds, whereas the N-domain remains folded; and at 360 K, both domains unfold extensively. This behavior could not be reproduced by molecular dynamics simulations alone under the same conditions. These results show an encouraging degree of convergence between experiment and LD simulation. The simulations are able to describe the overall plasticity of the apo-calmodulin structure and to reveal details such as reversible folding/unfolding events within single helices. The results show that by using the combined application of a fast and efficient sampling routine with a detailed molecular dynamics force field, unfolding simulations of proteins at atomic resolution are within the scope of current computational power.

Apoproteins↗

PubMed2003

Testing homology with Contact Accepted mutatiOn (CAO): a contact-based Markov model of protein evolution.

Point Accepted Mutation (PAM) is the Markov model of amino acid replacements in proteins introduced by Dayhoff and her co-workers (Dayhoff et al., 1978). The PAM matrices and other matrices based on the PAM model have been widely accepted as the standard scoring system of protein sequence similarity in protein sequence alignment tools. Here, we present Contact Accepted mutatiOn (CAO), a Markov model of protein residue contact mutations. The CAO model simulates the interchanging of structurally defined side-chain contacts, and introduces additional structural information into protein sequence alignments. Therefore, similarities between structurally conserved sequences can be detected even without apparent sequence similarity. CAO has been benchmarked on the HOMSTRAD database and a subset of the CATH database, by comparing sequence alignments with reference alignments derived from structural superposition. CAO yields scores that reflect coherently the structural quality of sequence alignments, which has implications particularly for homology modelling and threading techniques.

Amino Acid Sequence↗

PubMed2002

Parallelized multiple alignment.

UNLABELLED: Multiple sequence alignment is a frequently used technique for analyzing sequence relationships. Compilation of large alignments is computationally expensive, but processing time can be considerably reduced when the computational load is distributed over many processors. Parallel processing functionality in the form of single-instruction multiple-data (SIMD) technology was implemented into the multiple alignment program Praline by using 'message passing interface' (MPI) routines. Over the alignments tested here, the parallelized program performed up to ten times faster on 25 processors compared to the single processor version. AVAILABILITY: Example program code for parallelizing pairwise alignment loops is available from http://mathbio.nimr.mrc.ac.uk/~jkleinj/tools/mpicode. The 'message passing interface' package (MPICH) is available from http:/www.unix.mcs.anl.gov/mpi/mpich. CONTACT: jhering@nimr.mrc.ac.uk SUPPLEMENTARY INFORMATION: Praline is accessible at http://mathbio.nimr.mrc.ac.uk/praline.

Algorithms↗