Biomedical subjects

Cornelius Frömmel

Publications and source records attributed to Cornelius Frömmel.

14 recordsLinked to original sources

PubMed2006

Molecular flexibility in protein-DNA interactions.

In living cells protein-DNA interactions are fundamental processes. Here, we compare the 3D structures of several DNA-binding proteins frequently determined with and without attached DNA. We studied the global structure (backbone-traces) as well as the local structure (binding sites) by comparing pair-wise the related atoms. The DNA-interaction sites of uncomplexed proteins show conspicuously high local structural flexibility. Binding to DNA results in specific local conformations, which are clearly distinct from the unbound states. The adaptation of the protein's binding site to DNA can never be described by the lock and key model but in all cases by the induced fit model. Conformational changes in the seven protein backbone traces take place in different ways. Two of them dock onto DNA without a significant change, while the other five proteins are characterized by a backbone conformation change caused by DNA docking. In the case of three proteins of the latter group the DNA-complexed conformation also occurs in a few uncomplexed structures. This behavior can be described by a conformational ensemble, which is narrowed down by DNA docking until only one single DNA-complexed conformation occurs. Different docking models are discussed and each of the seven proteins is assigned to one of them.

Binding Sites↗

PubMed2005

SPOT synthesis: reliability of array-based measurement of peptide binding affinity.

Peptide arrays prepared by the SPOT synthesis technology have emerged as a proteomic tool to study molecular recognition and identify biologically active peptides. However, it was previously not clear how accurately signal intensities obtained by probing peptide arrays for protein binding really reflect the dissociation constants of the protein-peptide complexes. Using the monoclonal antibody CB4-1 as a model system, we systematically compared dissociation constants of antibody-peptide complexes with signal intensities obtained using the SPOT technology. By analyzing a set of peptides possessing different affinities to the antibody, we determined the strengths of the SPOT screening method. The accuracy of the measured results was improved by taking regional trends in the membrane surface into account. A model based on the mass action law compares well with the experimental results. Interestingly, the applied concentrations of the binding partners do not directly correspond to the effective concentrations in the assay. We show that the SPOT technology is an accurate method for assigning the spots' measured signal intensities to three different binding affinity classes. The dissociation constants of the intermediate region were found to be between pK(dis)=5 and pK(dis)=7. Altering the experimental parameters causes a directed change of this region.

Antibodies, Monoclonal↗

PubMed2005

Columba: an integrated database of proteins, structures, and annotations.

BACKGROUND: Structural and functional research often requires the computation of sets of protein structures based on certain properties of the proteins, such as sequence features, fold classification, or functional annotation. Compiling such sets using current web resources is tedious because the necessary data are spread over many different databases. To facilitate this task, we have created COLUMBA, an integrated database of annotations of protein structures. DESCRIPTION: COLUMBA currently integrates twelve different databases, including PDB, KEGG, Swiss-Prot, CATH, SCOP, the Gene Ontology, and ENZYME. The database can be searched using either keyword search or data source-specific web forms. Users can thus quickly select and download PDB entries that, for instance, participate in a particular pathway, are classified as containing a certain CATH architecture, are annotated as having a certain molecular function in the Gene Ontology, and whose structures have a resolution under a defined threshold. The results of queries are provided in both machine-readable extensible markup language and human-readable format. The structures themselves can be viewed interactively on the web. CONCLUSION: The COLUMBA database facilitates the creation of protein structure data sets for many structure-based studies. It allows to combine queries on a number of structure-related databases not covered by other projects at present. Thus, information on both many and few protein structures can be used efficiently. The web interface for COLUMBA is available at http://www.columba-db.de.

Base Sequence↗

PubMed2005

Conservation of cis prolyl bonds in proteins during evolution.

In proteins and peptides, the vast majority of peptide bonds occurs in trans conformation, but a considerable fraction (about 5%) of X-Pro bonds adopts the cis conformation. Here we study the conservation of cis prolyl residues in evolutionary related proteins. We find that overall, in contrast to local, protein sequence similarity is a clear indicator for the conformation of prolyl residues. We observe that cis prolyl residues are more often conserved than trans prolyl residues, and both are more conserved than the surrounding amino acids, which show the same extent of conservation as the whole protein. The pattern of amino acid exchanges differs between cis and trans prolyl residues. Also, the cis prolyl bond is maintained in proteins with sequence identity as low as 20%. This finding emphasizes the importance of cis peptide bonds in protein structure and function.

Amino Acids↗

PubMed2005

[Extramural research granting: effects and side effects].

Extramural funding is an indispensable support of the dual financing system of research and innovative teaching, and its importance will certainly grow in the future. Although individually necessary, supported by the government, and legally regulated, extramural funding is associated to a number of possible conflicts that complicate its management. Well-defined rules in faculty administration (extramural grant ordinance) and unambiguous contracts are the best preposition for successful and undisturbed usage of extramural funding.

Economics, Medical↗

PubMed2004

Molecular packing and packing defects in helical membrane proteins.

The packing of helices spanning lipid bilayers is crucial for the stability and function of alpha-helical membrane proteins. Using a modified Voronoi procedure, we calculated packing densities for helix-helix contacts in membrane spanning domains. Our results show that the transmembrane helices of protein channels and transporters are significantly more loosely packed compared with helices in globular proteins. The observed packing deficiencies of these membrane proteins are also reflected by a higher amount of cavities at functionally important sites. The cavities positioned along the gated pores of membrane channels and transporters are noticeably lined by polar amino acids that should be exposed to the aqueous medium when the protein is in the open state. In contrast, nonpolar amino acids surround the cavities in those protein regions where large rearrangements are supposed to take place, as near the hinge regions of transporters or at restriction sites of protein channels. We presume that the observed deficiencies of helix-helix packing are essential for the helical mobility that sustains the function of many membrane protein channels and transporters.

Computer Simulation↗

PubMed2004

Structural features of transmembrane helices.

A total of 160 transmembrane helices of 15 non-homologous high-resolution X-ray protein structures have been analyzed in respect of their structural features. The dihedral angles and hydrogen bonds of the helical sections that span the hydrophobic interior of the lipid bilayer have been investigated. The Ramachandran plot of protein channels and solute transporters exhibit a significant shift Delta (phi- and psi-angles) of Delta mean (+4.5 degrees and -5.4 degrees ), compared to a reference group of 151 alpha-helices of the same average length derived from water-soluble globular proteins. At the C-termini of transmembrane helices structural motifs equivalent to the Gly-caps of helices in globular proteins have been found, with two third of the transmembrane Gly-caps taking up a primary structure that is typically not found at helix termini exposed to a polar solvent. The structural particularities reported here are relevant for the three-dimensional modelling of membrane protein structures.

Amino Acid Sequence↗

PubMed2003

Accelerating screening of 3D protein data with a graph theoretical approach.

MOTIVATION: The Dictionary of Interfaces in Proteins (DIP) is a database collecting the 3D structure of interacting parts of proteins that are called patches. It serves as a repository, in which patches similar to given query patches can be found. The computation of the similarity of two patches is time consuming and traversing the entire DIP requires some hours. In this work we address the question of how the patches similar to a given query can be identified by scanning only a small part of DIP. The answer to this question requires the investigation of the distribution of the similarity of patches. RESULTS: The score values describing the similarity of two patches can roughly be divided into three ranges that correspond to different levels of spatial similarity. Interestingly, the two iso-score lines separating the three classes can be determined by two different approaches. Applying a concept of the theory of random graphs reveals significant structural properties of the data in DIP. These can be used to accelerate scanning the DIP for patches similar to a given query. Searches for very similar patches could be accelerated by a factor of more than 25. Patches with a medium similarity could be found 10 times faster than by brute-force search.

Algorithms↗

PubMed2003

KISS for STRAP: user extensions for a protein alignment editor.

SUMMARY: The Structural Alignment Program STRAP is a comfortable comprehensive editor and analyzing tool for protein alignments. A wide range of functions related to protein sequences and protein structures are accessible with an intuitive graphical interface. Recent features include mapping of mutations and polymorphisms onto structures and production of high quality figures for publication. Here we address the general problem of multi-purpose program packages to keep up with the rapid development of bioinformatical methods and the demand for specific program functions. STRAP was remade implementing a novel design which aims at Keeping Interfaces in STRAP Simple (KISS). KISS renders STRAP extendable to bio-scientists as well as to bio-informaticians. Scientists with basic computer skills are capable of implementing statistical methods or embedding existing bioinformatical tools in STRAP themselves. For bio-informaticians STRAP may serve as an environment for rapid prototyping and testing of complex algorithms such as automatic alignment algorithms or phylogenetic methods. Further, STRAP can be applied as an interactive web applet to present data related to a particular protein family and as a teaching tool. REQUIREMENTS: JAVA-1.4 or higher. AVAILABILITY: http://www.charite.de/bioinf/strap/

Computer Graphics↗

PubMed2003

Online tool for the discrimination of equi-distributions.

BACKGROUND: For many applications one wishes to decide whether a certain set of numbers originates from an equiprobability distribution or whether they are unequally distributed. Distributions of relative frequencies may deviate significantly from the corresponding probability distributions due to finite sample effects. Hence, it is not trivial to discriminate between an equiprobability distribution and non-equally distributed probabilities when knowing only frequencies. RESULTS: Based on analytical results we provide a software tool which allows to decide whether data correspond to an equiprobability distribution. The tool is available at http://bioinf.charite.de/equifreq/. CONCLUSIONS: Its application is demonstrated for the distribution of point mutations in coding genes.

Amino Acid Sequence↗

PubMed2003

Inhomogeneous molecular density: reference packing densities and distribution of cavities within proteins.

MOTIVATION: There is no consensus in the literature about how the deepest portions of protein structures are packed. Using an improved Voronoi procedure, we calculate reference packing densities for different regions in the protein interior. Furthermore, we want to clarify where cavities are located. RESULTS: Sets of reference packing densities are provided for regions in proteins that differ in their distance to the surface and to internal cavities, supplementing previous data. Packing in the protein interior is tight but generally inhomogeneous. There are about 4.4 cavities per 100 amino acids in protein structures, they occur in all regions, most frequently in a depth of 2.5-3.6 A underneath the Connolly surface. However, the deepest protein regions have a lower mean packing density than circumjacent regions, because more contacts to cavities occur in the core. AVAILABILITY/SUPPLEMENTARY INFORMATION: Calculation software and detailed packing data are available on request.

Amino Acid Sequence↗

PubMed2003

Inverse sequence similarity of proteins does not imply structural similarity.

There is a debate on the folding of proteins with inverted sequences. Theoretical approaches and experiments give contradictory results. Many proteins in the Protein Data Bank (PDB) show conspicuous inverse sequence similarity (ISS) to each other. Here we analyze whether this ISS is related to structural similarity. For the first time, we performed a large scale three-dimensional (3-D) superposition of corresponding Calpha atoms of forwardly and inversely aligned proteins and tested the degree of secondary structure identity between them. Comparing proteins of less than 50% pairwise sequence identity, only 0.5% of the inversely aligned pairs had similar folds (99 out of 19073), whereas about 9% of forwardly aligned proteins in the same score and length range show similar 3-D structures (1731 out of 19248). This observation strongly supports the view that the inversion of sequences in almost all cases leads to a different folding property of the protein. Inverted sequences are thus suitable as protein-like sequences for control purposes without relations to existing proteins.

Algorithms↗

PubMed2003

A comprehensive view on proteasomal sequences: implications for the evolution of the proteasome.

Proteasomes are large multimeric self-compartmentizing proteases, which play a crucial role in the clearance of misfolded proteins, breakdown of regulatory proteins, processing of proteins by specific partial proteolysis, cell cycle control as well as preparation of peptides for immune presentation. Two main types can be distinguished by their different tertiary structure: the 20S proteasome and the proteasome-like heat shock protein encoded by heat shock locus V, hslV. Usually, each biological kingdom is characterized by its specific type of proteasome. The 20S proteasomes occur in eukarya and archaea whereas hslV protease is prevalent in bacteria. To verify this rule we applied a genome-wide sequence search to identify proteasomal sequences in data of finished and yet unfinished genome projects. We found several exceptions to this paradigm: (1) Protista: in addition to the 20S proteasome, Leishmania, Trypanosoma and Plasmodium contained hslV, which may have been acquired from an alpha-proteobacterial progenitor of mitochondria. (2) Bacteria: for Magnetospirillum magnetotacticum and Enterococcus faecium we found that each contained two distinct hslVs due to gene duplication or horizontal transfer. Including unassembled data into the analyses we confirmed that a number of bacterial genomes do not contain any proteasomal sequence due to gene loss. (3) High G+C Gram-positives: we confirmed that high G+C Gram-positives possess 20S proteasomes rather than hslV proteases. The core of the 20S proteasome consists of two distinct main types of homologous monomers, alpha and beta, which differentiated into seven subtypes by further gene duplications. By looking at the genome of the intracellular pathogen Encephalitozoon cuniculi we were able to show that differentiation of beta-type subunits into different subtypes occurred earlier than that of alpha-subunits. Additionally, our search strategy had an important methodological consequence: a comprehensive sequence search for a particular protein should also include the raw sequence data when possible because proteins might be missed in the completed assembled genome. The structure-based multiple proteasomal alignment of 433 sequences from 143 organisms can be downloaded from the URL dagger and will be updated regularly.

Amino Acid Sequence↗

PubMed2003

Kinetics of prion growth.

We study the kinetics of prion fibril growth, described by the nucleated polymerization model analytically and by means of numerical experiments. The elementary processes of prion fibril formation lead us to a set of differential equations for the number of fibrils, their total mass, and the number of prion monomers. In difference to previous studies we analyze this set by explicitly taking into account the time-dependence of the prion monomer concentration. The theoretical results agree with experimental data, whereas the generally accepted hypothesis of constant monomer concentration leads to a fibril growth behavior which is not in agreement with experiments. The obtained size distribution of the prion fibril aggregates is shifted significantly toward shorter lengths as compared to earlier results, which leads to a enhanced infectivity of the prion material. Finally, we study the effect of filtering of the inoculated material on the incubation time of the disease.

Algorithms↗