Abstracts

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This aritcle contains the abstracts of the various papers I have published or from presentations I have given.

Papers published

  • Journal: Nucleic Acids Research (Web Issue) (2007; in press) [NAR-00339-Web-B-2007.R1]
  • Title: "FastContact: a free energy scoring tool for protein-protein complex structures"
  • Authors: P. Christoph Champ and Carlos J. Camacho

ABSTRACT: 'FastContact' is a server that estimates the direct electrostatic and desolvation interaction free energy between two proteins in units of kcal/mol. Users submit two proteins in PDB format, and the output is emailed back to the user in three files: one output file, and the two processed proteins. Besides the electrostatic and desolvation free energy, the server reports residue contact free energies that rapidly highlight the hotspots of the interaction and evaluates the van der Waals interaction using CHARMm. Response time is ~1 min. The server has been successfully tested and validated, scoring refined complex structures and blind sets of docking decoys, as well as proven useful predicting protein interactions. 'FastContact' offers unique capabilities from biophysical insights to scoring and identifying important contacts.

ABSTRACT: Predicting protein-protein interactions involves sampling and scoring docked conformations. Barring some large structural rearrangement, rapidly sampling the space of docked conformations is now a real possibility, and the limiting step for the successful prediction of protein interactions is the scoring function used to reduce the space of conformations from billions to a few, and eventually one high affinity complex. An atomic level free-energy scoring function that estimates in units of kcal/mol both electrostatic and desolvation interactions (plus van der Waals if appropriate) of protein-protein docked conformations is used to rerank the blind predictions (860 in total) submitted for six targets to the community-wide Critical Assessment of PRotein Interactions (CAPRI; http://capri.ebi.ac.uk). We found that native-like models often have varying intermolecular contacts and atom clashes, making unlikely that one can construct a universal function that would rank all these models as native-like. Nevertheless, our scoring function is able to consistently identify the native-like complexes as those with the lowest free energy for the individual models of 16 (out of 17) human predictors for five of the targets, while at the same time the modelers failed to do so in more than half of the cases. The scoring of high-quality models developed by a wide variety of methods and force fields confirms that electrostatic and desolvation forces are the dominant interactions determining the bound structure. The CAPRI experiment has shown that modelers can predict valuable models of protein-protein complexes, and improvements in scoring functions should soon solve the docking problem for complexes whose backbones do not change much upon binding. A scoring server and programs are available at http://structure.pitt.edu.

ABSTRACT: An analysis of the human chromosome 22 genomic sequence shows that both Z-DNA forming regions (ZDRs) and promoter sites for nuclear factor-I (NFI) are correlated with the locations of known and predicted genes across the chromosome and accumulate around the transcriptional start sites of the known genes. Thus, the occurrence of Z-DNA across human genomic sequences mirrors that of a known eukaryotic transcription factor. In addition, 43 of the 383 fully annotated chromosomal genes have ZDRs within 2 nucleosomes upstream of strong NFIs. This suggests a distinct class of human genes that may potentially be transcriptionally regulated by a mechanism that couples Z-DNA with NFI activation, similar to the mechanism previously elucidated for the human colony stimulation factor-I promoter [Liu et al. (2001) Cell, 106, 309–318]. The results from this study will facilitate the design of experimental studies to test the generality of this mechanism for other genes in the cell.

Howard Hughes Medical Institute (HHMI)

  • Session: 2001 HHMI Summer Undergraduate Research Program at OSU
  • Title: "ZHuntIII: A Computer Approach To Mapping Z-DNA Within Human Chromosomes 21 and 22"
  • Speaker: Christoph Champ

ABSTRACT: In this project (ZHuntIII), we have developed several processes and programs in order to map the potential Z-DNA-forming sequences within the recently sequenced human chromosomes 21 and 22. The seven programs developed (collectively called ZHuntIII) employ rigorous thermodynamic search strategies, statistical mechanics, and pattern matching and comparison. ZHuntIII has been built upon past research, biochemical and biophysical principles, and computational techniques. The ZHuntIII search algorithm considers sequence type, length, and cooperativity to determine a "Z-Score" for a specified stretch of potential Z-DNA-forming nucleotides. The higher a Z-Score, the more likely that sequence is to adopt the Z conformation. Since every base pair within the chromosomes is assigned a Z-Score, we must choose only those Z-Scores that represent the highest likelihood in forming potential Z-DNA-forming sequences. In genomic sequences, these Z-Scores have been found to have values covering seven orders of magnitude. When plotting these values on a graph, the highest Z-Scores are easily visible as relatively few peaks raising several orders of magnitude among the majority of lower Z-Scores. We have chosen a threshold that is in the same order of magnitude as there are genes within human chromosomes 21 and 22. We expect this determination to compliment past research which has shown potential Z-DNA-forming sequences to occur upstream of the first expressed exon in a gene. That is, they are most commonly found near the 5' end of genes. We hope to show that this is also the case with most genes in much larger sequences, as those of human chromosomes 21 and 22.

  • Session: 2001 HHMI Summer Undergraduate Research Program at OSU
  • Title: "Mapping Z-DNA in Human Chromosome 22"
  • Speaker: Christoph Champ

ABSTRACT: missing

Conferences

  • Session: Albany, New York
  • Title: "Map of Z-DNA in Human Chromosome 22" (poster #216)
  • Presenter: P. Christoph Champ

ABSTRACT: Although Z-DNA was discovered over 20 years ago, its function in a broad biological context remains largely undefined. We have subjected the sequence of human chromosome 22 to a rigorous thermodynamic search for this left-handed conformation using an extended version of the program Z-Hunt. The location of each potential Z-DNA forming region are compared relative to all the relevant markers for gene function, including known genes, pseudogenes, and open reading frames, and the relative positions within the genes and their exons and introns. The resulting map allows us to correlate this unusual structure with the functional elements of the human genome.

  • Session: Sweden
  • Title: "FastContact: a free energy scoring tool for protein-protein complex structures"
  • Presenter: P. Christoph Champ

ABSTRACT: Predicting protein-protein interactions involves sampling and scoring docked conformations. Barring some large structural rearrangement, rapidly sampling the space of docked conformations is now a real possibility, and the limiting step for the successful prediction of protein interactions is the scoring function used to reduce the space of conformations from billions to a few, and eventually one high affinity complex. An atomic level free energy scoring function that estimates both electrostatic and desolvation interactions in units of kcal/mol (plus van der Waals if appropriate) of protein-protein docked conformations is used to re-rank the blind predictions (860 in total) submitted for six targets to the community-wide Critical Assessment of PRediction of Interactions (CAPRI; http://capri.ebi.ac.uk). The score identifies native-like complexes as those with the lowest free energy for the models of 16 (out of 17) human predictors for five of the targets, while at the same time the modelers failed to do so in more than 50% of the cases. The correct scoring of high quality models developed by a wide variety of methods and force fields confirms that electrostatic and (de)solvation forces are the dominant protein interactions. Although for a given receptor/ligand either of these interactions might play a dominant role, only their complement offers a robust relative measure of the binding affinity for most systems. The CAPRI experiment has shown that modelers can predict excellent models of the co-crystals, and improvements on scoring functions should soon solve the docking problem for protein structures that do not change much upon binding. A scoring server and programs are available at http://structure.pitt.edu.

  • Session: ACA, Buffalo, New York
  • Title: "Identification of Functional Motifs and Binding Site Properties in Potential Drug Targets from Tropical Parasites" (W0211)
  • Presenters: Arakaki TL, Le Trong I, Larson ET, Champ PC, Neely H, Boni E, Mueller N, Napuli A, Kelley A, Krumm1 BE, Xiao1 L, Shibata S, Zhang Z, Deng W, Zucker F, Fan E, Buckner FS, van Voorhis WCE, Verlinde CLMJ, Hol WGJ, Merritt1 EA. Medical Structural Genomics of Pathogenic Protozoa Consortium.

ABSTRACT: The assignment of accurate functional annotations to proteins is one of many interesting challenges facing structural genomics. An intriguing example from the eukaryotic parasite Plasmodium vivax is the Raf kinase inhibitor protein (PvRKIP). PvRKIP is a member of the phosphatidylethanolamine-binding protein (PEBP) sequence family consisting of more than 500 sequences with diverse functions. While a handful of these sequences have been functionally characterized and are involved in membrane biogenesis or cell proliferation and differentiation, other PEBP family members have distinctly different functions. Some mammalian PEBPs bind to Raf-1 and inhibit Raf-1's ability to phosphorylate MEK1. Recent studies of the homologous P. falciparum RKIP suggest an analogous regulatory role involving P. falciparum Ca-dependent protein kinase (PfCDPK1). To learn more about PvRKIP's function, its structure was determined to 1.3 Å resolution. Structural analysis reveals a distinctive left-handed helix located at one edge of the putative phospholipid-binding region. Since left-handed helices are rare and often appear on the protein surface at ligand-binding sites, protein-protein interfaces or other functional sites, the left-handed helix may be important for PvRKIP's function. This unusual structural motif may be characteristic of a subfamily of the PEBP sequence family.

BibTeX

@article{P.Christoph Champ12142004,
  author =   {Champ, P. Christoph and Maurice, Sandor and Vargason, Jeffrey M. and 
              Camp, Tracy and Ho, P. Shing},
  title =    {{Distributions of Z-DNA and nuclear factor I in human chromosome 22: 
              a model for coupled transcriptional regulation}},
  journal =  {Nucl. Acids Res.},
  volume =   {32},
  number =   {22},
  pages =    {6501-6510},
  doi =      {10.1093/nar/gkh988},
  year =     {2004},
  abstract = {An analysis of the human chromosome 22 genomic sequence shows that both 
              Z-DNA forming regions (ZDRs) and promoter sites for nuclear factor-I (NFI) 
              are correlated with the locations of known and predicted genes across the 
              chromosome and accumulate around the transcriptional start sites of the 
              known genes. Thus, the occurrence of Z-DNA across human genomic sequences 
              mirrors that of a known eukaryotic transcription factor. In addition, 43 
              of the 383 fully annotated chromosomal genes have ZDRs within 2 nucleosomes 
              upstream of strong NFIs. This suggests a distinct class of human genes that 
              may potentially be transcriptionally regulated by a mechanism that couples 
              Z-DNA with NFI activation, similar to the mechanism previously elucidated 
              for the human colony stimulation factor-I promoter [Liu et al. (2001) Cell, 
              106, 309-318]. The results from this study will facilitate the design of 
              experimental studies to test the generality of this mechanism for other 
              genes in the cell.},
  URL =      {http://nar.oxfordjournals.org/cgi/content/abstract/32/22/6501},
  eprint =   {http://nar.oxfordjournals.org/cgi/reprint/32/22/6501.pdf}
}

@article{P.Christoph Champ03012006,
  author =   {Champ, P. Christoph and Binnewies, Tim T. and Nielsen, Natasja and Zinman, 
              Guy and Kiil, Kristoffer and Wu, Heng and Bohlin, Jon and Ussery, David W.},
  title =    {{Genome update: purine strand bias in 280 bacterial genomes}},
  journal =  {Microbiology},
  volume =   {152},
  number =   {3},
  pages =    {579-583},
  doi =      {10.1099/mic.0.28637-0},
  year =     {2006},
  URL =      {http://mic.sgmjournals.org},
  eprint =   {http://mic.sgmjournals.org/cgi/reprint/152/3/579.pdf}
}

Endnote

%0 Journal Article
%A Carlos J. Camacho, Hui Ma, P. Christoph Champ,
%T Scoring a diverse set of high-quality docked conformations: A metascore based on 
   electrostatic and desolvation interactions
%J Proteins: Structure, Function, and Bioinformatics
%V 63
%N 4
%P 868-877
%D 2006
%@ 1097-0134
%+ Department of Computational Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; 
   Molecular Biophysics Program, University of Pittsburgh, Pittsburgh, Pennsylvania
%1 10.1002/prot.20932
%U http://dx.doi.org/10.1002/prot.20932

See also

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