Ralf Bundschuh
Adjunct ProfessorThe biological sciences are undergoing a revolutionary change characterized by the emergence of experimental techniques that massively produce quantitative biological data waiting for interpretation. The broad goal of my research is to develop new methods to extract biological knowledge from such data. These methods will be derived using statistical physics tools since statistical physics provides a natural framework for the interpretation of high volume data. I am focusing on problems involving sequence data and RNA molecules. All the problems I study can be described in terms of physical systems with a complex energy landscape. Thus, beyond providing solutions of practical biological problems, the study of these systems leads to new insights into the statistical physics of disordered systems.
One particular area of my interest is sequence alignment. Sequence alignment is a computational technique which tries to identify similarities between two sequences which can be for example DNA or protein sequences. Sequence alignment is the most widely used computational tool in molecular biology and the identification of any newly sequenced gene depends on the accuracy with which the alignment can be performed. The crucial problem which sequence alignment shares with many of the common computational tools of molecular biology is that it will produce a result for any pair of sequences compared. Thus, the quality of a result has to be assessed in order to make a decision about its biological relevance. This is usually done by quoting the probability of getting the alignment just by chance. Being able to do this thus amounts to characterizing the background, i.e., the alignments of random sequences. Characterizing the behavior of a random system is clearly the domain of statistical physics and several of its tools can be used to tackle this problem. For sequence alignment many universal features can be studied by using a mapping between sequence alignment and surface growth as described by the Kardar-Parisi-Zhang equation. Additionally a newly established link between the Asymmetric Exclusion Process - one of the best studied exactly solvable systems of non equilibrium statistical physics - and sequence alignment can be exploited. In this context many explicit results addressing the problem of assessment of the statistical significance can be obtained while on the other hand calculating new interesting quantities for the corresponding physical systems.
The other system of my current interest is RNA secondary structure formation. RNA is a single-stranded heteropolymer which can gain energy by folding onto itself and forming "base pairs" between its monomers. Since only certain pairs of monomers are allowed, it is a non trivial problem to find the optimal fold for a given sequence of monomers. Thus, RNA secondary structure formation is a problem which shows many parallels to the popular protein folding problem - it can indeed be understood as the Hartree approximation of the protein folding problem. While the phenomenology of RNA secondary structure formation is very similar to protein folding, it has the enormous advantage that the bioinformatics community has worked out an algorithm to fold RNA in polynomial time. This makes it much more readily available to numerical studies. Interpreting the folding algorithm as diagrammatic equations also enables analytical approaches to the structure formation problem. Thus, RNA secondary structures are an ideal model system for studying concepts of heteropolymer structure formation. Characterizing the different phases and phase transitions involved numerically and analytically is an ongoing project. On the other hand, quantitative modeling of recent force-extension experiments on RNA molecules provides a foundation on which these experiments can be interpreted and new experimental ideas be explored.
R.A. Forties and R. Bundschuh, "Modeling the interplay of single-stranded binding proteins and nucleic acid secondary structure", Bioinformatics [free journal link]
R.A. Forties, R. Bundschuh, and M. Poirier, "The flexibility of locally melted DNA", Nucleic Acids Res. (2009) accepted.
M.M. Lee, M.K. Chan, and R. Bundschuh, "SIB-BLAST: a web server for improved delineation of true and false positives in PSI-BLAST searches", Nucleic Acids Res. (2009)accepted.
S. Shinichiro, N.M. Abdi, R. Bundschuh, and K. Fredrick, "Contribution of ribosomal residues to P-site tRNA binding", Nucleic Acids Res. (2009) accepted.
M. McCauley, R. Forties, U. Gerland, and R. Bundschuh, "Anomalous scaling in nanopore translocation of structured heteropolymers", Phys. Biol. 6 (2009) 036006.
C. Beargie, T. Liu, M. Corriveau, H.Y. Lee, J. Gott, and R. Bundschuh, "Genome annotation in the presence of insertional RNA editing", Bioinformatics.
M.M. Lee, M. Chan, and R. Bundschuh, "Simple is beautiful: a straightforward approach to improve the delineation of true and false positives in PSI-BLAST searches",Bioinformatics 24 (2008) 1339-1343.
M.M. Lee, R. Bundschuh, and M. Chan, "Distant homology detection using a LEngth and STructure-based sequence Alignment Tool (LESTAT)", Proteins (2008) Early view.
A. Itaya, R. Bundschuh, A.J. Archual, J.-G. Joung, Z. Fei, X. Dai, P.X. Zhao, Y. Tang, R.S. Nelson, and B. Ding, "Small RNAs in tomato fruit and leaf development", Biochim. Biophy. Act. - Gene Reg. Mech. 1779 (2008) 99-107.
M. Djordjevich and R. Bundschuh, "Formation of the Open Complex by Bacterial RNA Polymerase - a Quantitative Model", accepted for publication in Biophys. J.
R. Bundschuh and R. Bruinsma, "Melting of Branched RNA Molecules", accepted for publication in Phys. Rev. Lett.
A. Itaya, X. Zhong, R. Bundschuh, Y. Qi, Y. Wang, R. Takeda, A.R. Harris, C. Molina, R.S. Nelson, and B. Ding, "A Structured Viroid RNA Serves as a Substrate for Dicer-Like Cleavage To Produce Biologically Active Small RNAs but Is Resistant to RNA-Induced Silencing Complex-Mediated Degradation", Journal of Virology 91 (2007) 2980-2994.
F. Habib, A.D. Johnson, R. Bundschuh, and D. Janies, "Large scale genotype-phenotype correlation analysis based on phylogenetic trees", Bioinformatics 23 (2007) 785-788
P. Messer, R. Bundschuh, M. Vingron, and P. Arndt, "Alignment Statistics for Long-Range Correlated Genomic Sequences", Lecture Notes in Computer Science 3909 (2006) 426-440.
R. Bundschuh and U. Gerland, "Coupled dynamics of RNA folding and nanopore translocation", Phys. Rev. Lett. 95 (2005) 208104/1-208104/4.
N. Chia and R. Bundschuh, "Numerical Method for Accessing the universal scaling function for a multiparticle discrete rime asymmetric exclusion process", Phys. Rev. E 72 (2005)051102/1-051102/7.
T. Liu and R. Bundschuh, "Quantification of the differences between quenched and annealed averaging for RNA secondary structures", Phys. Rev. E 72 (2005) 061905/1--061905/9.
V. Guttal and R. Bundschuh, "A Model for Folding and Aggregation in RNA Secondary Structures" Phys. Rev. Lett. 96 (2005) 018105/1--018105/4.
Y. Li, M. Lauria, and R. Bundschuh, "Suboptimal Alignments Improve the Detection of Weak Homologs in Sequence Database Searches", Proceedings of BIBE05, 153-160.
J.M. Gott, N. Parimi, and R. Bundschuh, "Discovery of new genes and deletion editing in Physarum mitochondria enabled by a novel algorithm for finding edited mRNAs", Nucleic Acids Research 33 (2005) 5063-5072.
F. Habib and R. Bundschuh, "Modeling DNA unzipping in the presence of bound proteins", Phys. Rev. E 72 (2005) 031906/1-031906/6.
T. Liu and R. Bundschuh, "A model for codon position bias in RNA editing", Phys. Rev. Lett. 95 (2005) 088101.
N. Chia and R. Bundschuh, "A Practical Approach to Significance Assessment in Alignment with Gaps", Proceedings of the ninth annual international conference on computational molecular biology (RECOMB2005), S. Miyano et al., eds., Springer, (Berlin, Germany, 2005), 474-488 and J. Comp. Biol 13 (2006) 429-441.
D. Layton and R. Bundschuh, "A Statistical Analysis of RNA Folding Algorithms Through Thermodynamic Parameter Perturbation", Nucleic Acids Research 33 (2005), 519-524.
R. Bundschuh, "Computational prediction of RNA editing sites", Bioinformatics 20 (2004), 3214-3220.
N. Chia and R. Bundschuh, "Finite Width Model Sequence Comparison", Phys. Rev. E 70 (2004), 021906.
T. Liu and R. Bundschuh, "Analytical description of finite size effects for RNA secondary structures", Phys. Rev. E 69 (2004), 061912.
U. Gerland, R. Bundschuh, and T. Hwa, "Translocation of structured polynucleotides through nanopores", Phys. Biol. 1 (2004), 19-26.
Y. Li, M. Lauria, and R. Bundschuh, "Using Hybrid Alignment for Iterative Sequence Database Searches", Proceedings of HICOMB 2003 (IEEE CS press, Los Alamitos, CA) andConcurr. Comp. Pract. Exp. 16 (2004), 841-853.
U. Gerland, R. Bundschuh, and T. Hwa, "Mechanically probing the folding pathway of single RNA molecules", Biophys. J. 84 (2003), 2831-2840
R. Bundschuh, F. Hayot, and C. Jayaprakash, "Fluctuations and slow variables in genetic networks", Biophys. J. 84 (2003), 1606-1615
R. Bundschuh, F. Hayot, and C. Jayaprakash, "The role of dimerization in noise reduction of simple genetic networks", J. Theor. Biol. 220 (2003), 261-269.
R. Bundschuh and T. Hwa, "Phases of the secondary structures of RNA sequences", Europhys. Lett. 59 (2002), 903-909.
R. Bundschuh and M. Lässig, "Delocalization transitions of semi-flexible manifolds", Phys. Rev. E 65 (2002), 061502.
Y.-K. Yu, R. Bundschuh, and T. Hwa, "Statistical Significance and Extreme Ensemble of Gapped Local Hybrid Alignment", Biological Evolution and Statistical Physics, M. Lässig and A. Valeriani, eds., (2002), 3-22.
R. Bundschuh and T. Hwa, "Statistical mechanics of secondary structures formed by random RNA sequences", Phys. Rev. E 65 (2002), 031903.
R. Bundschuh, "Asymmetric exclusion process and extremal statistics of random sequences", Phys. Rev. E 65 (2002), 031911.
Y.-K. Yu, R. Bundschuh, and T. Hwa, "Hybrid Alignment: High Performance with Universal Statistics", Bioinformatics 18 (2002), 864-872.
R. Bundschuh, "High precision simulations of the longest common subsequence problem", Europ. Phys. J. B 22 (2001), 533-541.
R. Bundschuh, "Rapid Significance Estimation in Local Sequence Alignment with Gaps", Proceedings of the fifth annual international conference on computational molecular biology (RECOMB2001), S. Istrail et al., eds., ACM press, (New York, NY, 2001), 77-85 and J. Comp. Biol. 9 (2002), 243-260.
U. Gerland, R. Bundschuh, and T. Hwa, "Force-induced denaturation of RNA", Biophys. J. 81 (2001), 1324-1332.
S. Altschul, R. Bundschuh, R. Olsen, and T. Hwa, "The estimation of statistical parameters for local alignment score distributions", Nucl. Acids Res. 29 (2001), 351-361.
R. Bundschuh, M. Lässig, and R. Lipowsky, "Semi-flexible polymers with attractive interactions", Europ. Phys. J. E 3 (2000), 295--306.
R. Bundschuh, "An analytic approach to significance assessment in local sequence alignment with gaps", Proceedings of the fourth annual international conference on computational molecular biology (RECOMB2000), S. Istrail et al., eds., ACM press, (New York, NY, 2000), 86-95.
R. Bundschuh and T. Hwa, "RNA secondary structure formation: a solvable model of heteropolymer folding", Phys. Rev. Lett. 83 (1999), 1479-1482.
R. Olsen, R. Bundschuh, and T. Hwa, "Rapid Assessment of Extremal Statistics for Local Alignment with Gaps", Proceedings of the Seventh International Conference on Intelligent Systems for Molecular Biology, T. Lengauer et al., eds., AAAI Press, (Menlo Park, CA, 1999), 211-222.
R. Bundschuh, C. Cassanello, D. Serban, and M.R. Zirnbauer, "Weak localization of disordered quasiparticles in the mixed superconducting state", Phys. Rev. B 59 (1999), 4382-4389.
R. Bundschuh and T. Hwa, "An analytic study of the phase transition line in local sequence alignment with gaps", Discrete Applied Mathematics 104 (2000), 113-142.
R. Bundschuh, C. Cassanello, D. Serban, and M.R. Zirnbauer, "Localization of quasiparticles in a disordered vortex", Nucl. Phys. B 532 (1998), 689-732.
R. Bundschuh and M. Lässig, "Comment on 'Simplest possible self-organized critical system'", Phys. Rev. Lett. 77 (1996), 4273.
R. Bundschuh and M. Lässig, "Directed polymers in high dimensions", Phys. Rev. E 54 (1996), 304-320.
R. Everaers, R. Bundschuh, and K. Kremer, "Fluctuations and stiffness of double-stranded polymers: railway-track model", Europhys. Lett. 29 (1995), 263-268.
U. Fastenrath, G. Adams, R. Bundschuh, T. Hermes, B. Raab, I. Schlosser, T. Wehner, and T. Wichmann, "Universality in the 2D localization problem", Physica A 172 (1991), 302-308.
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