Research Focus

Research in the Tidor Group is focused on the analysis of complex biological systems at the molecular and network levels. Projects at the molecular level study the structure and properties of proteins, nucleic acids, and their complexes. Investigations probe the sources of stability and specificity that drive macromolecular folding, binding, and catalysis. Studies are aimed at dissecting the interactions responsible for the specific structure of folded proteins and the binding geometry of molecular complexes. The roles played by salt bridges, hydrogen bonds, side-chain packing, rotameric states, solvation, and the hydrophobic effect in native biomolecules are being explored, and strategies for re-casting these roles through structure-based molecular design are being developed. Work at the network level involves the study of biochemical regulatory networks and signal transduction pathways in cells. The development of approaches to relate network topology to functional characteristics is fundamental to this research. Significant effort is being applied to extracting the design principles for biological networks and to understanding the control functions implemented. The insights resulting from this work will provide a strong foundation for understanding biological systems; moreover, they will be useful for the development of therapies that ameliorate disease states, as well as for the construction of new synthetic systems from biological components. The methods of theoretical and computational biophysics and approaches from computer science, artificial intelligence, applied mathematics, and chemical and electrical engineering play fundamental roles in this work.

Selected Publications

J.P. Bardhan, M.D. Altman, D.J. Willis, S.M. Lippow, B. Tidor, and J.K. White. Numerical integration techniques for curved-element discretizations of molecule-solvent interfaces. J. Chem. Phys., in press.

M.D. Altman, E.A. Nalivaika, M. Prabu-Jeyabalan, C.A. Schiffer, and B. Tidor. Computational design and experimental study of tighter binding peptides to an inactivated mutant of HIV-1 protease. Proteins, in press.

S.M. Lippow and B. Tidor. Progress in computational protein design. Curr. Opin. Biotechnol., in press.

M.D. Altman, J.P. Bardhan, B. Tidor, and J.K. White. FFTSVD: A fast, multiscale boundary-element method solver suitable for Bio-MEMS and biomolecule simulation.  IEEE Transactions on Computer-Aided Design of Integrated Circuits and Systems 25: 274–284 (2006).

K.A. Armstrong, B. Tidor, and A.C. Cheng.  Optimal charges in lead progression: A structure-based neuraminidase case study.  J Med. Chem. 49: 2470–2477 (2006).

D.F. Green, A.T. Dennis, P.S. Fam, B. Tidor, and A. Jasanoff. Rational design of a new binding specificity by simultaneous mutagenesis of calmodulin and a target peptide.  Biochemistry 45:12547–12559 (2006).

B.S. Adiwijaya, P.I. Barton, and B. Tidor.  Biological network design strategies: Discovery through dynamic optimization. Mol. BioSyst. 2: 650–659 (2006).

B. Tadmor and B. Tidor. Interdisciplinary research and education at the biology–engineering–computer science interface: A persepective. Drug Discov. Today 10: 1183–1189 (2005).

M.D. Altman, J.P. Bardhan, J.K. White, and B. Tidor. An accurate surface formulation for biomolecule electrostatics in non-ionic solutions. IEEE Conference on Engineering in Medicine and Biology (2005).

B.A. Joughin, D.F. Green, and B. Tidor. Action-at-a-distance interactions enhance protein binding affinity. Protein Sci.14: 1363–1369 (2005).

B.A. Joughin, B. Tidor, and M.B. Yaffe. A computational method for the analysis and prediction of protein:phosphopeptide-binding sites. Protein Sci.14: 131­–139 (2005).

M. Bathe, G.C. Rutledge, A.J. Grodzinsky, and B. Tidor.  A coarse-grained molecular model for glycosaminoglycans: Application to chondroitin, condroitin sulfate, and hyaluronic acid.  Biophys. J. 88: 3870–3887 (2005).

M. Bathe, G.C. Rutledge, A.J. Grodzinsky, and B. Tidor. Osmotic pressure of aqueous chondroitin sulfate solution: A molecular modeling investigation. Biophys J. (2005).

D.F. Green and B. Tidor. Design of improved protein inhibitors of HIV-1 cell entry: Optimization of electrostatic interactions at the binding interface.  Proteins: Struct., Funct., Bioinf.60: 644-657 (2005).

J.P. Bardhan, J.H. Lee, M.D. Altman, S. Leyffer, S. Benson, B. Tidor and J.K. White. Biomolecule electrostatic optimization with an implicit Hessian. International Conference on Modeling and Simulation of Microsystems (2004).

D.F. Green and B. Tidor. Escherichia coli glutaminyl-tRNA synthetase is electrostatically optimized for binding of its cognate substrates. J. Mol. Biol.342: 435–452 (2004).

P.M. Kim and B. Tidor. Subsystem identification through dimensionality reduction of large-scale gene expression data. Genome Res. 13: 1706–1718 (2003).

J.P. Bardhan, J.H. Lee, S.S. Kuo, M.D. Altman, B. Tidor, and J.K. White. Fast methods for biomolecule charge optimization. International Conference on Modeling and Simulation of Microsystems, San Juan (2003).

D.F. Green and B. Tidor.  Evaluation of ab initio charge determination methods for use in continuum solvation calculations.  J. Phys. Chem. B107: 10261–10273 (2003).

P.M. Kim and B. Tidor.  Limitations of quantitative gene regulation models:  A case study.  Genome Res.13: 2391–2395 (2003).

C.A. Sarkar, K. Lowenhaupt, T. Horan, T.C. Boone, B. Tidor, and D.A. Lauffenburger.  Increased lifetime and enhanced potency using pH-activated “histidine switching”. Nature Biotechnol.20: 908–913 (2002).

L.-P. Lee and B. Tidor.  Barstar is electrostatically optimized for tight binding to barnase.  Nature Struct. Biol.8: 73–76 (2001).

E. Kangas and B. Tidor.  Electrostatic complementarity at ligand binding sites: Application to chorismate mutase.  J. Phys. Chem. B 105: 880–888 (2001).

Z.S. Hendsch, M.J. Nohaile, R.T. Sauer, and B. Tidor.  Preferential heterodimer formation via undercompensated electrostatic interactions.  J. Am. Chem. Soc. 123: 1264–1265 (2001).

L.-P. Lee and B. Tidor.  Optimization of electrostatic binding free energy.  J. Chem. Phys.106: 8681–8690 (1997).

Z.S. Hendsch and B. Tidor.  Do salt bridges stabilize proteins?  A continuum electrostatic analysis.  Protein Sci.3: 211–226 (1994).

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