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Department of Biological Engineering
Bruce Tidor, Ph.D.

Bruce Tidor, Ph.D.

Professor of Biological Engineering and Computer Science

Research group web site

E-mail: tidor@mit.edu
Office: 32-212
Phone: (617) 253-7258
Fax: (617) 252-1816
Administrative Assistants: Nira Manokharan

Courses: CSB100, 20.420, 6.581


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

B. M. King and B. Tidor. MIST: Maximum information spanning trees for dimension reduction of biological data sets. Bioinformatics 25: 1165–1172 (2009).

Y. L. Zhang, M. L. Radhakrishnan, X. Lu, A. W. Gross, B. Tidor, and H. F. Lodish. Symmetric signaling by an asymmetric 1 erythropoietin: 2 erythropoietin receptor complex. Mol. Cell 33:266–274 (2009).

J. E. Toettcher, A. Loewer, G. J. Ostheimer, M. B. Yaffe, B. Tidor, and G. Lahav. Distinct mechanisms act in concert to mediate cell cycle arrest. Proc. Natl. Acad. Sci. U.S.A. 106: 785–790 (2009).

E. J. Hong, S. M. Lippow, B. Tidor, and T. Lozano-Pérez. Rotamer optimization for protein design through MAP estimation and problem-size reduction. J. Comput. Chem. 30: 1923–1945 (2009).

D. J. Huggins, M. D. Altman, and B. Tidor. Evaluation of an inverse molecular design algorithm in a model binding site. Proteins: Struct., Funct., Bioinf. 75: 168–186 (2009).

M. D. Altman, J. P. Bardhan, J. K. White, and B. Tidor. Accurate solution of multi-region continuum biomolecule electrostatic problems using the linearized Poisson–Boltzmann equation with curved boundary elements. J. Comput. Chem. 30: 132–153 (2009).

M. L. Radhakrishnan and B. Tidor. Optimal drug cocktail design: Methods for targeting molecular ensembles and insights from theoretical model systems. J. Chem. Inf. Model. 48: 1055–1073 (2008).

M. D. Altman, A. Ali, G. S. K. K. Reddy, M. N. L. Nalam, S. G. Anjum, H. Cao, S. Chellappan, V. Kairys, M. X. Fernandes, M. K. Gilson, C. A. Schiffer, T. M. Rana, and B. Tidor. HIV-1 protease inhibitors from inverse design in the substate envelope exhibit subnanomolar binding to drug-resistant variants. J. Am. Chem. Soc. 130: 6099–6113 (2008).

M. D. Altman, E. A. Nalivaika, M. Prabu-Jeyabalan, C. A. Schiffer, and B. Tidor. Computationaldesign and experimental study of tighter binding peptides to an inactivated mutant of HIV-1 protease. Proteins: Struct., Funct., Bioinf. 70: 678–694 (2008).

J. F. Apgar, J. E. Toettcher, D. Endy, F. M. White, and B. Tidor. Stimulus design for model selection and validation in cell signaling. PLoS Comput. Biol. 4: e30 (2008).

K. A. Armstrong and B. Tidor. Computationally mapping sequence space to understand evolutionary protein engineering. Biotechnol. Prog. 24: 62–73 (2008).

A. K. Wilkins, P. I. Barton, and B. Tidor. The Per2 negative feedback loop sets the period in the mammalian circadian clock mechanism. PLoS Comput. Biol. 3: e242 (2007).

M. L. Radhakrishnan and B. Tidor. Specificity in Molecular Design: A Physical Framework for Probing the Determinants of Binding Specificity and Promiscuity in a Biological Environment. J. Phys. Chem. B 111: 13419–13435 (2007).

S. M. Lippow, K. D. Wittrup, and B. Tidor Computational design of antibody affinity improvement beyond in vivo maturation. Nature Biotechnol. 25: 1171–1176 (2007).

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. 127: 014701 (2007).

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).

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, A.J. Grodzinsky, B. Tidor, and G.C. Rutledge. Optimal linearized Poisson–Boltzmann theory applied to the simulation of flexible polyelectrolytes in solution J. Chem. Phys. 121: 7557–7561 (2004).

K.S. Midelfort, H.H. Hernandez, S.M. Lippow, B. Tidor, C.L. Drennan, K.D. Wittrup. Substantial energetic improvement with minimal structural perturbation in a high affinity mutant antibody. J. Mol. Biol. 343: 685–701 (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).

S. Spector, R.T. Sauer, and B. Tidor. Computational and experimental probes of symmetry mismatches in the Arc repressor–DNA complex. J. Mol. Biol. 340: 253–261 (2004).

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

D.F. Green and B. Tidor. Evaluation of ab initio charge determination methods for use in continuum solvation calculations J. Phys. Chem. B 107: 10261–10273 (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).

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

D.L. Luisi, C.D. Snow, J.J. Lin, Z.S. Hendsch, B. Tidor, and D.P. Raleigh. Surface salt bridges, double-mutant cycles, and protein stability: An experimental and computational analysis of the interaction of the Asp 23 side chain with the N-terminus of the N-terminal domain of the ribosomal protein L9. Biochemistry 42: 7050–7060 (2003).

C.M. Rienstra, L. Tucker-Kellogg, C.P. Jaroniec, M. Hohwy, B. Reif, M.T. McMahon, B. Tidor, T. Lozano-Pérez, and R.G. Griffin. De novo determination of peptide structure with solid-state magic-angle spinning NMR spectroscopy. Proc. Natl. Acad. Sci. U.S.A. 99: 10260–10265 (2002).

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 binding electrostatics: Charge complementarity in the barnase–barstar protein complex. Protein Sci. 10: 362–377 (2001).

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).

E. Kangas and B. Tidor. Electrostatic specificity in molecular ligand design. J. Chem. Phys. 112: 9120–9131 (2000).

Z.S. Hendsch and B. Tidor. Electrostatic interactions in the GCN4 leucine zipper: Effects of intramolecular interactions that are enhanced on binding. Protein Sci. 8: 1181–1192 (1999).

P.B. Harbury, J.J. Plecs, B. Tidor, T. Alber, and P.S. Kim. High-resolution protein design with backbone freedom. Science (Washington, D.C.) 282: 1462–1467 (1998).

E. Kangas and B. Tidor. Optimizing electrostatic affinity in ligand–receptor binding: Theory, computation, and ligand properties. J. Chem. Phys. 109: 7522–7545 (1998).

L.T. Chong, S.E. Dempster, Z.S. Hendsch, L.-P. Lee, and B. Tidor. Computation of electrostatic complements to proteins: A case of charge stabilized binding. Protein Sci. 7: 206–210 (1998).

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

Z.S. Hendsch, T. Jonsson, R.T. Sauer, and B. Tidor. Protein stabilization by removal of unsatisfied polar groups: Computational approaches and experimental tests. Biochemistry 35: 7621–7625 (1996).

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


Awards

American Association for the Advancement of Science: Fellow (2009)

Sloan Foundation: Research Fellowship (1999)

 

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