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Bruce Tidor, Ph.D.

Department of Electrical Engineering and Computer Science
Professor of Biological Engineering and Computer Science
CSBi Co-Director for Education, Outreach and Community
Member, MIT Computer Science and Artificial Intelligence Laboratory

Room 32-212
617-253-7258 (phone)
617-252-1816 (fax)

Biosketch

A.B. Chemistry & Physics, Harvard, 1983
M.Sc. Biochemistry, Oxford, 1985
Ph.D. Biophysics, Harvard, 1990
Whitehead Fellow, Whitehead Institute for Biomedical Research, 1990
Assistant Prof., Dept. of Chemistry, MIT, 1994
Associate Prof., Dept. of Chemistry, MIT, 1999
Associate Professor, Biological Engineering Division & Department of Electrical Engineering and Computer Science, MIT, 2001
Member, MIT Computer Science and Artificial Intelligence Laboratory, 2002

Research Summary

The Tidor lab is interested in understanding complex biological phenomena at the molecular and systems level. We use a combination of modeling, theory and computation to dissect biological molecules and networks to determine the underlying principles that govern biological function.

At the molecular level, we use models from physics to delineate the connection between structure and function through an understanding of energetics. The atomic structures of many biomolecules have been determined. We know that these molecules perform various functions such as breaking chemical bonds or binding and signalling, but these static structures do not inherently divulge functional information. Our lab has developed computational approaches to describe the interactions of atoms in molecules and determine how they cooperate to endow structure with biological function.

This methodology can be applied to designing proteins that have particular characteristics, such as the engineering of enzymes. We are using molecular simulations to understand the energetics of amino acid changes in protein structure resulting from mutations in DNA sequences. While these changes have an effect on the overall structure, our approach allows us to study their effect on function as well.

In the case of AIDS therapy, we are using our understanding of protein design to predict the interactions of drugs with proteins from the HIV virus. The virus mutates so rapidly that a single line of therapy is often evaded immediately. With knowledge of the mechanisms of drug binding, we can design drug candidates that bind many of the mutant proteins that might escape conventional therapy. This approach of developing universal therapies can be applied to other areas, such as antibiotics or antibody therapeutics.

The complexity of biochemical network systems requires that we dissect networks into their component parts, much as we have broken down the structure of molecules to active sites and positive or negative regulatory domains, and then determine how those parts function as a whole. To facilitate this process, our research is focused in two areas: high-throughput data sets and mathematical study of models. Many techniques in systems biology create large amounts of data that require computational methods to analyze and model them efficiently.

Network modeling efforts involve 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 biology and biological engineering as well as approaches from computer science, artificial intelligence, applied mathematics, and electrical, chemical and mechanical 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)

 

Last Updated: May 16, 2010