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Zachary T. Ball

Associate Professor of Chemistry

1.   Rhodium metallopeptides.

Polypeptides are the biological solution to ligand design for transition-metal catalysis. Metal cofactors within protein folds achieve reactivity that is generally inaccessible to traditional transition-metal catalysts. Efforts to understand these capabilities and apply them to new reactivity have been extensive: work by numerous groups has resulted in tremendous capabilities to build new metalloproteins with novel structure, spectroscopy, and other physical characteristics. However, designing new and useful reactivity and catalytic function has proven a daunting challenge. We have focused on designing metallopeptides with new catalytic capabilities that combine features of enzymes and traditional transition-metal catalysts. One crucial feature of biological catalysis that we have sought to emulate is the ability to override inherent chemical reactivity, performing site-specific chemistry in a functional-group-rich environment. From a practical perspective, exploring peptides as ligands for transition-metal catalysis facilitates (A) efficient screening of ligand diversity and (B) design of large-length-scale (nanometer) structure necessary for molecular recognition.

Metallopeptide synthesis and structure. The lab has developed methods for direct metalation of carboxylate side chains of fully deprotected peptides. The resulting rhodium metallopeptides are stable in serum and are readily purified by RP–HPLC. We have developed protecting-group methods for the synthesis of metallopeptides with multiple carboxylates and demonstrated the ability of rhodium metalation to create or destroy helical structure.

2. Rhodium metallopeptides that interact with proteins. A fundamental concept of our work in this area is the use of peptides as molecular recognition units to deliver a rhodium center to a specific site in a complex environment (Fig. 1). Localization allows both catalysis and metal-ligand interactions with peripheral side chains leading to stabilization of a protein-peptide interface.

Proximity-driven modification of polypeptides. We set out to combine peptide-based molecular recognition with rhodium-based catalysis to allow site-specific modification of polyfunctional substrates such as peptides and proteins. Initial examinations focused on coiled-coil peptide substrates as models for protein interactions. We observed remarkable rate accelerations for tryptophan modification (>103). The true potential of this approach was revealed upon discovering that many other side chains—wholly unreactive with Rh2(OAc)4—are efficient substrates for proximity-driven modification.

A new tool for site-specific protein modification. Initial peptide work has been extended to modification of whole proteins. In recombinant systems, we developed recognition elements that allow orthogonal modification of multiple proteins in lysate by judicious choice of catalyst. The ability to modify specific proteins in lysate is a remarkable and enabling attribute that speaks to the utility and robustness of our methods. These results have been extended to  entirely natural protein sequences, first with modification of the Myc bZip, and more recently with the Fyn SH3 domain. SH3 domains are a large class of medically relevant recognition motifs, and this result offers a new tool for site-specific functionalization of similar peptide-recognition domains.

Potent hybrid organic–inorganic inhibitors. The other major goal of localization-induced metal function has been templating reversible metal-ligand with peripheral histidine, methionine, or cysteine near the binding site. This stabilizing interaction has enabled us to discover the most potent inhibitors yet reported for PDZ domains regulating CFTR function, and to demonstrate successful function in lysate.

3.   Small-molecule catalysis. The ability to synthesize ligand diversity quickly and efficiently makes polypeptides an ideal platform for the discovery of new rhodium(II) catalysts. More recently, our efforts have focused on the role of axial ligands, peptides with non-traditional axial–equatorial coordination modes, and high-throughput catalyst discover methods.

 4.   Copper catalysis and other research. The group has developed novel copper catalysts for C–Si and C–H activation. For C–Si activation, we developed stable copper(I) fluoride complexes that efficiently transmetalate with silanes to afford organocopper compounds, in the first direct evidence of copper–silicon transmetallation from simple sp2silanes. This discovery has been extended to the development of catalytic methods employing silane activation. For C–H activation, we demonstrated a radical method based on atom-transfer ideas to achieve remote functionalization of unactivated sp3 C–H bonds. We have also received funding for two separate projects involving the synthesis of small molecules and responsive polymers for use in upstream oil research.


Ohata, J.; Vohidov, F.; Ball, Z. T. Convenient analysis of protein modification by chemical blotting with fluorogenic "click" reagents.  Mol. Biosyst. , 11: 2846-2849

Vohidov, F.; Popp, B. V.; Ball, Z. T. Designing enzyme-like catalysts: A rhodium(II) metallopeptide case study.  Proceedings of the 24th American Peptide Symposium, 2015: 24-26

Coughlin, J. M.; Kundu, R.; Cooper, J. C.; Ball, Z. T. Inhibiting prolyl isomerase activity by hybrid organic–inorganic molecules containing rhodium(II) fragments.  Bioorg. Med. Chem. Lett. , 24: 5203-5206

Ohata, J.; Vohidov, F.; Aliyan, A.; Huang, K.; Marti, A. A.; Ball, Z. T. Luminogenic iridium azide complexes.  Chem. Commun., 51: 15192-15195

Kinzurik, M. I.; Hristov, L. V.; Matsuda, S. P. T.; Ball, Z. T. Mixed Bioengineering–Chemical Synthesis Approach for the Efficient Preparation of Δ7-Dafachronic Acid.  Org. Lett. , 16: 2188-2191

Ball, Z. T. Molecular recognition in protein modification with rhodium metallopeptides.  Curr. Opin. Chem. Biol. , 25: 98-102

Vohidov, F.; Knudsen, S. E.; Leonard, P. G.; Ohata, J.; Wheadon, M. J.; Popp, B. V.; Ladbury, J. E.; Ball, Z. T. Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors.  Chem. Sci., 6: 4778-4783

Vohidov, F.; Coughlin, J. M.; Ball, Z. T. Rhodium(II) Metallopeptide Catalyst Design Enables Fine Control in Selective Functionalization of Natural SH3 Domains.  Angew. Chem. Int. Ed., 54: 4587-4591

Vohidov, F.; Coughlin, J. M.; Ball, Z. T. Rhodium(II) Metallopeptide Catalyst Design Enables Fine-Control in Selective Functionalization of Natural SH3 Domains.  Angew. Chem. Int. Ed.

Minus, M. B.; Liu, W.; Vohidov, F.; Kasembeli, M. M.; Long, X.; Krueger, M.; Stevens, A.; Kolosov, M. I.; Tweardy, D. J.; Redell, M. S.; Ball, Z. T. Rhodium(II) proximity-labeling identifies a novel target site on STAT3 for inhibitors with potent anti-leukemia activity.  Angew. Chem. Int. Ed., 54: 13085-13089

Popp, B. V.; Miles, D. H.; Smith, J. A.; Fong, I. M.; Pasquali, M.; Ball, Z. T. Stabilization and Functionalization of Single-Walled Carbon Nanotubes with Polyvinylpyrrolidone Copolymers for Applications in Aqueous Media.  Polym. Sci., Part A: Polym. Chem. , 53: 337-343

Ohata, Jun; Miller, Mary K; Mountain, Courtney M; Vohidov, Farrukh; Ball, Zachary Thomas; A three‐component organometallic tyrosine bioconjugation.  Angewandte Chemie 2018

Ohata, Jun; Ball, Zachary T; A Hexa-rhodium Metallopeptide Catalyst for Site-Specific Functionalization of Natural Antibodies.  Journal of the American Chemical Society, 139 2017: 12617-12622

Ohata, Jun; Ball, Zachary T; Ascorbate as a pro-oxidant: mild N-terminal modification with vinylboronic acids.  Chemical Communications, 53 2017: 1622-1625

Martin, Samuel C; Vohidov, Farrukh; Wang, Haopei; Knudsen, Sarah E; Marzec, Alex A; Ball, Zachary T; Designing Selectivity in Dirhodium Metallopeptide Catalysts for Protein Modification.  Bioconjugate chemistry, 28 2017: 659-665

Thomas, Emily E; Pandey, Naresh; Knudsen, Sarah; Ball, Zachary T; Silberg, Jonathan J; Programming Post-Translational Control over the Metabolic Labeling of Cellular Proteins with a Noncanonical Amino Acid.  ACS synthetic biology, 6 2017: 1572-1583

R. Sambasivan; W. Zheng; S. J. Burya; B. V. Popp; C. Turro; C. Clementi; and Z. T. Ball A tripodal peptide ligand for asymmetric Rh(II) catalysis highlights unique features of on-bead catalyst development.  , ASAP 2014: 1401–1407

R. Kundu, Z. T. Ball A rhodium-catalyzed method for serum-stable cysteine modification.  Chem. Commun., 49 2013: 4166-4168

Z. T. Ball Designing enzyme-like catalysts: a rhodium(II) metallopeptide case study.  Acc. Chem. Res., 46 2013: 560–570

R. Sambasivan, Z. T. Ball Studies of asymmetric styrene cyclopropanation with a rhodium(II) metallopeptide catalyst developed with a high-throughput screen.  Chirality, 25 2013: 493-497

R. Sambasivan and Z. T. Ball Studies of asymmetric styrene cyclopropanation with a rhodium(II) metallopeptide catalyst developed with a high-throughput screen.  , 25 2013: 493-497

Z. Chen, F. Vohidov, J. M. Coughlin, L. J. Stagg, S. T. Arnold, J. E. Ladbury, and Z. T. Ball Catalytic Protein Modiication with Dirhodium Metallopeptides: Specificity in Designed and Natural Systems.  J. Am. Chem. Soc., 134 2012: 10138-10145

R. Sambasivan and Z. T. Ball Determination of orientational isomerism in rhodium(II) metallopeptides by pyrene fluorescence.  Org. Biomol. Chem., 10 2012: 8203-8206

R. Kundu, P. R. Cushing, B. V. Popp, Y. Zhao, D. R. Madden, and Z. T. Ball Hybrid Organic-Inorganic Inhibitors of a PDZ Interaction that Regulates the Endocytic Fate of CFTR.  Angew. Chem. Int. Ed., 51 2012: 7217-7220

R. Sambasivan and Z. T. Ball Screening Rhodium Metallopeptide Libraries 'On Bead': Asymmetric Cyclopropanation and a Solution to the Enantiomer Problem.  Angew. Chem. Int. Ed., 51 2012: 8568-8572

B. V. Popp, Z. Chen and Z. T. Ball Sequence-specific Inhibition of a Designed Metallopeptide Catalyst.  Chem. Commun., 48 2012: 7492-7494

A. N. Zaykov and Z. T. Ball A general synthesis of dirhodium metallopeptides as MDM2 ligands.  Chem. Commun., 47 2011: 10927-10929

A. N. Zaykov, Z. T. Ball Kinetic and stereoselectivity effects of phosphite ligands in dirhodium catalysts.  Tetrahedron, 67 2011: 4397-4401

B. V. Popp, Z. T. Ball Proximity-Driven Metallopeptide Catalysts: Remarkable Side-Chain Scope Enables Modification of the Fos bZip Domain.  Chem, Sci., 2 2011: 690-695

Z. Chen, B. Popp, C. L. Bovet, Z. T. Ball Site-specific protein modification with a dirhodium metallopeptide catalyst.  ACS Chem. Biol., 6 2011: 920-925

V. Russo, J. R. Herron, Z. T. Ball Allylcopper Intermediates with N-Heterocyclic Carbene Ligands: Synthesis, Structure, and Catalysis.  Org. Lett., 12 2010: 220-223

Kundu, R.; Ball, Z.T. Copper-Catalyzed Remote sp3 C–H Chlorination of Alkyl Hydroperoxides.  Org. Lett., 12 2010: 2460–2463

Zaykov, A.N.; Popp, B.V.; Ball, Z.T. Helix Induction by Dirhodium: Access to Biocompatible Metallopeptides with Defined Secondary Structure.  Chem.—Eur. J., 16 2010: 6651 - 6659

Sambasivan, R.; Ball, Z.T. Metallopeptides for Asymmetric Dirhodium Catalysis.  J. Amer. Chem Soc, 132 2010: 9289-9291

Popp, B.V.; Ball, Z.T. Structure-Selective Modification of Aromatic Side Chains with Dirhodium Metallopeptide Catalysts.  J. Amer. Chem Soc, 132 2010: 6660–6662

B. M. Trost, J. D. Sieber, W. Qian, R. Dhawan, Z. T. Ball Asymmetric Total Synthesis of Soraphen A: A Flexible Alkyne Strategy.  Angew. Chem. Int. Ed., 48 2009: 5478-5481

J. R. Herron, V. Russo, E. J. Valente, Z. T. Ball Catalytic Organocopper Chemistry from Organosiloxane Reagents.  Chem. Eur. J., 15 2009: 8713-8716

A. N. Zaykov, K. R. MacKenzie, Z. T. Ball Controlling Peptide Structure with Coordination Chemistry: Robust and Reversible Peptide-Dirhodium Ligation.  Chem. Eur. J., 15 2009: 8961-8965

V. Russo, J. Allen, Z. T. Ball Synthesis and isotopic labeling of a naturally occurring alkyl-thiadiamondoid.  Chem. Commun. 2009: 595-596

Jessica R. Herron and Zachary T. Ball Synthesis and Reactivity of Functionalized Arylcopper Compounds by Transmetalation of Organosilanes.  J. Amer. Chem. Soc., 130 2008: 16486-16487

Ball, Z.T. Hydrosilylation of Alkynes and Related Reactions. In Comprehensive Organometallic Chemistry III; Crabtree, R. H. and Mingos, D. M. P., Eds.; Elsevier: Oxford 2006; vol. 10; pp 789-814.

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  • A.B. Chemistry (1999) Harvard University
  • Ph.D. Chemistry (2004) Stanford University
  • Center for Biological and Environmental Nanotechnology
  • Institute of Biosciences and Bioengineering
  • Smalley-Curl Institute
  • organic chemistry, catalysis, transition-metal chemistry, biological chemistry
Email: Zachary.Ball@rice.edu
Phone: (713) 348-6159
Office: BioScience Research Collaborative, 327