Highly Efficient Strategy for Constructing New Types of Peptide Macrocycles

  • By Burcu Ozden
  • 10 April 2018

Peng Liu and his colleagues report a highly efficient and generally applicable strategy for constructing new types of peptide macrocycles using palladium-catalyzed intramolecular C(sp3)–H arylation reactions on their newly published paper in Nature Chemistry. 

This strategy provides a powerful tool to address the long-standing challenge of size- and composition-dependence in peptide macrocyclization, and generates novel peptide macrocycles with uniquely buttressed backbones and distinct loop-type three-dimensional structures.

Department of chemistry, University of Pittsburgh
Ph.D. in Chemistry: Cornell University,1997

Saxena Group is focused on developing Fourier Transform electron spin resonance and its application to otherwise inaccessible problems in biophysics. The coupling of electron spin angular momentum to its environment—as revealed by the ESR spectrum—provides rich information about the electronic, structural and dynamical properties of the molecule. Saxena group creates the methods that measure the precise distance between two units in a protein, in order to determine their folding patterns and conformational dynamics. These ESR Spectroscopic Rulers— based on multiple quantum coherences and double resonance experiments—are unique in that they resolve distances in the 1-16 nm length scale even on bulk amorphous materials. Much of this work is based on the use of first-principles theory to develop new experimental protocols and to analyze experimental results.

His group continues to develop applications of these spectroscopic rulers that range from capturing the essence of structural changes - such as misfolding - in proteins, to measuring the atomic-level details of ion-permeation in a ligand gated ion-channel. The main projects of his group include:

  • Pulsed ESR methods to measure distance constraints in systems containing paramagnetic metals
  • Measurement of structural and dynamical determinants of the protein-DNA interactions and functional dynamics in pentameric ligand gated ion-channels.
  • Application of the spectroscopic ruler to measure and predict global structures of nanostructured materials.
  • Role of metals in aggregation of Amyloid-β peptide.
Most Cited Publications
  1. "Nonlinear-least-squares analysis of slow-motion EPR spectra in one and two dimensions using a modified Levenberg–Marquardt algorithm," D. E. Budil, S. Lee, S. Saxena, J. H. Freed, Journal of Magnetic Resonance, Series A 120, 155 (1996)
  2. "Amplification of xenon NMR and MRI by remote detection," A. J. Moulé, M. M. Spence, S. I. Han, J. A. Seeley, K. L. Pierce, S Saxena, A. Pines. Proceedings of the National Academy of Sciences 100, 9122 (2003)
  3. "Double quantum two-dimensional Fourier transform electron spin resonance: distance measurements," S. Saxena, J. H. Freed, Chemical physics letters 251,102 (1996)
  4. "Direct evidence that all three histidine residues coordinate to Cu (II) in amyloid-β1− 16," B. Shin, S. Saxena, Biochemistry 47, 9117 (2008)
  5. "Theory of double quantum two-dimensional electron spin resonance with application to distance measurements," J Freed, S. Saxena, Jounal of Chemiical Physics 107, 1317-1340 (1997).
Recent Publications
  1. “ESR shows that the C-terminus of Ligand Free Human Glutathione S-Transferase A1-1 exists in two conformations,” M. J. Lawless, J. R. Pettersson, G. S. Rule, F. Lanni, S. SaxenaBiophysical Journal 114, 592 (2018)
  2. “The Cu(II)-nitrilotriacetic acid complex improves loading of a-helical double-histidine sites for precise distance measurements by pulsed ESR,” S. Ghosh, M. J. Lawless, G. S. Rule, S. SaxenaJ. Magn. Reson., 286, 163 (2018)
  3. “On the use of Cu(II)-iminodiacetic acid complex in double-Histidine based distance measurements by pulsed electron spin resonance,” M. J. Lawless, S. Ghosh, T. F. Cunningham, A. Shimshi, and S. SaxenaPhys. Chem. Chem. Phys., 19, 20959 (2017)
  4. “An analysis of nitroxide based distance measurements by pulsed ESR spectroscopy in cell-extract and in-cell,” M. J. Lawless, A. Shimshi, T. F. Cunningham, M. Kinde, P. Tang, and S. SaxenaChemPhysChem., 18, 1653 (2017)
  5. “Nucleotide-independent Cu(II)-based distance measurements in DNA by pulsed ESR,” M. J. Lawless, J. L. Sarver, S. Saxena, Angew Chem, 56, 2115 (2017)

Molecular Phenotypes of Structurally Homologous ETS Transcriptions Factors

Gregory Poon
Thursday, September 28, 2017 - 4:30pm

 ETS transcription factors comprise an evolutionarily related family of genetic regulators that are ubiquitous in animals and control a myriad of physiologically critical processes. ETS proteins are united by a highly conserved DNA-binding domain, with overlapping target DNA preferences on the one hand, but are functionally diverse and non-redundant on the other. This so-called ìspecificity conundrumî besets not only our understanding of ETS homologs but also the structure-activity relationships of eukaryotic transcription factors in general. Translationally, it hampers efforts to develop...

Department of Chemistry, University of Pittsburgh
Ph.D., Physical Chemistry, University of Wisconsin-Madison, 2013

In the Laaser Lab, we are interested in developing a physical understanding of how changes at the molecular level translate to the macroscopic properties of responsive polymeric materials. For example, how does a change in charge spacing affect the interactions between charged polymers, and at what point do the polymers stop behaving like isolated chains in solution and start behaving like part of a bulk material? How do orientational changes in single polymer chains propagate through a material to achieve macroscopic ordering? And how do polymeric networks transduce force, to achieve things like mechanochemical responses?

We explore these questions by a number of optical and spectroscopic methods, such as light scattering and Raman and infrared spectroscopy, along with classical materials characterization methods like rheology and electron microscopy. Together, these methods allow us to develop new understanding of the structure and dynamic properties of responsive polymeric materials, and offer students the opportunity to gain broad experience in both physical chemistry and polymer science.

Most Cited Publications
  1. "Adding a dimension to the infrared spectra of interfaces using heterodyne detected 2D sum-frequency generation (HD 2D SFG) spectroscopy," Wei Xiong, Jennifer E. Laaser, Randy D. Mehlenbacher, and Martin T. Zanni, PNAS 108, 20902 (2011)
  2. "Transient 2D IR Spectroscopy of Charge Injection in Dye-Sensitized Nanocrystalline Thin Films," Wei Xiong, Jennifer E. Laaser, Peerasak Paoprasert, Ryan A. Franking, Robert J. Hamers, Padma Gopalanand Martin T. Zanni, J. Am. Chem. Soc. 131,18040 (2009)
  3. "Time-Domain SFG Spectroscopy Using Mid-IR Pulse Shaping: Practical and Intrinsic Advantages," Jennifer E. Laaser, Wei Xiong, and Martin T. Zanni, J. Phys. Chem. B 115, 2536 (2011)
  4. "Two-Dimensional Sum-Frequency Generation Reveals Structure and Dynamics of a Surface-Bound Peptide," Jennifer E. Laaser, David R. Skoff, Jia-Jung Ho, Yongho Joo, Arnaldo L. Serrano, Jay D. Steinkruger, Padma Gopalan, Samuel H. Gellman, and Martin T. Zanni, J. Am. Chem. Soc. 136, 95 (2014)
  5. "Bridge-Dependent Interfacial Electron Transfer from Rhenium−Bipyridine Complexes to TiO2 Nanocrystalline Thin Films," Peerasak Paoprasert, Jennifer E. Laaser, Wei Xiong, Ryan A. Franking, Robert J. Hamers, Martin T. Zanni, J. R. Schmidt and Padma Gopalan, J. Phys. Chem. C 114, 9898 (2010)
Recent Publications
  1. "Equilibration of Micelle–Polyelectrolyte Complexes: Mechanistic Differences between Static and Annealed Charge Distributions," Jennifer E. Laaser, Michael McGovern, Yaming Jiang, Elise Lohmann, Theresa M. Reineke, David C. Morse, Kevin D. Dorfman, and Timothy P. Lodge, J. Phys. Chem. B, 121, 4631 (2017)
  2. "Architecture-Dependent Stabilization of Polyelectrolyte Complexes between Polyanions and Cationic Triblock Terpolymer Micelles," Jennifer E. Laaser, Elise Lohmann, Yaming Jiang, Theresa M. Reineke, and Timothy P. Lodge, Macromolecules 49, 6644 (2016)
  3. "Tuning Cationic Block Copolymer Micelle Size by pH and Ionic Strength," Dustin Sprouse, Yaming Jiang, Jennifer E. Laaser, Timothy P. Lodge, and Theresa M. Reineke, Biomacromolecules 17, 2849 (2016)
  4. "Interpolyelectrolyte Complexes of Polycationic Micelles and Linear Polyanions: Structural Stability and Temporal Evolution," Jennifer E. Laaser, Yaming Jiang, Shannon R. Petersen, Theresa M. Reineke, and Timothy P. Lodge, J. Phys. Chem. B 119, 15919 (2015)
  5. "Probing Site-Specific Structural Information of Peptides at Model Membrane Interface In Situ," Bei Ding, Afra Panahi, Jia-Jung Ho, Jennifer E. Laaser, Charles L. BrooksIII, Martin T. Zanni, and Zhan Chen, J. Am. Chem. Soc. 137, 10190 (2015)

ACS Launches Chemistry Preprint Server

  • By Aude Marjolin
  • 15 August 2016

Authors can deposit draft chemistry papers in online archive before publication. The American Chemical Society announced today that it will create a preprint server for chemistry research to promote sharing of early scientific results.

Preprint servers allow researchers to publish draft papers or preliminary data online to get feedback from the larger research community before a paper goes through a journal’s more formal peer review process. “A preprint server dedicated to chemists will help speed the dissemination of research results, solicit valuable feedback, and foster international collaboration,” says Kevin Davies, a vice president in ACS’s Publications Division who is spearheading the effort.

ACS is currently seeking collaborators to join in development of the server, which is tentatively called ChemRxiv. The joint undertaking between two of ACS’s divisions—CAS and Publications—is expected to launch in the next few months.

Intermolecular Potentials from the Iterated Stockholder Atoms Approach

Alston Misquitta
Friday, July 8, 2016 - 2:00pm

The Iterated Stockholder Atom (ISA) algorithm [1] is proving to be one of the most interesting methods for atoms‐in‐a‐molecule (AIM): it leads to a unique definition of the atoms which are guaranteed to be maximally spherical while allowing for the effects of charge movement as a result of chemical bonding. Through a basis‐space, or BS‐ISA, algorithm [2] we are able to calculate the ISA solution at the basis‐set...

Nanostructure-Controlled Heterogeneous Catalysts with Superior Catalytic Properties

Wenyu Huang
Thursday, April 7, 2016 - 4:00pm to 5:30pm

Dr. Huang received a B.S. in Chemistry from Nanjing University, China in 2000. After receiving an M.S. in 2002 also from Nanjing University, he started his Ph.D. research with Professor Mostafa A. El-Sayed at Georgia Institute of Technology and received his Ph.D. in 2007. Dr. Huang then began postdoctoral research with Professor Gabor A. Somorjai at University of California,...

Department of Chemistry, University of Pittsburgh
Ph.D., Computational Organic Chemistry, University of California, 2010

Reactivity and Selectivity Rules in Organic and Organometallic Reactions
We are developing computational models to quantitatively describe the origins of reactivity and selectivity in organocatalytic and transition metal-catalyzed reactions. We perform quantum mechanical calculations to explore the reaction mechanism, followed by thorough analysis on various stereoelectronic effects to predict how changes of the catalyst structure, substituents, and solvent affect rate and selectivity. We use quantitative energy decomposition methods to dissect the key interactions in the transition state and provide chemically meaningful interpretation to the computed reactivity and selectivity. We apply these computational studies to a broad range of organic and organometallic reactions, such as C–H and C–C bond activations, coupling reactions, olefin metathesis, and polymerization reactions. 

Catalyst Screening and Prediction
We are developing a multi-scale computational screening protocol which could efficiently rank the catalysts based on ligand-substrate interaction energies in the transition state. 

Applications of Computational Chemistry in Understanding Organic Chemistry
We are collaborating with experimental groups at Pitt and many other institutions to solve problems in organic chemistry using computational methods and programs. Our goal is to establish the most effective strategy to use modern computational methods and hardware to help address the grand challenges in synthetic chemistry. 


Most Cited Publications
  1. ​​​​"Computational Explorations of Mechanisms and Ligand-Directed Selectivities of Copper-Catalyzed Ullmann-Type Reactions," Gavin O. Jones, Peng Liu, K. N. Houk and Stephen L. Buchwald, J. Am. Chem. Soc. 132, 6205 (2010)
  2. "Suzuki−Miyaura Cross-Coupling of Aryl Carbamates and Sulfamates: Experimental and Computational Studies," Kyle W. Quasdorf, Aurora Antoft-Finch, Peng Liu, Amanda L. Silberstein, Anna Komaromi, Tom Blackburn, Stephen D. Ramgren, K. N. Houk, Victor Snieckus, and Neil K. Garg, J. Am. Chem. Soc. 133, 6352 (2011)
  3. "Palladium-Catalyzed Meta-Selective C–H Bond Activation with a Nitrile-Containing Template: Computational Study on Mechanism and Origins of Selectivity," Yun-Fang Yang, Gui-Juan Cheng, Peng Liu, Dasheng Leow, Tian-Yu Sun, Ping Chen, Xinhao Zhang, Jin-Quan Yu, Yun-Dong Wu, and K. N. Houk, J. Am. Chem. Soc. 136, 344 (2014)
  4. "Conversion of amides to esters by the nickel-catalysed activation of amide C–N bonds," Liana Hie, Noah F. Fine Nathel, Tejas K. Shah, Emma L. Baker, Xin Hong, Yun-Fang Yang, Peng Liu, K. N. Houk& Neil K. Garg, Nature, 524, 79 (2015)
  5. "Z-Selectivity in Olefin Metathesis with Chelated Ru Catalysts: Computational Studies of Mechanism and Selectivity," Peng Liu, Xiufang Xu, Xiaofei Dong, Benjamin K. Keitz, Myles B. Herbert, Robert H. Grubbs, and K. N. Houk, J. Am. Chem. Soc. 134, 1464 (2012)
Recent Publications
  1. "C(alkenyl)−H Activation via Six-Membered Palladacycles: Catalytic 1,3-Diene Synthesis," Mingyu Liu, Pusu Yang, Malkanthi K. Karunananda, Yanyan Wang, Peng Liu, and Keary M. Engle, J. Am. Chem. Soc. (2018).
  2. "An Initiation Kinetics Prediction Model Enables Rational Design of Ruthenium Olefin Metathesis Catalysts Bearing Modified Chelating Benzylidenes" Shao-Xiong Luo, Keary M. Engle, Xiaofei Dong, Andrew Hejl, Michael K. Takase, Lawrence M. Henling, Peng Liu, K. N. Houk, and Robert H. Grubbs, ACS Catalysis (2018).
  3. "Disentangling Ligand Effects on Metathesis Catalyst Activity: Experimental and Computational Studies of Ruthenium–Aminophosphine Complexes Crystal," K. Chu, Tzu-Pin Lin, Huiling Shao, Allegra L. Liberman-Martin, Peng Liu, and Robert H. Grubbs, Journal of the American Chemical Society (2018).
  4. "A general strategy for synthesis of cyclophanebraced peptide macrocycles via palladiumcatalysed intramolecular sp3 C−H arylation," Xuekai Zhang, Gang Lu, Meng Sun, Madhu Mahankali, Yanfei Ma, Mingming Zhang, Wangde Hua, Yuting Hu, Qingbing Wang, Jinghuo Chen, Gang He, Xiangbing Qi , Weijun Shen, Peng Liu   and Gong Chen, Nature Chemistry (2018).
  5. "Catalytic C-H Trifluoromethoxylation of Arenes and Heteroarenes," Weijia Zheng, Cristian A. Morales-Rivera, Johnny W. Lee, Peng Liu, and Ming-Yu Ngai, Angew. Chem.,130, 1 (2018).
  6. "Glycosyl Cross-Coupling of Anomeric Nucleophiles: Scope, Mechanism, and Applications in the Synthesis of Aryl C-Glycosides", Feng Zhu, Jacob Rodriguez, Tianyi Yang, Ilia Kevlishvili, Eric Miller, Duk Yi, Sloane O’Neill, Michael J. Rourke, Peng Liu, and Maciej A. Walczak, J. Am. Chem. Soc 139, 17908 (2017)

Ken Jordan Organizes Session at the ACS Spring 2016 Meeting

  • By Aude Marjolin
  • 11 February 2016

The 251st American Chemical Society national meeting and exposition will be held from March 13-17, 2016 at San Diego, CA. The theme this year is "Computers in Chemistry", and PQI faculty Ken Jordan is co-organizing a session entitled Metastable Electronic States: Recent Advances In Theory and Experiment