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Emergence of Low-Symmetry Foldamers from Single Monomers
ARTICLES https://doi.org/10.1038/s41557-020-00565-2 Emergence of low-symmetry foldamers from single monomers Charalampos G. Pappas 1, Pradeep K. Mandal 2, Bin Liu1, Brice Kauffmann 3, Xiaoming Miao1, Dávid Komáromy 1, Waldemar Hoffmann 4,5, Christian Manz4,5, Rayoon Chang 4,5, Kai Liu 1, Kevin Pagel 4,5, Ivan Huc 2 ✉ and Sijbren Otto 1 ✉ Self-assembly is a powerful method to obtain large discrete functional molecular architectures. When using a single building block, self-assembly generally yields symmetrical objects in which all the subunits relate similarly to their neighbours. Here we report the discovery of a family of self-constructing cyclic macromolecules with stable folded conformations of low symmetry, which include some with a prime number (13, 17 and 23) of units, despite being formed from a single component. The forma- tion of these objects amounts to the production of polymers with a perfectly uniform length. Design rules for the spontaneous emergence of such macromolecules include endowing monomers with a strong potential for non-covalent interactions that remain frustrated in competing entropically favoured yet conformationally restrained smaller cycles. The process can also be templated by a guest molecule that itself has an asymmetrical structure, which paves the way to molecular imprinting tech- niques at the level of single polymer chains. he self-assembly of a defined number of identical molecu- objects that may be obtained by this method. They also introduce lar units into discrete objects is to some extent understood an unanticipated approach to the synthesis of macromolecules Tand amenable to design. -
Helicogenicity of Solvents in the Conformational Equilibrium of Oligo(M-Phenylene Ethynylene)S: Implications for Foldamer Research
Helicogenicity of solvents in the conformational equilibrium of oligo(m-phenylene ethynylene)s: Implications for foldamer research David J. Hill and Jeffrey S. Moore† Roger Adams Laboratory, Departments of Chemistry and Materials Science and Engineering, The Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana–Champaign, Urbana, IL 61801 Edited by Jack Halpern, University of Chicago, Chicago, IL, and approved February 7, 2002 (received for review December 1, 2001) A(R)-binaphthol tethered bis-hexameric oligo(m-phenylene ethy- impact of solvent on foldable chains has been addressed only nylene) foldamer was examined in 30 solvents to correlate the recently, and of these studies, only a limited scope of solvents has unfolded–folded conformational equilibrium to bulk solvent prop- been explored (7, 10–17). This fact is surprising considering the erties and specific solvent–chain interactions. The oligomer is ease with which this experimental variable can be modulated and soluble in a variety of solvents of intermediate polarity, with the the information that can be obtained about the nature of the majority of these solvents being helicogenic. The amphiphilic driving forces involved in the folding reaction. Therefore, un- nature of the chain allows the solvophobic backbone to be solu- derstanding how the conformational states of the chain respond bilized in a wide range of solvents through the polar triethylene to the surrounding media, a major focus already existing in the glycol side chains. As demonstrated through UV and CD spectro- fields of biological and polymer science, is the key to ascertaining scopic experiments, the helical conformation is increasingly stabi- the sensitivity of a foldamer backbone to solvent as well as lized with increasing solvent polarity in the absence of specific improving the design of foldable chains. -
Foldamers: from Design to Protein Recognition
FOLDAMERS: FROM DESIGN TO PROTEIN RECOGNITION January 25 – January 28, 2010 European Institute of Chemistry and Biology Bordeaux-Pessac, FRANCE BOOK OF ABSTRACTS Plenary lectures 1–9 Keynote lectures 1–12 Oral Communications 1–8 Posters 1–26 Plenary lecture 1 Foldamers: Accomplishments and Goals Samuel H. Gellman Department of Chemistry, University of Wisconsin, Madison, WI, 53706 USA [email protected] Proteins and nucleic acids perform a wide range of complex functions in biological systems. Nearly all of these molecular operations require the biopolymer chain to adopt a compact and specific folding pattern. The conformational behavior of biopolymers is usually analyzed hierarchically: secondary structure reflects local features of the backbone (helix and sheet are the secondary structures with long-range order), tertiary structure is formed when secondary structure elements pack against one another in intramolecular fashion, and quarternary structure arises when molecules with discrete secondary and/or tertiary structure assemble noncovalently into specific complexes. Over the past two decades many researchers have sought biopolymer-like folding behavior in unnatural oligomers ("foldamers"), with the long-range goal of using compact and specific conformations to generate biopolymer-like functions. [1-3] This lecture will provide a general overview of research in the foldamer area, and then focus on results obtained with peptidic foldamers. Beta-amino acid oligomers ("beta-peptides") were prominent in the development of the foldamer field, [4,5] and they remain subjects of intensive investigation today. However, recent years have seen growing interest in foldamers with heterogeneous backbones, [6] such as "alpha/beta- peptides", which contain both alpha- and beta-amino acid residues. -
Internalization of Foldamer-Based DNA Mimics Through a Site-Specific Antibody Conjugate to Target HER2-Positive Cancer Cells
pharmaceuticals Article Internalization of Foldamer-Based DNA Mimics through a Site-Specific Antibody Conjugate to Target HER2-Positive Cancer Cells Valentina Corvaglia 1,†, Imène Ait Mohamed Amar 2,†,Véronique Garambois 3, Stéphanie Letast 2, Aurélie Garcin 3,Céline Gongora 3 , Maguy Del Rio 3, Caroline Denevault-Sabourin 2 , Nicolas Joubert 2 , Ivan Huc 1 and Philippe Pourquier 3,* 1 Center for Integrated Protein Science, Department of Pharmacy, Ludwig-Maximilians-Universität, 81377 Munich, Germany; [email protected] (V.C.); [email protected] (I.H.) 2 GICC EA7501, Equipe IMT, Université de Tours, 10 Boulevard Tonnellé, F-37032 Tours, France; [email protected] (I.A.M.A.); [email protected] (S.L.); [email protected] (C.D.-S.); [email protected] (N.J.) 3 Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, F-34298 Montpellier, France; [email protected] (V.G.); [email protected] (A.G.); [email protected] (C.G.); [email protected] (M.D.R.) * Correspondence: [email protected]; Tel.: +33-467-613-765; Fax: +33-467-613-787 † V.C. and I.A.M.A. contributed equally. Citation: Corvaglia, V.; Ait Mohamed Amar, I.; Garambois, V.; Abstract: Inhibition of protein–DNA interactions represents an attractive strategy to modulate Letast, S.; Garcin, A.; Gongora, C.; Del essential cellular functions. We reported the synthesis of unique oligoamide-based foldamers that Rio, M.; Denevault-Sabourin, C.; adopt single helical conformations and mimic the negatively charged phosphate moieties of B-DNA. -
Heterogeneous H‑Bonding in a Foldamer Helix Brian F
Communication pubs.acs.org/JACS Heterogeneous H‑Bonding in a Foldamer Helix Brian F. Fisher, Li Guo,† Brian S. Dolinar, Ilia A. Guzei, and Samuel H. Gellman* Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States *S Supporting Information bones. Such differences are inherent for helices formed by ABSTRACT: Structural characterization of new α/γ- heterogeneous backbones because of subunit diversity. Thus, for peptide foldamers containing the cyclically constrained γ- example, an α/β-peptide contains H-bond-accepting groups amino acid I is described. Crystallographic and 2D NMR (CO) and -donating groups (N−H) from both α and β analysis shows that γ residue I promotes the formation of a residues. Different types of H-bonds are found also in foldameric 12/10-helical secondary structure in α/γ-peptides. This helices in which H-bond directionality alternates along the helix contains two different types of internal H-bond, and backbone, whether the backbone is homogeneous (as in the β- the data show that the 12-atom CO(i) → H−N(i+3) H- peptide 10/12-helix7 and 18/20-helix8) or heterogeneous (as in bond is more favorable than the 10-atom CO(i) → H− the α/β-peptide 11/9-helix9 and 18/16-helix10). These systems N(i−1) H-bond. Several foldamer helices featuring raise a fundamental question: are the different types of topologically distinct H-bonds have been discovered, but intrahelical H-bonds comparably favorable? Here we describe a our findings are the first to show that such H-bonds may new type of α/γ-peptide foldamer and provide the first evidence differ in their favorability. -
Folded Biomimetic Oligomers for Enantioselective Catalysis
Folded biomimetic oligomers for enantioselective catalysis Galia Maayan, Michael D. Ward1, and Kent Kirshenbaum1 Department of Chemistry and Molecular Design Institute, New York University, 100 Washington Square East, New York, NY 10003-6688 Edited by Ken A. Dill, University of California, San Francisco, CA, and approved July 6, 2009 (received for review March 26, 2009) Many naturally occurring biopolymers (i.e., proteins, RNA, DNA) owe their unique properties to their well-defined three-dimen- sional structures. These attributes have inspired the design and synthesis of folded architectures with functions ranging from molecular recognition to asymmetric catalysis. Among these are synthetic oligomeric peptide (‘‘foldamer’’) mimics, which can dis- play conformational ordering at short chain lengths. Foldamers, however, have not been explored as platforms for asymmetric catalysis. This report describes a library of synthetic helical ‘‘pep- toid’’ oligomers that enable enantioselective transformations at an embedded achiral catalytic center, as illustrated by the oxidative kinetic resolution of 1-phenylethanol. In an investigation aimed at elucidating key structure–function relationships, we have discov- ered that the enantioselectivity of the catalytic peptoids depends on the handedness of the asymmetric environment derived from the helical scaffold, the position of the catalytic center along the peptoid backbone, and the degree of conformational ordering of Scheme 1. the peptoid scaffold. The transfer of chiral information from a folded scaffold can enable the use of a diverse assortment of embedded achiral catalytic centers, promising a generation of motifs available for the construction of polypeptide-based cat- synthetic foldamer catalysts for enantioselective transforma- alysts may prove limiting. This has inspired the design of tions that can be performed under a broad range of reaction ‘‘foldamers’’—unnatural oligomers that fold into well-defined environments. -
How Fast Is Protein Hydrophobic Collapse?
How fast is protein hydrophobic collapse? Mourad Sadqi*, Lisa J. Lapidus†‡, and Victor Mun˜ oz*§ *Department of Chemistry and Biochemistry and Center for Biomolecular Structure and Organization, University of Maryland, College Park, MD 20742; and †Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 Edited by Michael Levitt, Stanford University School of Medicine, Stanford, CA, and approved August 18, 2003 (received for review June 21, 2003) One of the most recurring questions in protein folding refers to the Equilibrium FRET Experiments. Equilibrium FRET experiments interplay between formation of secondary structure and hydro- were performed at 25 M concentration in citrate buffer at pH phobic collapse. In contrast with secondary structure, it is hard to 3.0 in an Applied Photophysics (Surrey, U.K.) PiStar instrument. isolate hydrophobic collapse from other folding events. We have Efficiency of energy transfer between naphtyl-alanine (donor) directly measured the dynamics of protein hydrophobic collapse in and dansyl-lysine (acceptor) was determined from the fluores- the absence of competing processes. Collapse was triggered with cence quantum yield of the donor by using the equation: laser-induced temperature jumps in the acid-denatured form of a Qda simple protein and monitored by fluorescence resonance energy E ϭ 1 Ϫ . [1] transfer between probes placed at the protein ends. The relaxation Qd time for hydrophobic collapse is only Ϸ60 ns at 305 K, even faster than secondary structure formation. At higher temperatures, as the The intrinsic quantum yield of the donor (Qd) was measured by protein becomes increasingly compact by a stronger hydrophobic exciting at 288 nm in the protein labeled at the N terminus with naphtyl-alanine and nonlabeled at the C terminus and using force, we observe a slowdown of the dynamics of collapse. -
Expanding the Limits of the Second Genetic Code with Ribozymes
ARTICLE https://doi.org/10.1038/s41467-019-12916-w OPEN Expanding the limits of the second genetic code with ribozymes Joongoo Lee1,8, Kenneth E. Schwieter2,8, Andrew M. Watkins3, Do Soon Kim1, Hao Yu4, Kevin J. Schwarz2, Jongdoo Lim5, Jaime Coronado 5, Michelle Byrom6, Eric V. Anslyn 5, Andrew D. Ellington 6, Jeffrey S. Moore 2,7* & Michael C. Jewett 1* The site-specific incorporation of noncanonical monomers into polypeptides through genetic 1234567890():,; code reprogramming permits synthesis of bio-based products that extend beyond natural limits. To better enable such efforts, flexizymes (transfer RNA (tRNA) synthetase-like ribozymes that recognize synthetic leaving groups) have been used to expand the scope of chemical substrates for ribosome-directed polymerization. The development of design rules for flexizyme-catalyzed acylation should allow scalable and rational expansion of genetic code reprogramming. Here we report the systematic synthesis of 37 substrates based on 4 chemically diverse scaffolds (phenylalanine, benzoic acid, heteroaromatic, and aliphatic monomers) with different electronic and steric factors. Of these substrates, 32 were acylated onto tRNA and incorporated into peptides by in vitro translation. Based on the design rules derived from this expanded alphabet, we successfully predicted the acylation of 6 additional monomers that could uniquely be incorporated into peptides and direct N-terminal incor- poration of an aldehyde group for orthogonal bioconjugation reactions. 1 Department of Chemical and Biological Engineering, Northwestern University, Evanston 60208 IL, USA. 2 Department of Chemistry, University of Illinois at Urbana−Champaign, Urbana 61801 IL, USA. 3 Departments of Biochemistry and Physics, Stanford University, Stanford 94305 CA, USA. -
University of Szeged Faculty of Pharmacy Department of Medical Chemistry BOTTOM-UP DESIGN of FOLDAMERS for PROTEIN SURFACE RECOG
University of Szeged Faculty of Pharmacy Department of Medical Chemistry BOTTOM-UP DESIGN OF FOLDAMERS FOR PROTEIN SURFACE RECOGNITION Ph. D. Thesis Éva Karolina Bartus Supervisor: Prof. Dr. Tamás Martinek 2019 Table of content List of publications and lectures ............................................................................................................. iii Abbrevations ........................................................................................................................................... v 1. Introduction and aims ...................................................................................................................... 1 2. Literature background ..................................................................................................................... 3 2.1. Characterization of protein interfaces ..................................................................................... 3 2.1.1. Buried surface area and hot-spot residues ....................................................................... 3 2.1.2. Classification of protein–protein interactions .................................................................. 3 2.2. Targeting protein recognition surfaces .................................................................................... 5 2.2.1. Antibody mimetics .......................................................................................................... 5 2.2.2. Protein surface mimetics ................................................................................................ -
Self-Assembled Protein−Aromatic Foldamer Complexes with 2:3 And
Communication pubs.acs.org/JACS Self-Assembled Protein−Aromatic Foldamer Complexes with 2:3 and 2:2:1 Stoichiometries † ∥ † † † Michal Jewginski, , Thierry Granier,*, Beatricé Langlois d’Estaintot, Lucile Fischer, § † Cameron D. Mackereth, and Ivan Huc*, † CBMN (UMR5248), Univ. Bordeaux, CNRS, IPB, Institut Europeeń de Chimie et Biologie, 2 rue Robert Escarpit, 33600 Pessac, France ∥ Department of Organic and Pharmaceutical Technology, Faculty of Chemistry, Wrocław University of Science and Technology, 50-370 Wrocław, Poland § ARNA (U 1212), Univ. Bordeaux, INSERM, Institut Europeeń de Chimie et Biologie, 2 rue Robert Escarpit, 33600 Pessac, France *S Supporting Information Several groups have been investigating aromatic foldamers7 ABSTRACT: The promotion of protein dimerization as rigid helical or linear scaffolds that can be equipped with using the aggregation properties of a protein ligand was proteinogenic side chains to recognize protein,6,8 nucleic explored and shown to produce complexes with unusual acid,9,10 or saccharide11 surfaces. For example, 1 is a stable stoichiometries. Helical foldamer 2 was synthesized and helical oligoamide of 8-amino-2-quinolinecarboxylic acid.12 It bound to human carbonic anhydrase (HCA) using a was identified and characterized while studying interactions nanomolar active site ligand. Crystal structures show that between HCA and related foldamer sequences bearing varied the hydrophobicity of 2 and interactions of its side chains side chains protruding from the helix in position 4 of each 6 lead to the formation of an HCA2-23 complex in which quinoline unit. These foldamers possess an appended aryl- three helices of 2 are stacked, two of them being linked to sulfonamide HCA nanomolar ligand of the enzyme active site an HCA molecule. -
Translation and Folding of Single Proteins in Real Time PNAS PLUS
Translation and folding of single proteins in real time PNAS PLUS Florian Wrucka,1, Alexandros Katranidisb,2, Knud H. Nierhausc,3, Georg Büldtb,d, and Martin Hegnera,2 aCentre for Research on Adaptive Nanostructures and Nanodevices, School of Physics, Trinity College Dublin, Dublin 2, Ireland; bInstitute of Complex Systems ICS-5, Forschungszentrum Jülich, 52425 Jülich, Germany; cInstitute for Medical Physics and Biophysics, Charité–Universitätsmedizin Berlin, 10117 Berlin, Germany; and dLaboratory for Advanced Studies of Membrane Proteins, Moscow Institute of Physics and Technology, 141700 Dolgoprudny, Russia Edited by George H. Lorimer, University of Maryland, College Park, MD, and approved April 21, 2017 (received for review October 27, 2016) Protein biosynthesis is inherently coupled to cotranslational pro- ensemble methods. Optical tweezers have been used to observe tein folding. Folding of the nascent chain already occurs during stepping of motor proteins (19–23), DNA–protein complexes (24), synthesis and is mediated by spatial constraints imposed by the as well as unfolding and refolding of RNA molecules and proteins ribosomal exit tunnel as well as self-interactions. The polypeptide’s (25, 26). This powerful single-molecule method has provided in- vectorial emergence from the ribosomal tunnel establishes the possi- formation on (i) the translation machinery by reporting on the ble folding pathways leading to its native tertiary structure. How strength of interactions between the ribosome and mRNA (27), cotranslational protein folding and the rate of synthesis are linked (ii) its translocation along a short hairpin-forming mRNA mole- to a protein’s amino acid sequence is still not well defined. Here, we cule (28), as well as (iii) the release of an arrested nascent chain follow synthesis by individual ribosomes using dual-trap optical twee- (7). -
Cell-Penetrating Peptides: Design Strategies Beyond Primary Structure and Amphipathicity
molecules Review Cell-Penetrating Peptides: Design Strategies beyond Primary Structure and Amphipathicity Daniela Kalafatovic 1 and Ernest Giralt 1,2,* 1 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac, 10, 08028 Barcelona, Spain; [email protected] 2 Department of Inorganic and Organic Chemistry, University of Barcelona, Marti i Franques, 1-5, 08028 Barcelona, Spain * Correspondence: [email protected]; Tel.: +34-93-40-37125 Received: 26 September 2017; Accepted: 4 November 2017; Published: 8 November 2017 Abstract: Efficient intracellular drug delivery and target specificity are often hampered by the presence of biological barriers. Thus, compounds that efficiently cross cell membranes are the key to improving the therapeutic value and on-target specificity of non-permeable drugs. The discovery of cell-penetrating peptides (CPPs) and the early design approaches through mimicking the natural penetration domains used by viruses have led to greater efficiency of intracellular delivery. Following these nature-inspired examples, a number of rationally designed CPPs has been developed. In this review, a variety of CPP designs will be described, including linear and flexible, positively charged and often amphipathic CPPs, and more rigid versions comprising cyclic, stapled, or dimeric and/or multivalent, self-assembled peptides or peptido-mimetics. The application of distinct design strategies to known physico-chemical properties of CPPs offers the opportunity to improve their penetration efficiency and/or internalization kinetics. This led to increased design complexity of new CPPs that does not always result in greater CPP activity. Therefore, the transition of CPPs to a clinical setting remains a challenge also due to the concomitant involvement of various internalization routes and heterogeneity of cells used in the in vitro studies.