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Structure Elucidation of Helical Aromatic Foldamer DOI:10.1002/chem.201902942 Communication & Supramolecular Chemistry Structure Elucidation of Helical Aromatic Foldamer–Protein Complexes with Large Contact Surface Areas Post Sai Reddy,[a] BØatrice Langlois d’Estaintot,[a] Thierry Granier,[a] Cameron D. Mackereth,[b] LucileFischer,[a] and Ivan Huc*[a, c] quadruplex DNA[4] and some DNA-binding enzymes.[3f] Advan- Abstract: The development of large synthetic ligands tages of aromatic foldamersinclude their ease of synthesis, for could be useful to target the sizeable surfaceareas in- example through solid-phasemethodologies,[8] and the pre- volved in protein–protein interactions.Herein, we present dictability and stability of their folded conformations in both long helical aromatic oligoamide foldamersbearing pro- protic and aproticsolvents.[9] Because relativelylarge and well- 2 teinogenic side chainsthat cover up to 450 of the defined folded objects can be produced using aromatic amide human carbonic anhydrase II (HCA) surface. The foldamers backbones,[10] it maybeenvisaged to cover large surfaceareas are composed of aminoquinolinecarboxylic acids bearing of proteins and nucleic acids. For example, we recently report- proteinogenic side chains and of more flexible amino- ed protein binding using a9.2 kDa foldamer mimicking a methyl-pyridinecarboxylic acids that enhance helix hand- 16 base–pair DNA duplex.[3f] Nevertheless, designing objects edness dynamics. Crystal structures of HCA-foldamer com- that can recognize large surfaceareas of proteins is difficult: plexes were obtained with a9-and a14-mer both show- which side chains are to be selected and where should they ing extensive protein–foldamer hydrophobic contacts. In be located?Some of the published work concerned mimetics addition, foldamer–foldamer interactions seem to be prev- of a-helices,[2] B-DNA,[3f] or natural products.[5] Other ap- alent in the crystal packing, leading to the peculiar forma- proaches usescreening through directed evolution methods.[11] tion of an HCA superhelix woundaround arod of stacked It remains that no general approach exists for the ab initio foldamers. Solution studies confirmthe positioning of the designoflarge ligands for aprotein surface. Structuralinfor- foldamer at the protein surfaceaswell as adimerization mationabout aromatic foldamer–protein interactions would of the complexes. constitute afirm stepping-stonefor further design,but it can hardlybeobtained without having reasonable binding affinity in the first place. Aromatic foldamers[1] emerge as anew class of folded oligo- To overcomethis sort of deadlock, we endeavored to inves- mers that may be decorated with proteinogenic side chains to tigate foldamer–protein interfaces by confining foldamers at interactwith proteins[2,3] and nucleic acids,[4,5] andeventually the surface of aprotein.[12,13] For example, helical oligoamides serve as inhibitors of nucleic acid–proteinand protein–protein based on 8-aminoquinoline carboxylic acid Qweremaintained interactions. Amphipathic structures have also been shown to in close proximity to the surface of human carbonic anhydrase interactwith, or to insert themselves in,membranes.[6,7] Some (HCA) as amodel system by meansofananomolar HCA ligand possess antibiotic activity.[6] Both linear[2,5,6] and helical[3,4,7] fol- (Figure 1a). Interactions were first detected through induction damers have been developed and varied targets have been of foldamer helix handedness in response to contacts with identified, including hDM2 and B-cell lymphoma-2 (Bcl-2)regu- chiral elements at the protein surface, and subjected to struc- lator proteins,[2a,d,e] protein precursors of amyloids,[2c,3a–e] G- tural investigations both in the solid state and in solution.[13] Crystal structures provedtheir usefulness in that they revealed [a] Dr.P.S.Reddy,Dr. B. Langlois d’Estaintot, Dr.T.Granier,Dr. L. Fischer, multiple features that could not have been designed in the Prof. I. Huc CBMN (UMR5248), Univ.Bordeaux–CNRS–INP first place, including unusual foldamer–protein complex stoi- Institut EuropØen de ChimieetBiologie chiometries,[13c] andnow constitute startingpoints for iterative 2rue Escarpit,33600 Pessac (France) improvements. They also relate to crystal structuresofcom- [b] Dr.C.D.Mackereth plexesbetween proteins and other medium-sized aromatic li- ARNA (U1212), Univ.Bordeaux–INSERM–CNRS gands such as calixarenes,[14] suramine,[15] 1,3,6,8-pyrenetetra- Institut EuropØen de ChimieetBiologie [16] [17] 2rue Escarpit,33600 Pessac (France) sulfonicacid, or molecular tweezers. [c] Prof. I. Huc However,these earlier studies only concerned short (tetra- Department Pharmazie and Center for Integrated ProteinScience meric)foldamer segments and that could not cover very large Ludwig-Maximilians-Universität protein surfaceareas. To extend this approach to longer se- Butenandtstr.5–13, 81377 München (Germany) quences, we recentlydemonstrated that incorporating more E-mail:[email protected] flexible Punits (Figure1b) into Q sequences enhancehelix dy- Supporting information and the ORCID identification number(s) for the n author(s) of this articlecan be found under: namics and allow for protein-mediated handedness induction https://doi.org/10.1002/chem.201902942. in helical foldamerssuch as nonamer 3 and tetradecamer 5.[18] Chem. Eur.J.2019, 25,11042 –11047 11042 2019 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Communication Sequences 1, 2 and 4 were designed following the same principles as for 3 and 5:1)each has abenzenesulfonamide HCA ligand at its N-terminus;2)side chains of Qunits were se- lected with no other prejudicethan to generate some folda- mer surfacediversity,that is, with hydrophobic,polar neutral and charged groups;3)Punits aim at enhancing helix dynam- ics and were positioned on one face of the foldamer helix to allow for interactions between the other faceand the protein (Figure 1d,e);and 4) sequences contain no stereogenic center and initially fold as aracemic mixture of right- and left-handed helices, butthis equilibrium may be biasedbyfoldamer–pro- tein interactions. Oligomer solid-phase synthesis[8] and charac- terization are reported in the Supporting Information. Crude products typicallyhave 75–80 %purity.After reversed-phase HPLC purification, yields from initial Wang resin loadingsrange from 37 to 66 %. We used CD in the absorption region of quinoline chromo- phores at 360 nm to detect helix handedness induction in presence of HCA (Figure 1fand Figure S4, Supporting Informa- tion). At equilibrium, all five foldamersshowed aCDre- sponse[19] with slight variations dependingonsequence. As previously observed with shorter sequences,[13c] one foldamer (3)showedaninversion of CD sign, and thusofpreferredhelix handedness, suggesting the involvement of charged residues in the interaction:depending on pH, foldamer–protein interac- tions vary which may result in favoringthe P or the M helix handedness. Given these encouragingresults, crystallization of HCA–foldamer complexes was attempted for all compounds but 5,which gives the weakestCD. The structures of HCA-2 and HCA-4 could be solved and refinedat2.7 and 2.9 resolu- tion, respectively (Figure 2and Figure S5, Supporting Informa- tion). Despite the different lengths and side chain composition of 2 and 4,their complexes with HCA share multiple features:the HCA ligandsare well located in the HCA active site with the sulfonamide coordinated to ZnII ;canonical helical conforma- tions are retained, even when two consecutive flexible Punits Figure 1. a) Formula of functionalizedHCA ligands. b) Formula of amino acid are present as in the case of 4;the helicesare right-handed, in units color coded according to their side chain:hydrophobic (black), polar agreement with their positive CD bands;[20] the heliceslie neutral(green), cationic (blue), anionic (red). c) Foldamersequences 1–5. down on the protein with the helix axis parallel to the protein Five-pointed star representations of amphipathic hybrid Q/P foldamers 1– surfaceand cover asizeablearea, fulfilling our main objective. 3 (d) and 4–5 (e). Monomersare counted from the C-terminus. Numbersin red indicate the location of P units. f) CD spectra of HCA–foldamer com- Specifically,the foldamer–protein contact area (i.e. the inter- plexes after an 8day equilibration at two different pH conditionsinphos- face per component, protein or foldamer) at the exclusion of phate buffer at 258C. the HCA ligand was measured withPDBePISA[21] to be 308 and 448 2 in HCA-2 and HCA-4,respectively.Inboth complexes, the foldamer helix is located in awide and shallow grooveof In the following, we introduce additional sequences 1, 2 and 4 the protein exposingits Punits to HCA and its side chains to and report the structure elucidation of complexes HCA-2 and the solvent. Side chains thus do not contributetodirect inter- HCA-4.The structures again reveal an ensemble of hard-to-pre- actions with the protein to which the foldamer ligand is dict features, including extended shape complementarity be- bound, consistentwith the lack of effect of pH on helix hand- tween the cylinder-like helicesand ashallow groove at the edness induction. This arrangement appears to be drivenby protein surfaceaswell as multiple hydrophobic contacts with shape complementarity—the groovesurface is smooth and so the face of the foldamer that was initially not intended to in- is the face of the helix where Punits are located—and by hy- teract with the protein. The extensiveness of foldamer–protein drophobic effects. Indeed, the groove is lined with hydropho-
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