This work was supported by the U.S. Department of Energy, Office of Science, Basic Energy Sciences, under Award #DESC0012479. S.C.L. acknowledges support from the National Science Foundation Graduate Research Fellowship Program, and A.F.A. acknowledges support from Abu Dhabi National Oil Company (ADNOC).

CAUTION: Several chemicals used in this protocol are corrosive, flammable or toxic and should only be used under a chemical fume hood. Please use appropriate personal protective equipment and consult all relevant safety data sheets (SDS) before use.
1. Monomer synthesis
NOTE: Primary amines were synthesized according to published approaches.
<ol>
	<li>Synthesis of 4-(2-aminoethyl)-N-(allylcarbonyloxy)phenylamine (Npam)25,28
	<ol>
		<li>Add 5.0 g (36.7 mmol) of 4-(2-aminoethyl)aniline to 150 mL of 10% acetic acid (aqueous solution, v/v). 
		NOTE: The use of weak acid enables selective protection of the aromatic amine without affecting the aliphatic amine owing to the large difference in pKa value between the two groups.</li>
		<li>Prepare a solution of 4.9 g (40.4 mmol; 1.1 equiv.) allyl chloroformate in 150 mL of 1,4-dioxane.</li>
		<li>Combine the solutions in a 500 mL round bottom flask equipped with a magnetic stir bar and stir the reaction mixture at room temperature overnight.</li>
		<li>To work up the reaction, dilute with 500 mL of deionized (DI) water and wash with diethyl ether (Et2O, 300 mL &#215; 3). Discard the organic fractions.</li>
		<li>Adjust the aqueous phase to pH 14 by adding 2 M NaOH (aqueous solution), and extract with Et2O (150 mL &#215; 3).</li>
		<li>Combine the organic fractions and wash with DI water (150 mL &#215; 3).</li>
		<li>Dry over Na2SO4, then filter.</li>
		<li>Evaporate to dryness under reduced pressure.</li>
		<li>Confirm the identity of the isolated product, Npam, by nuclear magnetic resonance (NMR) spectroscopy. Expect the following results: 1H NMR (500 MHz, CdCl3) &#948;: 7.31 (d, J = 8.0 Hz, 2H, Ar), 7.14 (d, J = 8.5 Hz, 2H, Ar), 6.65 (s, 1H, -NH-), 6.04 &#8211; 5.89 (m, 1H, -CH=CH2), 5.36 (dq, J = 17.1, 1.6 Hz, 1H, -CH=CHH), 5.26 (dq, J = 10.5, 1.4 Hz, 1H, -CH=CHH), 4.66 (dt, J = 5.8, 1.5 Hz, 2H, -CH2-CH=CH2), 2.94 (t, J = 6.8 Hz, 2H, -CH2-NH2), 2.70 (t, J = 6.8 Hz, 2H, -CH2-Ar), 1.04 (s, 2H, -CH2-NH2). 13C NMR (125 MHz, CD3OD) &#948;: 154.85, 137.00, 134.98, 133.51, 129.36, 119.41, 116.92, 65.62, 59.89, 43.47, 38.72. 
		NOTE: The product is a light yellow solid and has an overall yield of 69%. Use the product without further purification.</li>
	</ol>
	</li>
	<li>Synthesis of 4-(1,3-dioxacyclopent-2-yl)benzonitrile29,30
	<ol>
		<li>Dissolve 25 g (0.19 mol) of 4-cyanobenzaldehyde in 200 mL of toluene.</li>
		<li>Add 42.2 mL (0.768 mmol; 4 equiv.) of ethylene glycol and 0.02 g (0.1 mmol; 0.05 mol%) of toluene-p-sulfonic acid to the reaction mixture.</li>
		<li>Stir and reflux overnight at 120 &#176;C using a Dean-Stark trap (i.e., azeotropic distillation) to remove water generated during the reaction.</li>
		<li>After the reaction is complete and cooled to room temperature, add 40 mL of 5% NaHCO3 (w/v) aqueous solution.</li>
		<li>Extract the organic layer, and wash with DI water three times.</li>
		<li>Dry over Na2SO4, then filter.</li>
		<li>Evaporate to dryness under reduced pressure.</li>
		<li>Confirm the identity of the isolated product, by NMR spectroscopy. Expect the following results: 1H NMR (400 MHz, CDCl3) &#948;: 7.67 (d, J = 8.0, 2H, Ar), 7.59 (d, J = 8.4, 2H, Ar), 5.84 (s, 1H, CH), 4.12 - 4.03 (AA&#697;BB&#697;, 4H, (CH2O)2). 13C NMR (100 MHz, CDCl3) &#948;: 143.20, 132.34, 127.30, 118.72, 113.02, 102.56, 65.57. 
		NOTE: The product is a white crystalline solid and has an overall yield of 86%. Use the product without further purification.</li>
	</ol>
	</li>
	<li>Synthesis of 4-(1,3-dioxacyclopent-2-yl)benzylamine (Npal)29
	<ol>
		<li>Prepare a solution of 10 g (0.057 mol) of 4-(1,3-dioxacyclopent-2-yl)benzonitrile in 100 mL of anhydrous Et2O.</li>
		<li>Carefully add 4.3 g (0.11 mol; 2 equiv.) of LiAlH4 to 100 mL of anhydrous Et2O in a round bottom flask at 0 &#176;C. Stir to create a well-mixed suspension and seal the system under an inert atmosphere using an argon-filled balloon. Carefully quench with ethanol any residual LiAlH4 on equipment used for weighing. 
		CAUTION: Lithium aluminum hydride (LiAlH4) is a mild pyrophore; handle under inert gas and protect from moisture.</li>
		<li>Add the 4-(1,3-dioxacyclopent-2-yl)benzonitrile solution slowly using an addition funnel or a syringe pump while maintaining the reaction mixture at a temperature of 0 &#176;C.</li>
		<li>Stir the reaction mixture for 4 h at 0 &#176;C, followed with 12 h at room temperature.</li>
		<li>After the reaction is complete and cooled to 0 &#176;C, slowly add 95% ethanol (30 mL). Further quench by adding 50% ethanol in water (v/v, 20 mL). A bubbler can be used to monitor the quenching process. 
		NOTE: Add additional anhydrous Et2O as needed to maintain an adequate stirring rate.</li>
		<li>Separate the ether supernatant and evaporate to dryness under reduced pressure.</li>
		<li>Filter the resultant oil through a 0.45 &#181;m syringe filter.</li>
		<li>Confirm the identity of the isolated product, NpaI, by NMR spectroscopy. Expect the following results: 1H NMR (400 MHz, CDCl3) &#948;: 7.44 (d, J = 8, 2H, Ar), 7.32 (d, J = 8, 2H, Ar), 5.80 (s, 1H, CH), 4.14 - 4.0 (AA&#697;BB&#697;, 4H, (CH2O)2), 3.87 (s, 2H, -CH2-NH2). 13C NMR (100 MHz, CDCl3) &#948;: 144.53, 136.53, 127.16, 126.77, 103.72, 65.39, 46.35. 
		NOTE: The product is a yellow oil and has an overall yield of 70%. Use the product without further purification.</li>
	</ol>
	</li>
	<li>Synthesis of 2-(2-ethoxyethoxy)ethyl tosylate29,31
	<ol>
		<li>Add 20 g (0.15 mol) of diethylene glycol monoethyl ether and 50 mL of tetrahydrofuran (THF) to a 250 mL round bottom flask with a magnetic stirrer.</li>
		<li>Cool to 0 &#176;C and seal the system under an inert atmosphere using an argon-filled balloon.</li>
		<li>Add 50 mL of 6 M aqueous NaOH (2 equiv.).</li>
		<li>Dissolve 54 g (0.28 mol; 2 equiv.) of tosyl chloride in 80 mL of THF and add the solution to the reaction mixture dropwise. Stir for 1 h at 0 &#176;C.</li>
		<li>Allow the reaction mixture to reach room temperature and stir for another hour.</li>
		<li>Extract the reaction mixture with Et2O (400 mL).</li>
		<li>Wash the organic layer with 1 M NaOH, then with DI water.</li>
		<li>Dry over Na2SO4, then filter.</li>
		<li>Evaporate to dryness under reduced pressure.</li>
		<li>Confirm the identity of the isolated product by NMR spectroscopy. Expect the following results: 1H NMR (400 MHz, CDCl3) &#948;: 7.78 (d, J = 8.0, 2H, -S-C=CH-CH), 7.33 (d, J = 8.5, 2H, -S-C=CH-CH), 4.15 (t, J = 5.0, 2H, -CH2-CH2-O-Ts), 3.68 (t, J = 5.0, 2H, CH2-CH2-O-Ts), 3.60-3.42 (m, 6H, O-CH2-CH2-O-CH2-CH3), 2.43 (s, 3H, C-CH3), 1.17 (t, J = 7.0, 3H, O-CH2-CH3). 13C NMR (100 MHz, CDCl3) &#948;: 144.79, 132.95, 130.26, 129.80, 127.90, 126.95, 70.75, 69.68, 69.29, 68.61, 66.57, 21.56, 15.11. 
		NOTE: The product is a colorless liquid and has an overall yield of 98%. Use the product without further purification.</li>
	</ol>
	</li>
	<li>Synthesis of 2-(2-ethoxyethoxy)ethyl azide29,31
	<ol>
		<li>Dissolve 40 g (0.14 mol) of 2-(2-ethoxyethoxy)ethyl tosylate in 250 mL of dimethylformamide (DMF) in a round bottom flask with a magnetic stirrer. Seal the system under an inert atmosphere using an argon-filled balloon.</li>
		<li>Add 32 g (0.49 mol; 3.5 equiv.) of NaN3 to the reaction mixture. 
		CAUTION: Do not use a metal spatula when weighing NaN3. NaN3 may react with lead and copper which results in the formation of highly explosive metal azides. It is acutely toxic and fatal if swallowed or in contact with skin.</li>
		<li>Heat the reaction mixture to 60 &#176;C and let it run for 36 h. Then cool to room temperature.</li>
		<li>Dilute with large amount of water (500 mL) and extract with Et2O (150 mL &#215; 3).</li>
		<li>Isolate the organic layer and perform water washes.</li>
		<li>Dry over Na2SO4, then filter.</li>
		<li>Evaporate to dryness under reduced pressure.</li>
		<li>Confirm the identity of the isolated product by NMR spectroscopy. Expect the following results: 1H NMR (400 MHz, CDCl3) &#948;: 3.64 (m, 4H, O-CH2-CH2-O), 3.58 (m, 2H, N3-CH2-CH2-O), 3.51 (q, J = 7.5, 2H, O-CH2-CH3), 3.38 (t, J = 5.0, 2H, N3-CH2-CH2-O), 1.19 (t, J = 7.5, 3H, O-CH2-CH3). 13C NMR (100 MHz, CDCl3) &#948;: 70.70, 69.97, 69.80, 66.63, 50.60, 15.08. 
		NOTE: The product is a yellow liquid and has an overall yield of 85%. Use the product without further purification.</li>
	</ol>
	</li>
	<li>Synthesis of 2-(2-ethoxyethoxy)ethylamine (Neee)29,31
	<ol>
		<li>Dissolve 20 g (0.13 mol) of 2-(2-ethoxyethoxy)ethyl azide in 160 mL of THF in a 500 mL round bottom flask with a magnetic stirrer.</li>
		<li>Add 40 g (0.15 mol, 1.1 equiv.) of triphenylphosphine and stir overnight at room temperature under argon.</li>
		<li>Quench the reaction mixture with water (220 mL) and allow it to stir for another day.</li>
		<li>Wash the resulting solution with toluene, followed by dichloromethane (DCM).</li>
		<li>Evaporate the aqueous layer under vacuum.</li>
		<li>Confirm the identity of the isolated product, Neee, by NMR spectroscopy. Expect the following results: 1H NMR (400 MHz, CDCl3) &#948;: 3.62-3.42 (m, 8H, NH2-CH2-CH2-O-CH2-CH2-O-CH2-CH3), 2.82 (m, 2H, NH2-CH2-CH2-O), 1.48 (s, 2H, NH2), 1.16 (t, J = 7.5, 3H, O-CH2-CH3). 13C NMR (100 MHz, CDCl3) &#948;: 73.14, 70.72, 69.64, 66.45, 41.35, 15.00. 
		NOTE: The product is a yellow liquid and has an overall yield of 58%. Use the product without further purification.</li>
	</ol>
	</li>
</ol>
2. Solid-phase submonomer synthesis of oligo(peptoids)
NOTE: The submonomer approach to solid-phase synthesis (SPS) was employed as it enables the production of sequence-specific oligomers with high coupling efficiency. An automated peptide synthesizer was adapted to rapidly generate oligo(peptoids). Settings may require modification for different instrumentation.
<ol>
	<li>Preparation
	<ol>
		<li>Weigh 0.125 g of Fmoc-Photolabile SS resin (0.8 mmol/g typical loading, 0.1 mmol scale, 100-200 mesh, 1% DVB) and add to a fritted automated synthesizer reaction vessel. Insert the vessel into the microwave portion of the synthesizer.</li>
		<li>Fill the main solvent bottle with DMF and the deprotection bottle with 20% 4-methylpiperidine in DMF (v/v). Empty waste.</li>
		<li>Prepare 1 M solutions of bromoacetic acid and N,N&#39;-diisopropylcarbodiimide (DIC) in DMF with total volumes of 1.5 mL &#215; (number of residues in sequence) + 5 mL. The extra 5 mL ensures that no air enters the machine. Add 0.47 mL of acetic anhydride to DMF to make a 5 mL capping solution. 
		CAUTION: DIC can cause serious eye damage, skin irritation and sensitization, and respiratory irritation and sensitization.</li>
		<li>Prepare 0.5 M solutions of each primary amine (Npam, Npal, Neee, and Nma (2-methoxyethylamine)) in N-methyl-2-pyrrolidone (NMP) used for the displacement step. Total volumes of the primary amine solutions should be 2.5 mL &#215; (number of residues of the appropriate primary amine) + 2.5 mL.</li>
		<li>Add all solutions to the automated synthesizer manifold.</li>
	</ol>
	</li>
	<li>Synthesis 
	NOTE: Perform using an automated peptide synthesizer.
	<ol>
		<li>Swell the resin at room temperature for 5 min with 10 mL of DMF. Drain the reaction vessel.</li>
		<li>Cleave the Fmoc group with 3 mL of the 20% 4-methylpiperidine solution for 30 s at 75 &#176;C and 90 s at 90 &#176;C. Drain the vessel. Repeat. Wash with DMF (2 mL &#215; 2).</li>
		<li>Add to the vessel 1.5 mL of the bromoacetic acid solution and 1.5 mL of the DIC solution. Heat the reaction at 75 &#176;C for 4.5 min to perform the bromoacetylation reaction. Wash the resin (5 mL of DMF &#215; 3).</li>
		<li>Perform the displacement reaction by addition of 2.5 mL primary amine monomer solution to the reaction vessel. Heat at 75 &#176;C for 4.5 min. Wash resin (5 mL of DMF &#215; 3).</li>
		<li>Repeat steps 2.2.3. and 2.2.4. while sequentially substituting the primary amine monomer used in step 2.2.4. to grow oligo(peptoid) chain in a sequence-specific manner.</li>
		<li>After the final displacement step, cap the sequence by adding 2.5 mL of the acetic anhydride solution and 2 mL of the DIC solution. Heat at 50 &#176;C for 2 min. Wash the resin (5 mL of DMF &#215; 6).</li>
		<li>Transfer the resin to a fritted glass reaction vessel equipped with a 3-way stopcock. The glass reaction vessel should be previously siliconized to prevent beads from adhering to the walls. Silanize the walls by filling the vessel with a 5% dichlorodimethylsilane in dichloroethane (DCE) (v/v) solution to the top and letting it sit for 30 min. Drain the vessel and wash with DCE and methanol. Dry glass vessel before use.</li>
		<li>Wash the resin with DCM (5 mL &#215; 3), bubbling with N2 through one arm and pulling vacuum with another.</li>
		<li>Dry and store resin and attached oligo(peptoid) until deprotection and cleavage.</li>
	</ol>
	</li>
	<li>Alloc-amine deprotection and cleavage from resin
	<ol>
		<li>If the resin has been stored for more than a day, reswell the resin by bubbling with 5 mL of DMF for 10 min. Then drain the vessel and add a small magnetic stir bar.</li>
		<li>Add 3 mL of dry DCM to the glass peptide vessel.</li>
		<li>Weigh 0.1 equivalents of tetrakis(triphenylphosphine)palladium(0) and 25 equivalents of phenylsilane per Alloc-group. Use a clamp to position the reaction vessel at an angle above a stir plate such that the resin undergoes gentle agitation while remaining suspended in the solvent. To prevent the DCM from evaporating, cap the reaction vessel.</li>
		<li>After 1 h, filter off the solution and wash the resin with DCM (3 &#215; 5 mL).</li>
		<li>Repeat steps 2.3.2. and 2.3.3.</li>
		<li>Rinse the resin sequentially with methanol and DCM twice.</li>
		<li>Transfer the resin and magnetic stir bar to a 20 mL vial.</li>
		<li>Submerge the resin in DMF, stir, and cleave under irradiation for 36 h at approximately 25 mW.cm-2 with 405 nm. A small portion of resin can be cleaved and characterized in ESI-MS before this step to ensure complete Alloc deprotection of amine. If any Alloc groups remain, repeat steps 2.3.2 and 2.3.3.</li>
		<li>Separate liberated oligo(peptoid) from resin via a syringe filter. Remove solvent under vacuum.</li>
	</ol>
	</li>
	<li>Purification and characterization of oligo(peptoids)
	<ol>
		<li>Reconstitute the peptoids in a 50/50 mixture of water/acetonitrile.</li>
		<li>Purify with reverse-phase preparative HPLC (C18). Combine purified fractions, freeze, and lyophilize to yield off-white powder. The powder can be stored for further use.</li>
		<li>Analyze with ESI-MS after purification.</li>
		<li>Perform MALDI mass spectrometry in reflectron positive ion mode. Mix 2 &#956;L of a solution of the sample (1 mM) with 6 &#956;L of a mixture of 10 mg of matrix [2-(4-hydroxyphenylazo)benzoic acid (HABA)] in 200 &#956;L of acetonitrile. Spot on a MALDI sample plate and allow to air dry.</li>
		<li>For purity, perform analytical HPLC of purified oligo(peptoids).</li>
	</ol>
	</li>
</ol>
3. Sequence-selective ladder self-assembly
<ol>
	<li>Self-assembly through dissociation/extraction/annealing
	<ol>
		<li>Prepare 10 mM stock solutions of each oligo(peptoid) sequence used for self-assembly and a 10 mM stock solution of scandium triflate (Sc(OTf)3) in anhydrous acetonitrile.</li>
		<li>To a 3 mL vial equipped with a magnetic stir bar, add 20 &#181;L of each peptoid stock solution. Add 1.5 eq of Sc(OTf)3 per potential imine bond from the stock solution. Add enough water and acetonitrile to form a 200 &#181;L 2% (v/v) of water/acetonitrile solution total.</li>
		<li>Stir gently at 70 &#176;C for 2 h for acetal-deprotection of the aldehyde and dissociation of all strands.</li>
		<li>Charge the vial with 200 &#181;L of chloroform and 2 mL of water. Shake gently.</li>
		<li>Allow the mixture to stand (at least 15 min) and, upon complete phase separation, extract the organic layer with a microliter syringe.</li>
		<li>Stir in a new vial at 70 &#176;C for oligomer annealing, typically 6 h. Ladder hybridization can also be performed at room temperature but over a longer period.</li>
	</ol>
	</li>
	<li>Characterization of self-assembled species
	<ol>
		<li>Perform MALDI-TOF mass spectrometry on the reaction mixture solutions after steps 3.1.3., 3.1.5., and 3.1.6. to monitor the reaction. If hybridization is incomplete, add 1.5 eq of Sc(OTf)3 per potential imine bond from the stock solution and repeat steps 3.1.3-3.1.6. until complete.</li>
		<li>Dry the sample under a steady stream of nitrogen and reconstitute in 1 mL of 2% nitric acid (aqueous solution, v/v). Dilute 4 &#215; 106-fold with HPLC water. Determine post-extraction scandium concentration with inductively coupled plasma mass spectrometry (ICP-MS).</li>
	</ol>
	</li>
</ol>

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Independent and constitutionally coupled reversible processes.</a> Journal of the American Chemical Society. 127 (15), 5528-5539 (2005).</li><li>Sh&#363;, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Scandium+triflate+in+organic+synthesis.">Scandium triflate in organic synthesis.</a> European Journal of Organic Chemistry. 1999 (1), 15-27 (1999).</li><li>Wei, T., Furgal, J. C., Scott, T. 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V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Peptoid+nanosheets+exhibit+a+new+secondary-structure+motif.">Peptoid nanosheets exhibit a new secondary-structure motif.</a> Nature. 526 (7573), 415-420 (2015).</li><li>Edison, J. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Conformations+of+peptoids+in+nanosheets+result+from+the+interplay+of+backbone+energetics+and+intermolecular+interactions.">Conformations of peptoids in nanosheets result from the interplay of backbone energetics and intermolecular interactions.</a> Proceedings of the National Academy of Sciences. 115 (22), 5647-5651 (2018).</li><li>Kobayashi, S., Sugiura, M., Kitagawa, H., Lam, W. W. 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The authors have nothing to disclose.

The technique herein describes the dynamic covalent assembly of information-bearing peptoid oligomers, where information is encoded in the sequence of their pendant groups. The use of an Alloc-protected amine monomer in conjunction with an ethylene acetal-protected aldehyde monomer allows for orthogonal deprotection, enabling Alloc deprotection on bead and acetal deprotection in situ during the self-assembly reaction, thereby ensuring the synthesized sequences do not prematurely react prior to oligomer purification and characterization. Importantly, the solid-phase synthesis is performed using a photolabile resin to enable oligomer cleavage from the bead under UV or violet light irradiation, precluding premature deprotection of the acid-labile, ethylene acetal-based protecting group. Several alternative deprotection schemes might be considered. For example, we initially employed dual acid-labile protecting groups (Boc-amine and ethylene acetal-aldehyde) with the intention of in situ deprotection by a strong acid followed with neutralization to allow the self-assembly reaction to proceed; however, this approach resulted in the immediate generation of precipitate upon addition of base. Alternatively, protection of the amine with a photolabile protecting group, 2-(2-nitrophenyl)propoxycarbonyl (NPPOC), was envisioned as the aldehyde could be selectively deprotected upon treatment with trifluoroacetic acid (TFA) prior to purification. Unfortunately, in situ photolysis of the protecting group with UV light did not afford quantitative deprotection, even in the presence of photosensitizers and after extended irradiation periods25. Trimethylsilylethoxycarbonyl (i.e., Teoc) can be employed as an amine protecting group and is subject to cleavage upon treatment with rare-earth metal triflates; however, quantitative Teoc deprotection requires much higher rare-earth metal triflate loadings than that necessary for ethylene acetal deprotection. For this protocol, Teoc-amines may be used, but the Lewis acid concentration must be adjusted accordingly as sub-quantitative amine deprotection could prove problematic for larger self-assembled structures. Aliphatic functional groups were briefly considered, but deprotection of aliphatic aldehydes requires harsh conditions that truncate peptoid sequences32,33.
Incorporation of Neee and Nma as inert spacer residues serve to improve oligomer solubility and enable facile mass-tagging of the precursor oligomers to afford ready identification of the generated species by mass spectroscopy. Furthermore, given the &#39;&#931;-strand&#39; conformation of peptoids where adjacent backbone segments adopt opposing rotational states to form a linear, twist-free oligomer34,35, sequences incorporating alternating dynamic covalent and inert spacer residues facilitates a structure in which reactive pendant groups are oriented in the same direction. Given the versatility of the submonomer method, a large and diverse library of primary amines can be employed to further modify the peptoid oligomers but may require adjustments to the protocol to maintain high coupling efficiency.
Whereas oligo(peptoids) can be synthesized manually in a glass reaction vessel19, automation of the process decreases the time for each residue addition from several hours to half an hour. Additionally, automation diminishes the quantity of monomer and wash solvent waste, particularly desirable when using primary amine monomers that are not commercially available. Although Alloc cleavage from the protected-amine residues is an efficient reaction, palladium oxidation can result in incomplete deprotection. Consequently, it is suggested to test cleave a portion of the resin and characterize the extent of deprotection with ESI-MS. For test cleavages, 30 min under 405 nm irradiation releases sufficient peptoid for mass spectrometry. Partial deprotection can be limited with the use of anaerobic conditions or repeating the deprotection reaction.
Whereas this article focuses on Sc(OTf)3 as a multi-role reagent, other rare-earth metal triflates, such as ytterbium triflate, have been shown to successfully mediate the information-directed assembly of molecular ladders. Notably, Sc(OTf)3 is the most Lewis acidic of the rare-earth metal triflates; thus, owing to the reduced catalytic ability afforded by other rare-earth metal triflates24,36, greater equivalents may be required to effect complete ethylene acetal deprotection and strand dissociation. The number of equivalents required can be determined with MALDI mass spectrometry by observing point at which strands completely dissociate. Dissociation is critical in the self-assembly process and is analogous to the melting of nucleic acid strands at raised temperature. The subsequent extraction of catalyst enables the formation and disruption of dynamic covalent pairings propelling the assembly of sequence-specific duplexes. This gradual annealing of the oligomeric strands circumvents the kinetic trapping (which, for molecular ladders, can yield out-of-registry species or incorrectly pair sequences) experienced by other methods.
Chloroform is an excellent solvent as phase separation in the chloroform/acetonitrile/water ternary system used here promotes the partial extraction of Lewis acid without resulting in precipitation of self-assembled structures37. Additionally, chloroform is one of the few solvents that promotes imine formation while maintaining molecular ladder solubility. Trace amounts of out-of-registry and incorrectly paired duplexes can often be observed owing to the dynamic nature of the system. Although this system is largely unaffected by small variation in rare-earth metal triflate concentrations upon extraction, on occasion, insufficient catalyst extraction generates a significant portion of incomplete hybridization and non-specific oligomer couplings. In this case, it is generally preferable to first re-dissociate with a further 1.5 equivalents of catalyst and then extract a second time rather than to re-extract immediately, as the complete dissociation of single strands is vital to the process. To simultaneously assemble several unique information-encoded molecular ladders, it may be necessary to increase the concentration of the rare-earth metal triflate stock solution used to maintain equivalents and total reaction volume.
While these self-assemblies are primarily characterized by mass spectrometry, other techniques including fluorescence resonance energy transfer (FRET) are possible. Limitations include quantity of material necessary, affordability of monomers, and signal-to-noise ratio. Techniques requiring solvents, such as 1H NMR, can additionally suffer from insolubility of self-assembled structures. Furthermore, rare-earth metal triflate concentrations post-extraction can be determined through such methods as ICP-MS or 19F NMR with an internal standard.
As progress towards improved control over macro- and supra-molecular nanostructures and materials proceeds, the challenge of designing and fabricating regular, but modifiable, assemblies arises. The protocol described in this report provides a pathway to achieve such nanostructures through sequence-selective assemblies via dynamic covalent interactions.

Progress in self-assembly, the process by which small sub-units generate larger architectures through thermodynamically-driven pathways, has afforded improved control over macro- and supra-molecular nanostructures typically by exploiting intermolecular interactions such as &#960;-stacking and hydrogen bonding1,2,3,4. In particular, nucleic acids (i.e., polynucleotides) have emerged as remarkably versatile nano-construction media as the high information density provided by Watson-Crick base pairing permits the assembly of complex, sequence-selective structures4,5. Whereas the inherently low strength of these transient intermolecular bonds enables sub-unit rearrangement and error-correction, the resultant structures are often susceptible to thermal and mechanical degradation6. In contrast, dynamic covalent interactions7,8,9, a class of covalent bond-forming reactions that are reversible or rearrangeable under mild conditions and have recently been employed to yield intricate macromolecules such as ladders10,11,12,13, cages14,15,16, and stacks17, offer increased bond strengths and robust structures. Unfortunately, the capacity for rearrangement and error-checking is diminished by the relatively low rearrangement rates of these covalent species, curtailing their capacity for self-assembly into desired products18. To address this kinetic trapping, catalysts or harsh reaction conditions are often utilized in conjunction with simple building blocks. Here, we report a process which circumvents kinetic trapping to enable the self-assembly of molecular ladders from sequence-specific oligomers where the hybridization is directed by the information encoded in the oligomer residue sequences.
Given their synthetic accessibility, poly(N-substituted glycine)s (i.e., peptoids) are employed as the oligomeric precursors from which the molecular ladders are assembled19. Peptoids are structural isomers of peptides in which pendant groups are affixed to the backbone-borne nitrogen instead of being coupled with the &#945;-carbon20. Using solid-phase synthesis, exact placement of dynamic covalent pendant groups along the peptoid chain is readily achieved, allowing for the design of precursor oligomers that can assemble into complex supramolecular structures21.
The dynamic covalent rearrangement of imine connectivity is employed in this procedure as the imine-generating condensation reaction provides a convenient means to characterize the self-assembly by mass spectrometry as each bond formed results in a mass reduction of 18 g/mol22. Furthermore, the equilibrium between the amine and aldehyde reactants and imine product can be varied by altering the acid concentration. Specifically, rare-earth metal triflates are used to affect equilibrium, and additionally deprotect ethylene acetal-protected aldehydes23,24,25. To note, scandium triflate is already commonly used in the field of dynamic covalent self-assembly, including its recent success in aiding the synthesis of covalent organic frameworks (COFs) at room temperature26,27. Additionally, the contrasting solubility of the oligo(peptoid) sequences and the rare-earth metal triflate enables equilibrium control through liquid-liquid extraction. The process reported utilizes this control to circumvent the kinetic barriers preventing information-directed self-assembly.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>1,4-Dioxane</td>
			<td>Fisher Scientific</td>
			<td>D1114</td>
			<td>Certified ACS</td>
		</tr>
		<tr>
			<td>2-(4-Hydroxyphenylazo)benzoic acid (HABA)</td>
			<td>Millipore-Sigma</td>
			<td>54793</td>
			<td>Matrix substance for MALDI-MS; &#8805;99.5%</td>
		</tr>
		<tr>
			<td>4-(2-Aminoethyl)aniline</td>
			<td>Ontario Chemicals</td>
			<td>A2076</td>
			<td>98%</td>
		</tr>
		<tr>
			<td>4-Cyanobenzaldehyde</td>
			<td>Oakwood Chemical</td>
			<td>049317</td>
			<td>99%</td>
		</tr>
		<tr>
			<td>4-Methylpiperidine</td>
			<td>TCI America</td>
			<td>P0445</td>
			<td>&#8805;98.0%</td>
		</tr>
		<tr>
			<td>4-Toluenesulfonyl chloride</td>
			<td>Oakwood Chemical</td>
			<td>BR1703</td>
			<td>99%</td>
		</tr>
		<tr>
			<td>50 mL High Performance Centrifuge Tubes</td>
			<td>VWR International</td>
			<td>21008-240</td>
			<td>Centrifuge Tubes used for automated synthesizer</td>
		</tr>
		<tr>
			<td>Acetic acid</td>
			<td>Fisher Scientific</td>
			<td>A38-212</td>
			<td>Glacial</td>
		</tr>
		<tr>
			<td>Acetic anhydride</td>
			<td>Fisher Scientific</td>
			<td>A10</td>
			<td>Certified ACS</td>
		</tr>
		<tr>
			<td>Acetonitrile</td>
			<td>Millipore-Sigma</td>
			<td>34851</td>
			<td>For HPLC; Gradient grade; &#8805;99.9%</td>
		</tr>
		<tr>
			<td>All-plastic Norm-Ject syringes</td>
			<td>Thermo Fisher Scientific</td>
			<td>S7510-10</td>
			<td>Luer-Slip Syringe</td>
		</tr>
		<tr>
			<td>Allyl chloroformate</td>
			<td>Acros Organics</td>
			<td>221741000</td>
			<td>97%</td>
		</tr>
		<tr>
			<td>Bromoacetic acid</td>
			<td>Alfa Aesar</td>
			<td>A14403</td>
			<td>&#8805;98.0%</td>
		</tr>
		<tr>
			<td>Chloroform</td>
			<td>Millipore-Sigma</td>
			<td>288306</td>
			<td>Anhydrous; &#8805;99%; Contains 0.5-1.0% ethanol as stabilizer</td>
		</tr>
		<tr>
			<td>Chloroform-d</td>
			<td>Acros Organics</td>
			<td>AC320690075</td>
			<td>For NMR; 99.8 atom % D; Packaged in 0.75 ml ampoules</td>
		</tr>
		<tr>
			<td>Dichlorodimethylsilane</td>
			<td>Acros Organics</td>
			<td>1133100</td>
			<td>&#8805;99.0%</td>
		</tr>
		<tr>
			<td>Dichloroethane</td>
			<td>Fisher Scientific</td>
			<td>E175</td>
			<td>Certified ACS</td>
		</tr>
		<tr>
			<td>Dichloromethane</td>
			<td>Fisher Scientific</td>
			<td>D37-4</td>
			<td>Stabalized; Certified ACS</td>
		</tr>
		<tr>
			<td>Diethyl ether</td>
			<td>Acros Organics</td>
			<td>615080010</td>
			<td>Anhydrous; ACS reagent</td>
		</tr>
		<tr>
			<td>Diethylene glycol monoethyl ether</td>
			<td>TCI America</td>
			<td>E0048</td>
			<td>&#8805;99.0%</td>
		</tr>
		<tr>
			<td>Ethanol</td>
			<td>Decon Labs</td>
			<td>2701</td>
			<td>200 Proof; Anhydrous</td>
		</tr>
		<tr>
			<td>Ethylene glycol</td>
			<td>Fisher Scientific</td>
			<td>E178</td>
			<td>Certified</td>
		</tr>
		<tr>
			<td>Fmoc-Photolabile SS resin</td>
			<td>CreoSalus</td>
			<td>SA50785</td>
			<td>100-200 mesh; 1% DVB</td>
		</tr>
		<tr>
			<td>Glass Peptide Vessel</td>
			<td>Chemglass</td>
			<td>CG-1866-02</td>
			<td>Solid Phase, T-Bore PTFE Stpk, Vacuum, Medium Frit, GL 25 Thread</td>
		</tr>
		<tr>
			<td>LC-6AD HPLC pumps</td>
			<td>Shimadzu Corporation</td>
			<td></td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>LED 405nm</td>
			<td>ThorLabs</td>
			<td>M405L2-C1</td>
			<td>405 nm LED used for photocleavage of peptoid</td>
		</tr>
		<tr>
			<td>LED Driver</td>
			<td>ThorLabs</td>
			<td>LEDD1B</td>
			<td>Driver for LED light used in photocleavage of peptoid</td>
		</tr>
		<tr>
			<td>Liberty Blue Automated Peptide Synthesizer</td>
			<td>CEM Corporation</td>
			<td></td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>Lithium aluminum hydride</td>
			<td>Millipore-Sigma</td>
			<td>199877</td>
			<td>Powder; Reagent grade; 95%; CAUTION: Mildly pyrophoric, handle under inert gas and protect from moisture</td>
		</tr>
		<tr>
			<td>Luna C18 analytical RP-HPLC column</td>
			<td>Phenomenex</td>
			<td>00G-4252-E0</td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>Luna C18 prepatory RP-HPLC column</td>
			<td>Phenomenex</td>
			<td>00G-4253-P0-AX</td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>Methanol</td>
			<td>Fisher Scientific</td>
			<td>A412</td>
			<td>Certified ACS</td>
		</tr>
		<tr>
			<td>Microliter Syringe</td>
			<td>Hamilton Company</td>
			<td>80700</td>
			<td>Cemented Needle (N)</td>
		</tr>
		<tr>
			<td>N,N&#39;-Diisopropylcarbodiimide (DIC)</td>
			<td>Oakwood Chemical</td>
			<td>M02889</td>
			<td>&#8805;99.0%; CAUTION: DIC is hazardous to eyes, skin, via respiratory inhalation, and may cause skin sensitization</td>
		</tr>
		<tr>
			<td>N,N-Dimethylformamide</td>
			<td>Millipore-Sigma</td>
			<td>319937</td>
			<td>ACS reagent; &#8805;99.8%</td>
		</tr>
		<tr>
			<td>Nitric acid</td>
			<td>Fisher Scientific</td>
			<td>A200-212</td>
			<td>Certified ACS Plus</td>
		</tr>
		<tr>
			<td>Nitrogen gas</td>
			<td>Cryogenic Gases</td>
			<td></td>
			<td>Contents under pressure, may explode if heated</td>
		</tr>
		<tr>
			<td>Phenylsilane</td>
			<td>Oakwood Chemical</td>
			<td>S13600</td>
			<td>97%</td>
		</tr>
		<tr>
			<td>Prominence SPD-10A UV/vis Detector</td>
			<td>Shimadzu Corporation</td>
			<td></td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>p-Toluenesulfonic acid monohydrate</td>
			<td>Millipore-Sigma</td>
			<td>402885</td>
			<td>ACS reagent; &#8805;98.5%</td>
		</tr>
		<tr>
			<td>Scandium(III) triflate</td>
			<td>Oakwood Chemical</td>
			<td>009343</td>
			<td>99%</td>
		</tr>
		<tr>
			<td>Single-use Needle</td>
			<td>Exel International</td>
			<td>26420</td>
			<td>18G x 1 1/2&#8243;</td>
		</tr>
		<tr>
			<td>Sodium azide</td>
			<td>Oakwood Chemical</td>
			<td>094448</td>
			<td>99%; CAUTION: NaN3 may react with lead and copper which results in the formation of highly explosive metal azides. It is acutely toxic and fatal if swallowed or in contact with skin.</td>
		</tr>
		<tr>
			<td>Sodium bicarbonate</td>
			<td>Fisher Scientific</td>
			<td>S233</td>
			<td>Powder; Certified ACS</td>
		</tr>
		<tr>
			<td>Sodium hydroxide</td>
			<td>Fisher Scientific</td>
			<td>S318-100</td>
			<td>Pellets; Certified ACS</td>
		</tr>
		<tr>
			<td>Sodium sulfate</td>
			<td>Fisher Scientific</td>
			<td>S421-500</td>
			<td>Anhydrous; Granular; Certified ACS</td>
		</tr>
		<tr>
			<td>Syringe Filter 0.45 &#181;m</td>
			<td>VWR International</td>
			<td>28145-497</td>
			<td>PTFE, Syringe Filters with Polypropylene Housing</td>
		</tr>
		<tr>
			<td>Tetrahydrofuran</td>
			<td>Fisher Scientific</td>
			<td>T397</td>
			<td>Certified</td>
		</tr>
		<tr>
			<td>Tetrakis(triphenylphosphine) palladium(0)</td>
			<td>Oakwood Chemical</td>
			<td>034279</td>
			<td>98%</td>
		</tr>
		<tr>
			<td>Toluene</td>
			<td>Fisher Scientific</td>
			<td>T324</td>
			<td>Certified ACS</td>
		</tr>
		<tr>
			<td>Triphenylphosphine</td>
			<td>Oakwood Chemical</td>
			<td>037818</td>
			<td>99%</td>
		</tr>
	</tbody>
</table>

synthesis of information-bearing peptoids and their sequence-directed dynamic covalent self-assembly

This protocol presents the use of Lewis acidic multi-role reagents to circumvent kinetic trapping observed during the self-assembly of information-encoded oligomeric strands mediated by paired dynamic covalent interactions in a manner mimicking the thermal cycling commonly employed for the self-assembly of complementary nucleic acid sequences. Primary amine monomers bearing aldehyde and amine pendant moieties are functionalized with orthogonal protecting groups for use as dynamic covalent reactant pairs. Using a modified automated peptide synthesizer, the primary amine monomers are encoded into oligo(peptoid) strands through solid-phase submonomer synthesis. Upon purification by high-performance liquid chromatography (HPLC) and characterization by electrospray ionization mass spectrometry (ESI-MS), sequence-specific oligomers are subjected to high-loading of a Lewis acidic rare-earth metal triflate which both deprotects the aldehyde moieties and affects the reactant pair equilibrium such that strands completely dissociate. Subsequently, a fraction of the Lewis acid is extracted, enabling annealing of complementary sequence-specific strands to form information-encoded molecular ladders characterized by matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS). The simple procedure outlined in this report circumvents kinetic traps commonly experienced in the field of dynamic covalent assembly and serves as a platform for the future design of robust, complex architectures.

To demonstrate the ability of information-encoded peptoids to undergo sequence-selective dynamic covalent self-assembly into molecular ladders, a representative strand, H2N-[Npam-Neee-Npal-Neee]2-Npam-Nma, was synthesized and hybridized with its complementary peptoid sequence. The monomers Npam and Npal (characterized by 1H NMR (500 MHz), Figure 1) were employed as dynamic covalent reactant pairs with Neee aiding solubility of final self-assembled products. Additionally, the incorporation of the commercially available Nma monomer enables a mass differentiation between the two complementary sequences. Upon completion of the solid-phase submonomer synthesis, the Alloc-group was removed with Pd(PPh3)4. Prior to and after deprotection, portions of the resin were cleaved under 405 nm light and characterized by ESI-MS (Figure 2). The sequence was purified by prep HPLC, lyophilized to achieve an off-white powder, and purity confirmed with analytical HPLC (Figure 3). The oligo(peptoid) was subsequently hybridized with its complementary sequence, H2N-[Npal-Neee-Nam-Neee]2-Npal, to afford an in-registry ladder confirmed by MALDI-MS (Figure 4).
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/60442/60442fig1a.jpg" /> 
Figure 1: Monomer synthetic schemes and 1H-NMR spectra. (A) Monomer synthetic schemes with reagents and conditions: (i) allyl chloroformate, 10% aqueous acetic acid, 1,4-dioxane, room temperature, overnight; (ii) ethylene glycol, toluene-p-sulfonic acid, toluene, reflux, overnight; (iii) LiAlH4, anhydrous Et2O, 0 &#176;C for 4 h then room temperature for 12 h; (iv) tosyl chloride, THF, 0 &#176;C; (v) NaN3, DMF, 60 &#176;C, 36 h; (vi) triphenylphosphine, THF, overnight. (B) Monomer 1H-NMR spectra (500 MHz, CDCl3): (i) 4-(2-aminoethyl)-N-(allylcarbonyloxy)phenylamine (Npam); (ii) 4-(1,3-dioxacyclopent-2-yl)benzylamine (Npal); (iii) 2-(2-ethoxyethoxy)ethylamine (Neee). <a href="https://www.jove.com/files/ftp_upload/60442/60442fig1alarge.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/60442/60442fig2.jpg" /> 
Figure 2: Synthesis and deprotection of a sequence-specific oligo(peptoid). (A) Structures of H2N-[Npam-Neee-Npal-Neee]2-Npam-Nma before and after Alloc-protecting group removal with accompanying (B) ESI mass spectrum. <a href="https://www.jove.com/files/ftp_upload/60442/60442fig2alarge.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/60442/60442fig3a.jpg" /> 
Figure 3: Purification and characterization of an information-encoded peptoid. (A) HPLC chromatogram of the strand purification by preparative HPLC with a linear gradient of acetonitrile (MeCN) and water: (1) 30% MeCN, 0.1-2.1 min; (2) 30-95% MeCN, 2.1-16.1 min; (3) 95% MeCN, 16.1-23.1 min; (4) 95% MeCN, 23.1-26.1 min. Peaks i and ii correspond to low molecular weight reaction by-products, primarily DIC-urea, and oligomeric species including the desired product, respectively. (B) Analytical HPLC chromatogram and (C) ESI mass spectrum of H2N-[Npam-Neee-Npal-Neee]2-Npam-Nma after lyophilization. <a href="https://www.jove.com/files/ftp_upload/60442/60442fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/60442/60442fig4.jpg" /> 
Figure 4: Self-assembly of H2N-[Npam-Neee-Npal-Neee]2-Npam-Nma and its complementary sequence, H2N-[Npal-Neee-Nam-Neee]2-Npal. (A) Structures of the two sequences and the resulting sequence-driven assembly. (B) MALDI mass spectrum of the molecular ladder following annealing at room temperature overnight. Masses: expected [M+Na]+ = 3306.7, found 3306.0; expected [M-1 imine+Na]+ = 3324.7, found 3323.9; expected [M-2 imine +Na]+ = 3342.7, found 3342.8; expected [M-2 imine +CH3OH+H]+ = 3352.8, found 3352.0. <a href="https://www.jove.com/files/ftp_upload/60442/60442fig4large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

Watch this Scientific Journal Video about Synthesis of Information-bearing Peptoids and their Sequence-directed Dynamic Covalent Self-assembly at JoVE.com

Synthesis of Information-bearing Peptoids and their Sequence-directed Dynamic Covalent Self-assembly

A protocol is presented for the synthesis of information-encoded peptoid oligomers and for the sequence-directed self-assembly of these peptoids into molecular ladders using amines and aldehydes as dynamic covalent reactant pairs and Lewis acidic rare-earth metal triflates as multi-role reagents.

This protocol presents the use of Lewis acidic multi-role reagents to circumvent kinetic trapping observed during the self-assembly of information-encoded ...

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7.1K Views.  University of Michigan. A protocol is presented for the synthesis of information-encoded peptoid oligomers and for the sequence-directed self-assembly of these peptoids into molecular ladders using amines and aldehydes as dynamic covalent reactant pairs and Lewis acidic rare-earth metal triflates as multi-role reagents.

Video: Synthesis of Information-bearing Peptoids and their Sequence-directed Dynamic Covalent Self-assembly

Origami Inspired Self-assembly of Patterned and Reconfigurable Particles

There are numerous techniques such as photolithography, electron-beam lithography and soft-lithography that can be used to precisely pattern two dimensional (2D) structures. These technologies are mature, offer high precision and many of them can be implemented in a high-throughput manner. We leverage the advantages of planar lithography and combine them with self-folding methods1-20 wherein physical forces derived from surface tension or residual stress, are used to curve or fold planar structures into three dimensional (3D) structures. In doing so, we make it possible to mass produce precisely patterned static and reconfigurable particles that are challenging to synthesize.
In this paper, we detail visualized experimental protocols to create patterned particles, notably, (a) permanently bonded, hollow, polyhedra that self-assemble and self-seal due to the minimization of surface energy of liquefied hinges21-23 and (b) grippers that self-fold due to residual stress powered hinges24,25. The specific protocol described can be used to create particles with overall sizes ranging from the micrometer to the centimeter length scales. Further, arbitrary patterns can be defined on the surfaces of the particles of importance in colloidal science, electronics, optics and medicine. More generally, the concept of self-assembling mechanically rigid particles with self-sealing hinges is applicable, with some process modifications, to the creation of particles at even smaller, 100 nm length scales22, 26 and with a range of materials including metals21, semiconductors9 and polymers27. With respect to residual stress powered actuation of reconfigurable grasping devices, our specific protocol utilizes chromium hinges of relevance to devices with sizes ranging from 100 &mu;m to 2.5 mm. However, more generally, the concept of such tether-free residual stress powered actuation can be used with alternate high-stress materials such as heteroepitaxially deposited semiconductor films5,7 to possibly create even smaller nanoscale grasping devices.

We describe experimental details of the synthesis of patterned and reconfigurable particles from two dimensional (2D) precursors. This methodology can be used to create particles in a variety of shapes including polyhedra and grasping devices at length scales ranging from the micro to centimeter scale.

There are numerous techniques such as photolithography, electron-beam lithography and soft-lithography that can be used to precisely pattern two ...

Formation of Ordered Biomolecular Structures by the Self-assembly of Short Peptides

In nature, complex functional structures are formed by the self-assembly of biomolecules under mild conditions. Understanding the forces that control self-assembly and mimicking this process in vitro will bring about major advances in the areas of materials science and nanotechnology. Among the available biological building blocks, peptides have several advantages as they present substantial diversity, their synthesis in large scale is straightforward, and they can easily be modified with biological and chemical entities1,2. Several classes of designed peptides such as cyclic peptides, amphiphile peptides and peptide-conjugates self-assemble into ordered structures in solution. Homoaromatic dipeptides, are a class of short self-assembled peptides that contain all the molecular information needed to form ordered structures such as nanotubes, spheres and fibrils3-8. A large variety of these peptides is commercially available.
This paper presents a procedure that leads to the formation of ordered structures by the self-assembly of homoaromatic peptides. The protocol requires only commercial reagents and basic laboratory equipment. In addition, the paper describes some of the methods available for the characterization of peptide-based assemblies. These methods include electron and atomic force microscopy and Fourier-Transform Infrared Spectroscopy (FT-IR). Moreover, the manuscript demonstrates the blending of peptides (coassembly) and the formation of a &#34;beads on a string&#34;-like structure by this process.9 The protocols presented here can be adapted to other classes of peptides or biological building blocks and can potentially lead to the discovery of new peptide-based structures and to better control of their assembly.

This paper describes the formation of highly ordered peptide-based structures by the spontaneous process of self-assembly. The method utilizes commercially available peptides and common lab equipment. This technique can be applied to a large variety of peptides and may lead to the discovery of new peptide-based assemblies.

In nature, complex functional structures are formed by the self-assembly of biomolecules under mild conditions. Understanding the forces that control ...

Self-assembly of Complex Two-dimensional Shapes from Single-stranded DNA Tiles

Current methods in DNA nano-architecture have successfully engineered a variety of 2D and 3D structures using principles of self-assembly. In this article, we describe detailed protocols on how to fabricate sophisticated 2D shapes through the self-assembly of uniquely addressable single-stranded DNA tiles which act as molecular pixels on a molecular canvas. Each single-stranded tile (SST) is a 42-nucleotide DNA strand composed of four concatenated modular domains which bind to four neighbors during self-assembly. The molecular canvas is a rectangle structure self-assembled from SSTs. A prescribed complex 2D shape is formed by selecting the constituent molecular pixels (SSTs) from a 310-pixel molecular canvas and then subjecting the corresponding strands to one-pot annealing. Due to the modular nature of the SST approach we demonstrate the scalability, versatility and robustness of this method. Compared with alternative methods, the SST method enables a wider selection of information polymers and sequences through the use of de novo designed and synthesized short DNA strands.

DNA tiling is an effective approach to make programmable nanostructures. We describe the protocols to construct complex two-dimensional shapes by the self-assembly of single-stranded DNA tiles.

Current methods in DNA nano-architecture have successfully engineered a variety of 2D and 3D structures using principles of self-assembly. In this ...

Synthesis of Non-uniformly Pr-doped SrTiO3 Ceramics and Their Thermoelectric Properties

We demonstrate a novel synthesis strategy for the preparation of Pr-doped SrTiO3 ceramics via a combination of solid state reaction and spark plasma sintering techniques. Polycrystalline ceramics possessing a unique morphology can be achieved by optimizing the process parameters, particularly spark plasma sintering heating rate. The phase and morphology of the synthesized ceramics were investigated in detail using X-ray diffraction, scanning electron microcopy and energy-dispersive X-ray spectroscopy. It was observed that the grains of these bulk Pr-doped SrTiO3 ceramics were enhanced with Pr-rich grain boundaries. Electronic and thermal transport properties were also investigated as a function of temperature and doping concentration. Such a microstructure was found to give rise to improved thermoelectric properties. Specifically, it resulted in a significant improvement in carrier mobility and the thermoelectric power factor. Simultaneously, it also led to a marked reduction in the thermal conductivity. As a result, a significant improvement (> 30%) in the thermoelectric figure of merit was achieved for the whole temperature range over all previously reported maximum values for SrTiO3-based ceramics. This synthesis demonstrates the steps for the preparation of bulk polycrystalline ceramics of non-uniformly Pr-doped SrTiO3.

Synthesis of Non-uniformly Pr-doped SrTiO3 Ceramics and Their Thermoelectric Properties

A protocol for the synthesis and processing of polycrystalline SrTiO3 ceramics doped non-uniformly with Pr is presented along with the investigation of their thermoelectric properties.

We demonstrate a novel synthesis strategy for the preparation of Pr-doped SrTiO3 ceramics via a combination of solid state reaction and spark plasma ...

Microfluidic-based Synthesis of Covalent Organic Frameworks (COFs): A Tool for Continuous Production of COF Fibers and Direct Printing on a Surface

Covalent Organic Frameworks (COFs) are a class of porous covalent materials which are frequently synthesized as unprocessable crystalline powders. The first COF was reported in 2005 with much effort centered on the establishment of new synthetic routes for its preparation. To date, most available synthetic methods for COF synthesis are based on bulk mixing under solvothermal conditions. Therefore, there is increasing interest in developing systematic protocols for COF synthesis that provide for fine control over reaction conditions and improve COF processability on surfaces, which is essential for their use in practical applications. Herein, we present a novel microfluidic-based method for COF synthesis where the reaction between two constituent building blocks, 1,3,5-benzenetricarbaldehyde (BTCA) and 1,3,5-tris(4-aminophenyl)benzene (TAPB), takes place under controlled diffusion conditions and at room temperature. Using such an approach yields sponge-like, crystalline fibers of a COF material, hereafter called MF-COF. The mechanical properties of MF-COF and the dynamic nature of the approach allow the continuous production of MF-COF fibers and their direct printing onto surfaces. The general method opens new potential applications requiring advanced printing of 2D or 3D COF structures on flexible or rigid surfaces.

Microfluidic-based Synthesis of Covalent Organic Frameworks COFs: A Tool for Continuous Production of COF Fibers and Direct Printing on a Surface

We present a novel microfluidic-based method for synthesis of covalent organic frameworks (COFs). We demonstrate how this approach can be used to produce continuous COF fibers, and also 2D or 3D COF structures on surfaces.

Covalent Organic Frameworks (COFs) are a class of porous covalent materials which are frequently synthesized as unprocessable crystalline powders. The ...

Grafting Multiwalled Carbon Nanotubes with Polystyrene to Enable Self-Assembly and Anisotropic Patchiness

We demonstrate a straightforward protocol to graft pristine multiwalled carbon nanotubes (MWCNTs) with polystyrene (PS) chains at the sidewalls through a free-radical polymerization strategy to enable the modulation of the nanotube surface properties and produce supramolecular self-assembly of the nanostructures. First, a selective hydroxylation of the pristine nanotubes through a biphasic catalytically mediated oxidation reaction creates superficially distributed reactive sites at the sidewalls. The latter reactive sites are subsequently modified with methacrylic moieties using a silylated methacrylic precursor to create polymerizable sites. Those polymerizable groups can address further polymerization of styrene to produce a hybrid nanomaterial containing PS chains grafted to the nanotube sidewalls. The polymer-graft content, amount of silylated methacrylic moieties introduced and hydroxylation modification of the nanotubes are identified and quantified by Thermogravimetric Analysis (TGA). The presence of reactive functional groups hydroxyl and silylated methacrylate are confirmed by Fourier Transform Infrared Spectroscopy (FT-IR). Polystyrene-grafted carbon nanotube solutions in tetrahydrofuran (THF) provide wall-to-wall collinearly self-assembled nanotubes when cast samples are analyzed by transmission electron microscopy (TEM). Those self-assemblies are not obtained when suitable blanks are similarly cast from analogous solutions containing non-grafted counterparts. Therefore, this method enables the modification of the nanotube anisotropic patchiness at the sidewalls which results into spontaneous auto-organization at the nanoscale.

A procedure for the synthesis of polystyrene-grafted multiwalled carbon nanotubes using successive chemical modification steps to selectively introduce the polymer chains to the sidewalls and their self-assembly via anisotropic patchiness is presented.

We demonstrate a straightforward protocol to graft pristine multiwalled carbon nanotubes (MWCNTs) with polystyrene (PS) chains at the sidewalls through a ...

Liquid-cell Transmission Electron Microscopy for Tracking Self-assembly of Nanoparticles

Drying a nanoparticle dispersion is a versatile way to create self-assembled structures of nanoparticles, but the mechanism of this process is not fully understood. We have traced the trajectories of individual nanoparticles using liquid-cell transmission electron microscopy (TEM) to investigate the mechanism of the assembly process. Herein, we present the protocols used for liquid-cell TEM studies of the self-assembly mechanism. First, we introduce the detailed synthetic protocols used to produce uniformly sized platinum and lead selenide nanoparticles. Next, we present the microfabrication processes used to produce liquid cells with silicon nitride or silicon windows and then describe the loading and imaging procedures of the liquid-cell TEM technique. Several notes are included to provide helpful tips for the entire process, including how to manage the fragile cell windows. The individual motions of nanoparticles tracked by liquid-cell TEM revealed that changes in the solvent boundaries caused by evaporation affected the self-assembly process of nanoparticles. The solvent boundaries drove nanoparticles to primarily form amorphous aggregates, followed by flattening of the aggregates to produce a 2-dimensional (2D) self-assembled structure. These behaviors are also observed for different nanoparticle types and different liquid-cell compositions.

Here we introduce experimental protocols for the real-time observation of a self-assembly process using liquid-cell transmission electron microscopy.

Drying a nanoparticle dispersion is a versatile way to create self-assembled structures of nanoparticles, but the mechanism of this process is not fully ...

Synthesis and Mass Spectrometry Analysis of Oligo-peptoids

Peptoids are sequence-controlled peptide-mimicking oligomers consisting of N-alkylated glycine units. Among many potential applications, peptoids have been thought of as a type of molecular information storage. Mass spectrometry analysis has been considered the method of choice for sequencing peptoids. Peptoids can be synthesized via solid phase chemistry using a repeating two-step reaction cycle. Here we present a method to manually synthesize oligo-peptoids and to analyze the sequence of the peptoids using tandem mass spectrometry (MS/MS) techniques. The sample peptoid is a nonamer consisting of alternating N-(2-methyloxyethyl)glycine (Nme) and N-(2-phenylethyl)glycine (Npe), as well as an N-(2-aminoethyl)glycine (Nae) at the N-terminus. The sequence formula of the peptoid is Ac-Nae-(Npe-Nme)4-NH2, where Ac is the acetyl group. The synthesis takes place in a commercially available solid-phase reaction vessel. The rink amide resin is used as the solid support to yield the peptoid with an amide group at the C-terminus. The resulting peptoid product is subjected to sequence analysis using a triple-quadrupole mass spectrometer coupled to an electrospray ionization source. The MS/MS measurement produces a spectrum of fragment ions resulting from the dissociation of charged peptoid. The fragment ions are sorted out based on the values of their mass-to-charge ratio (m/z). The m/z values of the fragment ions are compared against the nominal masses of theoretically predicted fragment ions, according to the scheme of peptoid fragmentation. The analysis generates a fragmentation pattern of the charged peptoid. The fragmentation pattern is correlated to the monomer sequence of the neutral peptoid. In this regard, MS analysis reads out the sequence information of the peptoids.

A protocol is described for the manual synthesis of oligo-peptoids followed by sequence analysis by mass spectrometry.

Peptoids are sequence-controlled peptide-mimicking oligomers consisting of N-alkylated glycine units. Among many potential applications, peptoids have ...

Fabrication of Spherical and Worm-shaped Micellar Nanocrystals by Combining Electrospray, Self-assembly, and Solvent-based Structure Control

Micellar nanocrystals (micelles with encapsulated nanocrystals) have become an emerging major class of nanobiomaterials. We describe a method of fabricating micellar nanocrystals based on combining top-down electrospray, bottom-up self-assembly, and solvent-based structure control. This method involves first using electrospray to generate uniform ultrafine liquid droplets, each of which functions as a micro-reactor in which self-assembly reaction occurs forming micellar nanocrystals, with the structures (micelle shape and nanocrystal encapsulation) controlled by the organic solvent used. This method is largely continuous and produces high quality micellar nanocrystal products with an inexpensive structure control approach. By using a water-miscible organic solvent tetrahydrofuran (THF), worm-shaped micellar nanocrystals can be produced due to solvent-induced/facilitated micelle fusion. Compared with the common spherical micellar nanocrystals, worm-shaped micellar nanocrystals can offer minimized non-specific cellular uptake, thus enhancing biological targeting. By co-encapsulating multiple nanocrystals into each micelle, multifunctional or synergistic effects can be achieved. Current limitations of this fabrication method, which will be part of the future work, primarily include imperfect encapsulation in the micellar nanocrystal product and the incompletely continuous nature of the process.

The present work describes a method to fabricate micellar nanocrystals, an emerging major class of nanobiomaterials. This method combines top-down electrospray, bottom-up self-assembly, and solvent-based structure control. The fabrication method is largely continuous, can produce high quality products, and possesses an inexpensive means of structure control.

Micellar nanocrystals (micelles with encapsulated nanocrystals) have become an emerging major class of nanobiomaterials. We describe a method of ...

Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the aziridine ring. The utility of bicyclic aziridinium ions, specifically 1-azoniabicyclo[3.1.0]hexane and 1-azoniabicyclo[4.1.0]heptane tosylate highlighted in the aziridine ring openings by the nucleophile with the release of the ring strain to yield the corresponding ring-expanded azaheterocycles such as pyrrolidine, piperidine and azepane with diverse substituents on the ring in regio- and stereospecific manner. Herein, we report a simple and convenient method for the preparation of the stable 1-azabicyclo[4.1.0]heptane tosylate followed by selective ring opening via a nucleophilic attack either at the bridge or at the bridgehead carbon to yield piperidine and azepane rings, respectively. This synthetic strategy allowed us to prepare biologically active natural products containing piperidine and azepane motif including sedamine, allosedamine, fagomine and balanol in highly efficient manner.

Bicyclic aziridinium ions such as 1-azoniabicyclo[4.1.0]heptane tosylate were generated from 2-[4-tolenesulfonyloxybutyl]aziridine, which was utilized for the preparation of substituted piperidines and azepanes via regio- and stereospecific ring-expansion with various nucleophiles. This highly efficient protocol allowed us to prepare diverse azaheterocycles including natural products such as fagomine, febrifugine analogue and balanol.

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the ...