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John interactions and intermolecular energetics backbone of from interplay result the nanosheets in peptoids of Conformations www.pnas.org/cgi/doi/10.1073/pnas.1800397115 states the but untwisted, and linear remain to rotational them alternating allowing nanosheet states, display the also model of refined this model back- within Peptoid Here bones data. refined experimental current model. a all with produce previous consistent is to the that data in these with seen use not states we but principle, rotational general solid-state specific this the with recoupling consistent are dipolar (4) NMR time elements PITHIRDS-constant backbone adjacent with of Atomicdistancesprobed are virtue rotationalstates. polymers by adoptingtwist-opposed constituent untwisted, their and predict because linear (9) flat simulations are previous nanosheets that Our (5–8). nanostructures sequences extended flat peptoid into self-assemble of principle design variety general this A obey that type. charge by segregated and charge being opposite having and latter the hydrophobic with of monomers, sequence hydrophilic alternating an pep- in nanosheet-forming arranged assem- are of nanoscale toids residues bilayer The within nanosheets. called polymers blies peptoid molec- of and to conformations order classical local (4) ular the use data of experimental we understanding our and Here extend methods self-assembly. simulation super- quantum what upon or and molecule makes, adopts, single it it a one which structure of suggest conformations necessarily the solu- not in does of accessible inspection conformations and of ensemble tion, the (3). reflect sim- freedom not in complex of do structures in self-assembled degrees seen in molecules and many of is conformations (2) with the Thus, interplay proteins, freedom as of This such degrees (1). molecules, few molecule with molecules the ple of shape the T cis-amide structure secondary peptoid intra- of combination a from data results interactions. experimental intermolecular structure and its available that all show pep- with and the consistent of model nanosheet molecular within a toid made provide results interactions combi- Our the a nanosheet. and the by energetics determined backbone is of specific con- nation experiment the backbone but in from linear, peptoid observed being built of combination their sets with nanostructures consistent several flat are that formations of show space data, We design experimental peptoids. the quan- with explore and polymer together dynamics we simulations, of molecular mechanical Using virtue cancel. tum by and whose untwisted, oppose states rotational twists and alternating adopting linear individual elements backbone be because sequence- exist can nonnatural Nanosheets from polymers polymers. made interplay molecules peptoid this nanosheets by specific study flat assemblies we extended Here in in conformations. made their the influence interactions At can order. the a large-scale of time, 2018) 8, its constituents same January molecular influence review for the assembly (received 2018 by supramolecular 13, April adopted approved and conformations NY, Brook, The Stony University, Brook Stony Dill, A. 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Benjamin , 1073/pnas.1800397115/-/DCSupplemental aohe-omn eti sdfie yterttoa states a rotational of the state residues, rotational by successive two the defined of Thus, is water. peptoid to nanosheet-forming exposed charged and that are nanosheet so the residues of directions, interior opposing the form in peptoid residues chains aromatic successive side that their suggest display and 9) residues (5–7) (7, Experiments nanosheets 13). of (12, simulations diagram Ramachandran the as defining values, two ψ of one around (ω fluctuates usually ter ulse nieMy1,2018. 14, May online Published at online information supporting contains article This 1 the under Published Submission. Direct PNAS a is article This interest. of conflict no declare data; authors analyzed The A.K.P. and paper. A.I.H., the wrote B.C.H., S.W. G.L.B., and and R.K.S., R.K.S., J.R.E. J.R.E., J.R.E., research; research; designed S.W. performed and G.L.B. R.N.Z., R.K.S., J.R.E., contributions: Author that indicate (9) nanosheets of simulations dynamics Molecular dihedral the by the specified by defined and is backbone peptoids the angles of of structure state secondary rotational or local The Polymers Peptoid Linear packed Designing densely order. combi- a of degree in the high results that a flat, displaying experiment and structure into with nanosheets consistent formation extended nation their with consistent for structures molecular are different prerequisite that show can a We polymers structures. extended linear, peptoid which made within be space configuration the ing in peptoids individual between of interactions the properties nanosheets. by the selected of are but inspection strands, from obvious experiment not with strain. consistent are backbone conformations molecular some the incurring nanosheet is, of the That expense within the interactions at and optimized packing are the that such are owo orsodnesol eadesd mi:[email protected]. Email: addressed. be should correspondence whom To ieradutitdadealssrnst akdneyinto is densely nanosheets. pack structure bilayer to strands extended This enables (pseudo)chirality. and untwisted opposed and linear by of displayed states structure tional exhibits backbone secondary the which the a in polymers report peptoid Ramachandran biomimetic we the of Here region single plot. a sampling residues with as such proteins, α of structures secondary observed Commonly Significance b nwa olw edsrb u td.W ei yassess- by begin We study. our describe we follows what In eateto hmclEgneig&MtrasSine nvriyof University Science, Materials & Engineering Chemical of Department ayi oecniuu aho n pnwa sknown is what span and fashion continuous more a in vary ≈ hlcsand -helices and 180) cis φ, a,1 ofrainadatraigrsde ipa rota- display residues alternating and conformation ψ and , NSlicense. PNAS β cis PNAS set,aebitfo a from built are -sheets, d ω lo .Hochbaum I. Allon , (ω Fg 1 (Fig. | ≈ a 9 2018 29, May ofrain 1,1) while 11), (10, conformations 0) {φ A . i , and ψ i , | ω .A nppie,telat- the peptides, in As B). i o.115 vol. } www.pnas.org/lookup/suppl/doi:10. b and md backbone trans-amide , {φ | o 22 no. i +1 , ψ i | +1 5647–5651 , ω φ i trans +1 and }.

BIOPHYSICS AND COMPUTATIONAL BIOLOGY A B

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Fig. 1. The trans-peptoid backbone is disposed toward linearity, but the form observed in nanosheets is cis.(A and B) Schematic of a trans- (A) and cis- (B) peptoid backbone showing the dihedral angles of two adjacent residues, i and i + 1. (C and D) Linearity (actual length divided by maximum possible length) L of an eight-residue trans-polysarcosine (C) and cis-polysarcosine (D) as a function of backbone dihedral angles φi and ψi. Here the dihedral angles of successive residues satisfy (φi+1, ψi+1) = (−ψi, −φi) (opposed twist). The red contours shown indicate regions that lie within 4 kcal/mol of the minima in the free-energy landscape of a disarcosine peptoid in vacuum. E and F are the same as C and D, but under the design rule (φi+1, ψi+1) = (−φi, −ψi) (opposed chirality). G and H show candidate structures used to build models of nanosheets for MD simulations, using design rules 1 and 2, respectively. I and J are Ramachandran probability plots obtained from MD simulations of all-trans and all-cis polymers in nanosheets.

successive residues spontaneously adopt an alternating pattern in (Fig. 1A) and so produces linear, untwisted strands (Fig. 1C). ◦ ◦ which (on average) (φi , ψi ) = (75 , −145 ) and (ψi+1, φi+1) = The same is not true of cis residues (Fig. 1B), for which only (135◦, −75◦). These values are related by a reflection about a small subset of the Ramachandran diagram leads to linear the negative-sloping diagonal of the Ramachandran plot (12, strands (Fig. 1D). Moreover, the regions of the Ramachandran 13); i.e., they are twist-opposed states that satisfy (φi+1, ψi+1) = plot favored energetically by the isolated peptoid backbone (−ψi , −φi ). Those simulations were initiated with residues in the (enclosed by the red contours in Fig. 1 C and D) are consis- trans state (ωi = ωi+1 ≈ 180), a conformation that disposes the tent with linear strands for the trans backbone but not for cis.A peptoid backbone toward linearity. For trans residues, any choice similar conclusion is drawn by considering, in Fig. 1F, the linear- of angle pairs of this nature causes the bonds N-Cα of residue ity of cis strands under a second design rule, in which adjacent i and Cα-CO of residue i + 1 to point in the same direction rotational states possess opposing chirality. Such states satisfy

5648 | www.pnas.org/cgi/doi/10.1073/pnas.1800397115 Edison et al. Downloaded by guest on September 25, 2021 Downloaded by guest on September 25, 2021 htthe that 1C). than (Fig. corresponds less much ener- plot but the Ramachandran strands, of linear the section to small of A region 14). favored (10, alter- acids getically with amino polypeptides L of and context D the nating design in This earlier plot. studied Ramachandran was the rule of diagonals two the in tions a n elctsi aon.W loso h ieve foeo h tad ohglgttebcbn tutr cmaewt i.1 Fig. with (compare structure backbone the highlight to strands al. the et of Edison one of view side the show also M06-2X/6-31G We the maroon). at in simulations replicates (K initio and (I Raytracer. tan ab Vision sphere. of using unit Persistence optimized a and monolayers on (15) glycine (VMD) plotted dynamics groups molecular phenyl visual the using configurations of distribution orientation the show In name. residue ( by nanosheets. colored atoms with charged nanosheet, negatively a from taken peptoid single 2. Fig. (φ K G E C AB I hs emtia nlsso h eti akoeindicates backbone peptoid the of analysis geometrical a Thus, i +1 , ψ The i trans +1 cis E 2.6 nm ( = ) and aohe (B, nanosheet ofrainahee iert ftebackbone the of linearity achieves conformation −φ F N o iwo h akoeaoso h o ae fnnset.(G nanosheets. of layer top the of atoms backbone the of view Top ) (-abxehl lcn eiusaesoni lc,and black, in shown are residues glycine -(2-carboxyethyl) i , −ψ i ) D, n r eae yscesv reflec- successive by related are and F, 9.35 nm H, and J, trans smr ree n oedneypce hnthe than packed densely more and ordered more is L) ne h rvosrule previous the under J F D L H ∗ ergtdit lcsb hretp Fg 2 (Fig. being type and charge charge by opposite blocks having of and into latter residues segregated hydrophobic the The alternately with residues 2). hydrophilic, are these (Fig. that peptoids predict environments nanosheet-forming simulations different our predomi- because experience are 15, and nanosheets in 8, in preferred and backbones sense nantly peptoid geometric experiments NMR that a solid-state in indicate new natural However, sense. is energetic that an way a in N A–J ee fter ne Dproi onaycniin ui elsonin shown cell (unit conditions boundary periodic 2D under theory of level (-hnlty)gyiersde r hw ntn ( tan. in shown are residues glycine -(2-phenylethyl) and oiieycharged positively cis and J ieveso h aohes l edrnsaedn rmMD from done are renderings All nanosheets. the of views Side ) 4.TeNRsuyfcsdo akoersde 7, residues backbone on focused study NMR The (4). H hnlrnsblnigt h o ae fnanosheets. of layer top the to belonging rings Phenyl ) 3.1 nm and o iwo lentn sarcosine, alternating of view Top L) trans PNAS N (-mnehl lcn eiusaesoni red, in shown are residues glycine -(2-aminoethyl) aohe (A, nanosheet | a 9 2018 29, May 8.2 nm C, | E, o.115 vol. G, and I, C and A N G | and K -(2-phenylethyl) o iw of views Top D) and o 22 no. .(A ). H .A a As B). and ). | Insets 5649 A B)

BIOPHYSICS AND COMPUTATIONAL BIOLOGY result, the electrostatic energy of the nanosheet is minimized Table 1. Experimental and simulation measurements when polymers adopt a “brick” configuration in which certain Measurement Value, A˚ Experimental Simulation Simulation residues, including residues 7 and 8, sit adjacent to residues in technique trans, A˚ cis, A˚ neighboring peptoids, while residue 15 sits adjacent to gaps in the structure (7, 9). NMR shows that residues 7 and 8 in peptoid Thickness of 30 AFM 26 31 backbones adopt the cis conformation with high probability and nanosheets that residue 15 is equally likely to be cis or trans, thereby indicat- Spacing 4.5 XRD 4.8 4.45 ing that these residues indeed experience different environments between strands in the nanosheets. The high cis propensity of residues 7 and 8, Lamellar spacing 28 XRD 23 30 however, is not consistent with the existing nanosheet model (9) between sheets and therefore warrants another modeling study. AFM, atomic force microscopy; XRD, X-ray diffraction. Nanosheet Design To perform this study we built two versions of the nanosheet, of order than the trans nanosheet. The backbones of the cis using either all-trans or all-cis backbones; details can be found nanosheet are linear, with the exception of a kink at the middle in SI Appendix, 1. Simulation setup. We used a staged scheme to residue (which sits adjacent to gaps in the brick pattern), and the obtain ordered nanosheets. First, we built peptoid polymers into phenyl rings in the interior of the sheet exhibit both positional brick nanosheet structures (7, 9), solvated them, and simulated and orientational order. As a result, the interpeptoid interactions them using Nanoscale Molecular Dynamics (NAMD) (16) in the made in the cis nanosheet are more favorable than those made in NPT (fixed number of particles N, pressure P, temperature T) the trans nanosheet, and the sum of the intra- and interpeptoid ensemble (simulations done using the constant-tension ensem- energies per molecule of the cis nanosheet is lower, by about 9 ble yielded similar results). Upon initial relaxation some parts kBT (5.3 kcal/mol) per residue, than that of the trans nanosheet. of these nanosheets became disordered, but a majority of back- In other words, the interactions made by peptoids within the cis bones adopted the ordered forms shown in Fig. 1 G and H. These nanosheet compensate for the penalty incurred to keep the cis are Σ (“sigma”) strands (9) whose residues alternate between the backbone in a linear configuration. rotational states shown in Fig. 1 I and J, respectively [the cis-Σ Our quantum mechanical calculations are consistent with strand’s rotational states are similar to those of the “ω-strand” structures obtained from molecular-dynamics simulations. Model motif found in crystalline peptoid trimers (17)]. Second, we built chains of alternating sarcosine, N-(2-phenylethyl) glycine res- structures in which all polymers were initialized with these rota- idues optimized at the M06-2X/6-31G∗ level of theory (18) under tional states (SI Appendix, Fig. S1); these nanosheets remained 2D periodic boundary conditions with a unit cell of two four- stable and ordered upon 200 ns of simulation. residue chains yield all-trans and all-cis strands consistent with In Fig. 2 we show that the cis nanosheet is more densely packed the Σ motifs shown in Fig. 2 K and L (compare with Fig. 1 G and ('31% more chains per unit area) and has a higher degree H). The aromatic rings in the phenyl layer of the all-cis system

A BC

DE

Fig. 3. The cis nanosheet’s properties agree with experimental measurements. (A and B) X-ray diffraction scattering spectra [I∗(q) vs. q] of the simulated cis and trans nanosheets computed using the Debye scattering equation (for details see SI Appendix, 4. Simulation of X-ray Scattering). (C) Height distribution of the simulated cis and trans nanosheets plotted together with Gaussian curves of mean µ and SD σ that best fit the data. (D) Free-energy profiles for rotation of the amide bond (ω) in residues 6/7 and 14/15 in a randomly chosen chain in an all-cis nanosheet. (E) Snapshot from our biased simulations (using softened dihedral angle potential terms) that reveal an increased propensity to form trans amides at the hinge region (residue 15) of the nanosheet. Backbone atoms are shown in blue if they are cis and in red if they are trans. The two shaded gray circles highlight residues 6/7 and 14/15 of a strand. E, Inset shows the fraction of trans-like residues as a function of residue number after 20 ns of our biased simulation.

5650 | www.pnas.org/cgi/doi/10.1073/pnas.1800397115 Edison et al. Downloaded by guest on September 25, 2021 Downloaded by guest on September 25, 2021 2 aahnrnG aarsnnC aiehrnV(93 trohmsr of Stereochemistry (1963) V Sasisekharan C, Ramakrishnan of hydrogen- Two G, configuration proteins: layer Ramachandran of structure 12. new The a (1951) HR sheet, Branson pleated RB, Corey The L, (1951) Pauling 11. RB Corey L, Pauling 10. 3 ang V ud ,Wiea 21)TeRmcada ubr norder An number: Ramachandran The (2016) S Whitelam J, Kundu RV, Mannige 13. hwa defc nesrn akn atr ossetwith 2L). consistent (Fig. simulations pattern (MD) dynamics packing molecular interstrand the edge-face an show dsne al. et Edison and experiment with consistent are features Such 3E). (Fig. bility adopt to 15 of residue terms causes speeds energy field potential force angle peptoid dihedral the the of from (21) 15 “softening” residue of conversion trans for barrier free-energy the of less mixture is near-equal all-cis a so adopt and propen- a to structure possess to sity brick appears residues, the other sits the in than which constrained (gaps) 15, residue pockets that to found adjacent we potentials are modified and 15 ods residue of angle possible, dihedral ≈40% the not that sample therefore indicate to experiments is (19) simulation, barriers It direct free-energy (20)]. using associated estimates the experimental of and estimates expected [as our simulation from during observed were events merization all-trans and Scattering are X-ray nanosheets wet and dry in charged described for maximally methods remain (simulation to dried likely experiments when are dry residues the hydrophilic the from dry However, and results state. solvated the the dry and the between dis- in charge consistency residues the the of hydrophilic probe the direct of a have from tribution not obtained do are We paper) nanosheets. this dry in summarized data experimental the of cis .MnieR,e l 21)Ppodnnset xii e secondary-structure new nanosheet a peptoid exhibit the nanosheets Peptoid of (2015) engineering al. et Molecular RV, polypeptoid (2016) Mannige information-rich al. 9. single-chain, et a of EJ, Folding Robertson (2011) 8. al. produce et to monolayer R, peptoid a Kudirka Collapsing stirred: 7. not Shaken, (2011) al. et B, Sanii sequence- from 6. crystals two-dimensional ultrathin Free-floating nanosheets. (2010) peptoid al. in et KT, bonds Nam amide cis 5. for Evidence (2018) protein- al. G et B1 BC, type Hudson a 4. of domain N-terminal the of Structure biphenyl. (2007) of al. et structure CRR, molecular Grace and 3. crystal The biological (1961) of J crystallization Trotter in change 2. Shape (2016) KN Olafson S, Chung PG, Vekilov 1. ssoni al n i.3 Fig. and 1 Table in shown As h oespeetdcnb eadda daie all-cis idealized as regarded be can presented models The oyetd hi configurations. chain polypeptide chain. polypeptide the of 37:205–211. configurations helical bonded chains. polypeptide motif. core. hydrophobic nanosheet. ordered highly a into sequence nanosheets. stable free-floating, polymers. peptoid specific Lett Chem ligand. peptide 4863. a with complex in receptor coupled 14:1135–1140. macromolecules. aaee o rti geometry. protein for parameter aohe r nbte gemn iheprmn hnthose than experiment with agreement better in are nanosheet side esta htfrrsde7 ute,a dhoc ad an Further, 7. residue for that than less indeed is oso that show to 3D) (Fig. sampling umbrella used we model trans Nature 9:2574–2578. aohe.W oeta M aa(n nedall indeed (and data NMR that note We nanosheet. IApni,1 iuainsetup Simulation 1. Appendix, SI 526:415–420. esoso h aohe,bcueno because nanosheet, the of versions R Bull MRS ). Langmuir rcNt cdSiUSA Sci Acad Natl Proc a Mater Nat 41:375–380. 32:11946–11957. nnsetsmltosidctsthat indicates simulations cis-nanosheet 0 frsde n are 8 and 7 residues of ≈90% sn nacdsmln meth- sampling enhanced Using cis. mCe Soc Chem Am J LSOne PLoS cis o Biol Mol J 9:454–460. or cis–trans trans A 37:251–256. 11:e0160023. Biopolymers 7:95–99. and 133:20808–20815. ihruhyeulproba- equal roughly with cis smrzto vnsand events isomerization h iesoso the of dimensions the B, rcNt cdSiUSA Sci Acad Natl Proc and 96:586–595. and rcNt cdSiUSA Sci Acad Natl Proc aigthe Taking trans. .Smlto of Simulation 4. cis–trans caCrystallogr Acta ω 104:4858– NMR . cis cis Phys J and iso- to 5 agt (2006) V Daggett 25. Corey’s and Pauling (2004) V Daggett DO, Alonso ML, DeMarco RS, Armen 24. pro- in ribbons and Rings (2014) EJ Milner-White F, Al-Shubailly DP, Leader S, Hayward 23. of geometry The (2008) EJ Milner-White S, Hayward A 22. dynamics: molecular Accelerated (2004) JA McCammon isomer- J, cis/trans of Mongan equilibria D, and Hamelberg Kinetics 21. (2007) DL Rabenstein D, Borchardt Q, Sui 20. use and Development (2014) S Whitelam RN, Zuckermann RV, Mannige enantiomeric DT, Mirijanian of (2009) al. incorporation 19. et Tandem MJ, Frisch (2016) RR 18. Conry EM, NAMD. Mumford with BC, dynamics Gorske molecular 17. Scalable (2005) dynamics. al. molecular et VMD–Visual JC, (1996) Phillips K 16. Schulten (D, A, poly Dalke alternating in W, structures Humphrey Sheet (1981) 15. G Spach F, Vovelle G, Detriche F, Heitz 14. yteOfieo cec fteU eateto nryudrContract under Energy of Department US the of supported Science is of DE-AC02-05CH11231. which Computing Office Center, the the High-Performance Computing FA9550-14-1-0350. of by Scientific resources the Award used Research work on Energy This Research Dhabi. National supported Abu out Scientific University York were carried New of at A.I.H. resources were Office and calculations Force R.K.S. QM Air with program. the Polymers Fx) Non-Natural by Folded (Fold Depart- DARPA Function the US were by Biological the supported R.Z. was of and DTRA10027- R.Z. Contract/Grant Sciences, J.R.E. 1587. Agency Reduction DE-AC02-05CH11231. Energy Threat Defense Contract Basic by under supported of Energy Office of Science, ment of by supported Office Laboratory, National the Berkeley Lawrence at Foundry Molecular ACKNOWLEDGMENTS. of design the inform type. can this exper- of modeling that nanostructures molecular shown and have we data here proteins imental (22–25); that motifs twist-opposed shows similar work of form of body can adoption growing their A (9). is states rotational linearity motif building peptoid The allows polymers. built that peptoid are untwisted extended—potentially they and and catalysis—because linear and from flat sensing kink are for a features Nanosheets (with useful untwisted 15). and residue linear at remains and states a rotational is conformation resulting The cis-Σ linearity. required backbone strain maintain energetic to slight the compensate interactions toid conformational order the of to degree and high accessible the contacts Specifically, backbone. the interpeptoid of preference of that interplay from indicate result nanosheets an (4) in peptoids data by adopted experimental conformations the and results simulation Our Conclusions experiment. in observed structure the of all-cis the that suggest 39:594–602. amyloid in intermediate amyloidogenic prefibrillar the disease. define may structure sheet plots Ramachandran and parameters dipeptides. repeating helical for using Characterization structures: tein proteins. in precursor 71:415–425. amyloid as function sible biomolecules. 11929. for method simulation efficient and promising peptoids. in bonds amide backbone of ization simulation. peptoid for forcefield 35:360–370. CHARMM-based atomistic an of structures. peptoid discrete engenders residues 26:1781–1802. Graph L-peptides). tad()i hc h akoeatrae ewe two between alternates backbone the which in (9) strand 14:33–38. rcNt cdSiUSA Sci Acad Natl Proc Macromolecules cis α akoe n h eutn aoal interpep- favorable resulting the and backbones Set h oi ofre nayoddiseases? amyloid in conformer toxic The -Sheet: asin9Rvso E.01 Revision Gaussian09 hswr a oea ato srpoeta the at project User a of part as done was work This PNAS rtisSrc uc Bioinformatics Funct Struct Proteins aohe oe sago approximation good a is model nanosheet 14:47–50. 101:11622–11627. | a 9 2018 29, May mCe Soc Chem Am J r Lett Org Gusa n,Wligod CT). Wallingford, Inc, (Gaussian rtisSrc uc Bioinformatics Funct Struct Proteins | α set mlctosfrispos- its for Implications -sheet: o.115 vol. 18:2780–2783. hmPhys Chem J 82:230–239. 129:12042–12048. | o 22 no. optChem Comput J optChem Comput J c hmRes Chem Acc 120:11919– α-pleated | Mol J 5651

BIOPHYSICS AND COMPUTATIONAL BIOLOGY