Cis-trans Research Articles

Cis-Trans Reisomerization Preceding Reprotonation of the Retinal Chromophore Is Common to the Schizorhodopsin Family: A Simple and Rational Mechanism for Inward Proton Pumping.

The creation of unidirectional ion transporters across membranes represents one of the greatest challenges in chemistry. Proton-pumping rhodopsins are composed of seven transmembrane helices with a retinal chromophore bound to a lysine side chain via a Schiff base linkage and provide valuable insights for designing such transporters. What makes these transporters particularly intriguing is the discovery of both outward and inward proton-pumping rhodopsins. Surprisingly, despite sharing identical overall structures and membrane topologies, these proteins facilitate proton transport in opposite directions, implying an underlying rational mechanism that can transport protons in different directions within similar protein structures. In this study, we unraveled this mechanism by examining the chromophore structures of deprotonated intermediates in schizorhodopsins, a recently discovered subfamily of inward proton-pumping rhodopsins, using time-resolved resonance Raman spectroscopy. The photocycle of schizorhodopsins revealed the cis-trans thermal isomerization that precedes reprotonation at the Schiff base of the retinal chromophore. Notably, this order has not been observed in other proton-pumping rhodopsins, but here, it was observed in all seven schizorhodopsins studied across the archaeal domain, strongly suggesting that cis-trans thermal isomerization preceding reprotonation is a universal feature of the schizorhodopsin family. Based on these findings, we propose a structural basis for the remarkable order of events crucial for facilitating inward proton transport. The mechanism underlying inward proton transport by schizorhodopsins is straightforward and rational. The insights obtained from this study hold great promise for the design of transmembrane unidirectional ion transporters.

Sequence effects on the thermal cis–trans isomerization of side‐chain stearate‐containing azobenzene polymers

AbstractPhotochromic azobenzenes undergo light‐mediated trans–cis isomerization. The cis isomer reverts to the trans isomer thermally. To investigate the effect of different monomer sequences on the thermal stability of cis‐azobenzene, a series of copolymers, namely, block, and random structures containing stearic acid and azobenzene moieties as their side chains have been synthesized through reversible addition–fragmentation chain transfer (RAFT) polymerization. In this study, we investigate the photoisomerization of the trans and cis forms of the polymers and also the thermal reversal of the cis‐azobenzene photochromic systems. The isomerization data revealed significant differences in the isomerization timescales between the polymers and the corresponding monomer. It was observed that the local polarity around the azobenzene units within a polymer was significantly influenced by the chain segment depending on whether it was in the vicinity of the hydrophobic alkyl chains or other azobenzene units. This local environment of the azobenzene units regulates the stabilization of the transition states during the cis–trans thermal isomerization, consequently affecting the half‐life of the cis isomer.

Photoisomerization pathways of trans-resveratrol.

Resveratrol is well-known for promoting health benefits due to its antioxidant, anti-aging, anti-carcinogenic, and other beneficial activities. Understanding the photophysics of resveratrol is essential for determining its applicability to pharmaceutical innovations. In the present work, we used an explore-then-assess strategy to map the internal conversion pathways of trans-resveratrol. This strategy consists of exploring the multidimensional configurational space with nonadiabatic dynamics simulations based on a semiempirical multireference method, followed by a feasibility assessment of reduced-dimensionality pathways at a high ab initio theoretical level. The exploration step revealed that internal conversion to the ground state may occur near five distinct conical intersections. The assessment step showed that the main photoisomerization pathway involves a twisted-pyramidalized S1/S0 conical intersection, yielding either trans or cis isomers. However, a secondary path was identified, where cis-trans isomerization happens in the excited state and internal conversion occurs at a cyclic conical intersection, yielding a closed-ring resveratrol derivative. This derivative, which can be formed through this direct path or an indirect photoexcitation, may be connected to the production of oxygen-reactive species previously reported and have implications in photodynamic therapy.

Light-regulated morphology control in supramolecular polymers.

Stimuli-responsive materials have gained significant recent interest owing to their versatility and wide applications in fields ranging from materials science to biology. In the majority of examples, external stimuli, including light, act as a remote source of energy to depolymerize/deconstruct certain nanostructures or provide energy for exploring their functional features. However, there is little emphasis on the creation and precise control of these materials. Although significant progress has been made in the last few decades in understanding the pros and cons of various directional non-covalent interactions and their specific molecular recognition ability, it is only in the recent past that the focus has shifted toward controlling the dimension, dispersity, and other macroscopic properties of supramolecular assemblies. Control over the morphology of supramolecular polymers is extremely crucial not only for material properties they manifest but also for effective interactions with biological systems for their potential application in the field of biomedicine. This could effectively be achieved using photoirradiation which has been demonstrated by some recent reports. The concept as such offers a broad scope for designing versatile stimuli-responsive supramolecular materials with precise structure-property control. However, there has not yet been a compilation that focuses on the present subject of employing light to impact and regulate the morphology of supramolecular polymers or categorize the functional motif for easy understanding. In this review, we have collated recent examples of how light irradiation can tune the morphology and nanostructures of supramolecular polymers and categorized them based on their chemical transformation such as cis-trans isomerization, cycloaddition, and photo-cleavage. We have also established a direct correlation among the structures of the building blocks, mesoscopic properties and functional behavior of such materials and suggested future directions.

Photo-responsive nanoporous liquid crystal polymer films for selective dye adsorption.

Photo-responsive nanoporous polymer films (AZOF-R(NC6)) have been developed by a template method based on a hydrogen-bonding supramolecular liquid crystal (LC) and a light-sensitive azobenzene LC crosslinker in this work. Anionic nanopores were obtained after the removal of template NC6 using KOH solution. The AZOF-R(NC6) demonstrates charge-selective dye adsorption and the maximum adsorption capacity for Rh6G is 504.6 mg g-1. The AZOF-R(NC6) film without UV light treatment shows a 32% higher adsorption capacity for Rh6G than the AZOF-R(NC6) film treated with UV light within the initial 10 min. In addition, UV light can trigger the release of the adsorbed dye from the polymer film due to the pore size change arising from the trans-cis isomerization. Besides, the used polymer film can be effectively regenerated using a HCl solution. Such functional polymer films with highly ordered nanopores and photo-responsive properties hold great promise in selective adsorption and mass separations.

Solubility of selected polymers in cyclohexane: comparison between Flory-Huggins interaction parameters calculated using three different molecular dynamics simulation approaches.

Accurate prediction of solubility of polymers in solvents a priori is highly desirable in practice. To this end, the Flory-Huggins interaction parameter χ is commonly used and molecular dynamics simulation, a powerful computational tool, has been used for such a purpose. To calculate χ, there exist three possible strategies using molecular dynamics simulation. One is through the calculation of Hildebrand solubility parameters of the pure components while the other two are to calculate the enthalpy of solvation and Gibbs free energy of solvation for the solution, respectively. This study evaluated these three strategies using binary solutions containing a hydrophobic or hydrophilic polymer (polyisobutylene, polystyrene, cis and trans polybutadiene, cis and trans polyisoprene, poly(ethylene oxide), and polyacrylamide) and an aliphatic solvent - cyclohexane. We found that χ determined via solubility parameters predicted the solubility trend but deviated significantly from experimental values. On the other hand, the enthalpy of solvation approach provided the most accurate χ values, compared to experiment, at a reasonable computational demand, especially for hydrocarbon polymers, while the Gibbs free energy of solvation approach, though more computationally intensive, did not significantly improve χ from the enthalpy of solvation approach. In particular, the Gibbs free energy of solvation approach overestimated χ for non-polar polymers. A conformational analysis of the solvated polymers revealed that all polymers collapsed in cyclohexane with polyethylene oxide and polyacrylamide collapsed the most as expected. For the two polar polymers used, the collapse was evidenced by abrupt changes in radius of gyration (Rg) and solvent accessible surface area (SASA) in the early stage of molecular dynamics simulation trajectories, and plateauing at much lower final values. Conversely, the hydrocarbon polymers exhibited minimal deviation from the expected Rg and barely any change in SASA with time. Our findings demonstrated that there exist differences in the accuracy and computational resources used when different molecular dynamics simulation strategies are used in the determination of χ.

Intermediate diradical character and thermal cis–trans isomerization of near-infrared absorbing thionated squaraine dyes

Near-infrared absorbing squaraine dyes incorporating 4-membered thionated oxocarbon and chalcogenopyrylium moieties exhibit intermediate diradical character, which impacts thermal cis–trans isomerization.

Quantum tunnelling effect in the cis-trans isomerization of uranyl tetrahydroxide.

The role of quantum tunnelling (QT) in the proton transfer kinetics of the uranyl tetrahydroxide (UTH, [UO2(OH)4]2-) cis to trans isomerization was computationally studied under three possible reaction pathways. The first pathway involved a direct proton transfer from the hydroxide ligand to the oxo atom. In the other two pathways, one or two water molecules were added to the second sphere. The first H2O, bound by hydrogen bonds to the ligands, acts as a bridge enabling a proton shuttling, a concerted hopping of a proton from the hydroxide to the oxo atom similar to the Grotthuss mechanism. In the third pathway, the second water molecule does not participate in the H-transfer chain, but works as an anchor for the first water molecule, limiting its movement and therefore enhancing the QT. Since experimentally the reaction occurs in water, the first two pathways (no water or one H2O) serve only as models of the gas phase behaviour, while the third pathway will always be thermodynamically and kinetically preferred. The effects were investigated in the gas phase as well as in a continuum aqueous model, including the H/D Kinetic Isotope Effect (KIE). The results indicate that at very low temperatures, QT is the only mechanism that permits the reaction kinetics, consistent with the large computed KIE. At higher temperatures, thermally activated tunnelling competes with the classical crossing over the potential barrier.

Cis-Trans Isomerization of Unsaturated Fatty Acid Methyl Ester by Natural Sulfur Compounds in Model Systems.

Growing evidence indicates that the intake of trans fatty acids (TFAs) increases the risk of numerous diseases, such as cardiovascular diseases. Recently, our group found that certain natural sulfur compounds (allyl isothiocyanate [AITC] and diallyl disulfide [DADS]) promote cis to trans isomerization of fatty acid esters during heat treatment. However, little information is available on the fatty acid isomerization with them. In this study, we investigated the effects of oxygen and α-tocopherol (antioxidant) on isomerization of oleic acid (18:1) methyl ester (OA-ME) in the presence of AITC and DADS. Furthermore, the effect of the simultaneous use of AITC and DADS was evaluated. Our results indicate that oxygen enhances the AITC-induced trans isomerization, and DADS was found to promote trans isomerization but inhibit AITC-induced trans isomerization during heating. Both AITC- and DADS-induced trans isomerization were inhibited by α-tocopherol. These results indicate that the trans isomerization of fatty acids induced by sulfur compounds can be controlled by devising a cooking process and the food ingredients used together.

An ab initio study on the photoisomerization in 2-styrylpyridine.

We report results of a theoretical study on photoinduced processes in 2-styrylpyridine. The geometries and the relative energies of the possible conformers were investigated using the second-order Møller-Plesset (MP2) and algebraic diagrammatic construction to second-order (ADC(2)) methods and the cc-pVTZ basis set. The complete active space self consistent field (CASSCF) method is used for locating the minimum-energy conical intersection (MECI) geometries between the S0 and S1 states. In addition to the twisted-pyramidalized MECI points along the trans and cis isomerization pathways, S1/S0 cooperating-ring MECI and cyclized-ring MECI structures, lying on the cyclization pathways of cis-2-styrylpyridine, were also located. Except the twisted pyramidalized CI2 and cyclized Cyc-CI3, all the other MECI points are found to be accessible from either one or more Franck-Condon points. The possibilities for the cis-trans isomerization and cyclization processes are discussed along the image-dependent pair potential (IDPP) paths.

Homochiral vs. heterochiral preference in chiral self-recognition of cyclic diols.

The structure and clustering propensity of a chiral derivative of cis-1,2-cyclohexanediol, namely, 1-phenyl-cis-1,2-cyclohexanediol (cis-PCD), has been studied under supersonic expansion conditions by combining laser spectroscopy with quantum chemistry calculations. The presence of the phenyl substituent induces conformational locking relative to cis-1,2-cyclohexanediol (cis-CD), and only one conformer of the bare molecule is observed by both Raman and IR-UV double resonance spectroscopy. The homochiral preference inferred for the dimer formation at low enough temperature is in line with the formation of a conglomerate in the solid state. The change in clustering propensity in cis-PCD relative to trans-1,2-cyclohexanediol (trans-CD), which shows heterochiral preference, is explained by the presence of the phenyl substituent rather than the effect of cis-trans isomerism. Indeed the transiently chiral cis-CD also forms preferentially heterodimers, whose structure is very close to that of the corresponding trans-CD dimer.

Synthesis and characterization of mesoporous silica supported metallosalphen-azobenzene complexes: efficient photochromic heterogeneous catalysts for the oxidation of cyclohexane to produce KA oil.

The oxidation of cyclohexane to produce KA oil (cyclohexanone and cyclohexanol) is important industrially but faces challenges such as low cyclohexane conversion at high KA oil selectivity, and difficult catalyst recyclability. This work reports the synthesis and evaluation of new heterogeneous catalysts consisting of Co(ii), Mn(ii), Ni(ii) and Cu(ii) salphen-azobenzene complexes [ML1] immobilized on amino-functionalized mesoporous silica (SBA-15, MCM-41, MCM-48) through coordination bonding. In the first step, the salphen-azobenzene ligand was synthesized and complexed with Co, Mn, Ni and Cu metal ions. In the second step, aminopropyltriethoxysilane (APTES) was grafted onto the surface of different types of commercial mesoporous silica. The immobilization of [ML1] onto the mesoporous silica surface and the thermal stability of the obtained materials were confirmed using different characterization techniques such as FT-IR, powder XRD, SEM, TEM, BET, and TGA. The obtained results revealed high dispersion of [ML1] through the silica surface. The catalytic activity of the prepared materials Silica-N-ML1 was evaluated on the cyclohexane oxidation to produce KA oil using various oxidants. The cis-trans isomerization of the azobenzene upon UV irradiation was found to affect the catalytic performance of Silica-N-ML1. The cis isomer of SBA-15-N-CoL1 exhibited the highest cyclohexane conversion (93%) and KA selectivity (92%) under mild conditions (60 °C, 6 h) using m-CPBA as oxidant. Moreover, The SBA-15-N-CoL1 showed high stability during four successive cycles.

Photoinduced isomerization mechanism of isatin N<sup>2</sup>-diphenylhydrazones molecular switch

Hydrazone molecular switches have significant application value in supramolecular chemistry. A new type of hydrazone molecular switch, named isatin N<sup>2</sup>-diphenylhydrazone, has been synthesized. Owing to its cis-trans isomerization characteristics under visible light excitation, ease of synthesizing of derivatives, and sensitivity to external stimuli, it has important application value in the field of biochemistry. Because of its forward and backward visible light excitation characteristics, it is considered a class of compound that is very suitable for molecular switches, and it has a wide application value in fields such as biotechnology. In addition, the derivatives compound exhibits strong interactions with negative ions, which enhances its function as a molecular switch, making it a four-state molecular switch that can be achieved by a single molecule. However, the photo-induced isomerization mechanism of these new molecular switches is not yet clear, and whether there are novel phenomena in the isomerization process is also unknown. In this work, a semi empirical OM2/MRCI based trajectory surface hopping dynamics method is adopted to systematically study a photo induced isomerization mechanism based on the E-Z isomerization process of the isatin N<sup>2</sup>-diphenylhydrazones molecular switch. Optimization configuration and the average lifetime of the first excited S<sub>1</sub> state are obtained by using the semi-empirical OM2/MRCI method of molecular switch. It is found that the average lifetime of the S<sub>1</sub> excited state of the E-configuration molecular switch is about 107 fs, and the quantum yield of E-Z isomerization of the molecular switch is 16.01%. By calculating the photo induced isomerization process of the molecular switch, two different isomerization mechanisms of the molecular switch are identified. In addition to the traditional molecular switch isomerization mechanism revolving around the C=N bond, a new isomerization mechanism, i.e. the face-to-face twisting of the molecular switch rotor part is elucidated. By calculating the time-resolved fluorescence radiation spectrum, it is predicted that there may be a very fast fluorescence quenching phenomenon occurring in about 75 fs in the isomerization process, slightly faster than the S<sub>1</sub> average decay events (107 fs). The information about wavelength-resolved attenuation at different times is also calculated, which reflects the ultrafast fluorescence quenching process accompanied by fluorescence red shift, ranging from 2.1 × 10<sup>4</sup> cm<sup>–1</sup> to 3.4 × 10<sup>4</sup> cm<sup>–1</sup>. By comparing the calculated fluorescence spectra with the average lifetime of excited states, the existence of “dark states” is proposed, and possible explanations for the existence of “dark states” are provided, and those “dark states” may be related to lower quantum yields. The research results can provide theoretical guidance for the design and application of new molecular switches. The ease of synthesis and sensitivity to external stimuli of its derivatives make those compounds extremely valuable in molecular switching and light measurement applications.

Polymers with quadruple hydrogen-bonding end groups: controlling molecular weight using a small molecule photoswitch

A photoswitch capable of quadruple hydrogen-bonding interactions is used to effect reversible reconfiguration of polymer molecular weight of PMA bearing a complementary hydrogen-bonding motif upon cis–trans photoswitching.

Fabrication and Enzymatic Disorganization of Multiresponse Worm-Like Micelles.

How to fabricate multiresponse worm-like micelles (WLMs) and the corresponding green disposal is still challenging. A strategy of fabricating the surfactant-based WLMs that can respond simultaneously to light, heat, and pH was developed by using triple-response sodium (E)-2-(4-(phenyldiazenyl)phenoxy) acetate (AzoNa) and butyrylcholinesterase (BChE)-hydrolyzable palmitoylcholine bromide (PCB). Under the optimal molar ratio of AzoNa to PCB (∼0.5), the PCB-AzoNa WLMs formed with a maximum zero-shear viscosity (η0) value of about 2.1 × 105 mPa·s and an average diameter (D) of 4.1 ± 0.6 nm under conditions of 37 °C and pH 7.4. After irradiated with 365 nm UV light for 80 min, AzoNa underwent the trans-to-cis transition, by which the PCB-AzoNa WLMs was destroyed; however, the PCB-AzoNa WLMs could be reformed upon the irradiation of 455 nm blue light for 18 h or heating at 70 °C for 45 min due to the cis-to-trans isomerization of AzoNa. When pH changed from 7.4 to 2.0, the PCB-AzoNa WLMs was destroyed rapidly because of the conversion of AzoNa to the acid form of AzoH, whereas the PCB-AzoNa WLMs could be reformed after pH was restored to 7.4. The multiple responsiveness of the PCB-AzoNa WLMs was reversible due to the reversible trans-cis isomerization or protonation of AzoNa. Besides, the average D values of light, heat, and pH-regenerated PCB-AzoNa WLMs were 4.2 ± 0.7, 4.0 ± 0.7, and 4.0 ± 0.6 nm, respectively. Finally, the PCB-AzoNa WLMs could be enzymatically disorganized under conditions of 37 °C and pH 7.4 due to the BChE-catalyzed hydrolysis of PCB. We hope that the fabrication and enzymatic disorganization strategies for PCB-based multiresponse WLMs presented here will find potential applications in the formulation of antimicrobial household and personal care products containing PCB and in the green disposal of viscous waste containing PCB.

Fluorescence Bar-Coding and Flowmetry Based on Dark State Transitions in Fluorescence Emitters.

Reversible dark state transitions in fluorophores represent a limiting factor in fluorescence-based ultrasensitive spectroscopy, are a necessary basis for fluorescence-based super-resolution imaging, but may also offer additional, largely orthogonal fluorescence-based readout parameters. In this work, we analyzed the blinking kinetics of Cyanine5 (Cy5) as a bar-coding feature distinguishing Cy5 from rhodamine fluorophores having largely overlapping emission spectra. First, fluorescence correlation spectroscopy (FCS) solution measurements on mixtures of free fluorophores and fluorophore-labeled small unilamellar vesicles (SUVs) showed that Cy5 could be readily distinguished from the rhodamines by its reversible, largely excitation-driven trans-cis isomerization. This was next confirmed by transient state (TRAST) spectroscopy measurements, determining the fluorophore dark state kinetics in a more robust manner, from how the time-averaged fluorescence intensity varies upon modulation of the applied excitation light. TRAST was then combined with wide-field imaging of live cells, whereby Cy5 and rhodamine fluorophores could be distinguished on a whole cell level as well as in spatially resolved, multiplexed images of the cells. Finally, we established a microfluidic TRAST concept and showed how different mixtures of free Cy5 and rhodamine fluorophores and corresponding fluorophore-labeled SUVs could be distinguished on-the-fly when passing through a microfluidic channel. In contrast to FCS, TRAST does not rely on single-molecule detection conditions or a high time resolution and is thus broadly applicable to different biological samples. Therefore, we expect that the bar-coding concept presented in this work can offer an additional useful strategy for fluorescence-based multiplexing that can be implemented on a broad range of both stationary and moving samples.

Phenalenyl-substituted stilbenes as the basis for spin switches: quantum-chemical modeling

Isomers of stilbenes containing phenalenyl substituents in the para - and meta -positions of phenyl rings were studied by means of density functional theory method. Exchange coupling in structures with the trans -form of stilbenes is absent. In the cis -isomer of a meta -substituted compound, the state with a closed electron shell is stabilized due to two-electron multicenter interactions, which is confirmed by CASSCF calculations. The predicted transition between the triplet and singlet states as a result of trans-cis isomerization opens up prospects for using the discovered effect in the development of organic spin switches.

Precise Regulation of Juvenile Hormone III R-Stereoisomer Synthesis by Apis mellifera through Specifically Binding Methyl-(2E,6E)-farnesoate and Strictly Controlling Its Titer.

Juvenile hormone III (JH III) is a crucial hormone synthesized exclusively as R-stereoisomer in most insects. Herein, we established a mature Tris-HCl culture system for essential biochemical reactions and applied stable instrumental detection methods to analyze JH III, methyl farnesoate (MF) and juvenile hormone acid (JHA) using UPLC-MS/MS. Our results revealed that the R-JH III terminal synthesis pathway in Apis mellifera follows the "esterify then epoxidize" sequence, with precise methyl-(2E,6E)-farnesoate titer regulation and its spatial cis-trans isomerism, achieving selective R-JH III synthesis. Furthermore, we observed that the preferred generation of S/R-JH III chiral enantiomers varied depending on the spatial cis-trans isomerism of different MFs. Our results suggest that S-JH III could theoretically exist in insects, offering a novel perspective for understanding the synthesis mechanism of diverse complex juvenile hormones in different insect species.

Organic-inorganic composite of polypropylene fumarate and nanohydroxyapatite as carrier of antibiotics for the treatment of bone infections

Current treatment approaches in clinics to treat the infectious lesions have partial success thus demanding the need for development of advanced treatment modalities. In this study we fabricated an organic-inorganic composite of polypropylene fumarate (PPF) and nanohydroxyapatite (nHAP) by photo-crosslinking as a carrier of two clinically used antibiotics, ciprofloxacin (CIP) and rifampicin (RFP) for the treatment of bone infections. Carboxy terminal-PPF was first synthesized by cis-trans isomerization of maleic anhydride which was then photo-crosslinked using diethylfumarate (DEF) as crosslinker and bis-acylphosphine oxide (BAPO) as photo-initiator under UV lights (P). A composite of PPF and nHAP was fabricated by incorporating 40 % of nHAP in the polymeric matrix of PPF (PH) which was then characterized for different physicochemical parameters. CIP was added along with nHAP to fabricated CIPloaded composite scaffolds (PHC) which was then coated with RFP to synthesize RFP coated CIP-loaded scaffolds (PHCR). It was observed that there was a temporal separation in the in vitro release of two antibiotics after coating PHC with RFP with 80.48 ± 0.40 % release of CIP from PHC and 62.43 ± 0.21 % release of CIP from PHCR for a period of 60 days. Moreover, in vitro protein adsorption was also found to be maximum in PHCR (154.95 ± 0.07 μg/mL) as observed in PHC (75.42 ± 0.06 μg/mL), PH (24.47 ± 0.08 μg/mL) and P alone (4.47 ± 0.02 μg/mL). The scaffolds were also evaluated using in vivo infection model to assess their capacity in reducing the bacterial burden at the infection site. The outcome of this study suggests that RFP coated CIP-loaded PPF composite scaffolds could reduce bacterial burden and simultaneously augment bone healing during infection related fractures.

Cis-trans isomerization of peptoid residues in the collagen triple-helix

Cis-peptide bonds are rare in proteins, and building blocks less favorable to the trans-conformer have been considered destabilizing. Although proline tolerates the cis-conformer modestly among all amino acids, for collagen, the most prevalent proline-abundant protein, all peptide bonds must be trans to form its hallmark triple-helix structure. Here, using host-guest collagen mimetic peptides (CMPs), we discover that surprisingly, even the cis-enforcing peptoid residues (N-substituted glycines) form stable triple-helices. Our interrogations establish that these peptoid residues entropically stabilize the triple-helix by pre-organizing individual peptides into a polyproline-II helix. Moreover, noting that the cis-demanding peptoid residues drastically reduce the folding rate, we design a CMP whose triple-helix formation can be controlled by peptoid cis-trans isomerization, enabling direct targeting of fibrotic remodeling in myocardial infarction in vivo. These findings elucidate the principles of peptoid cis-trans isomerization in protein folding and showcase the exploitation of cis-amide-favoring residues in building programmable and functional peptidomimetics.