Conformational Disorder Research Articles

Structure and Dynamics of ATP and the ATP-Zn2+ Complex in Solution.

Despite the crucial role of ATP in life and artificial life-like applications, fundamental aspects relevant to its function, such as its conformational properties and its interaction with water and ions, remain unclear. Here, by integrating linear and two-dimensional infrared spectroscopy with ab initio molecular dynamics, we provide a detailed characterization of the vibrational spectra of the phosphate groups in ATP and in its complex with Zn2+ in water. Our study highlights the role of conformational disorder and solvation dynamics, beyond the harmonic normal-mode analysis, and reveals a complex scenario in which electronic and environmental effects tune the coupling between phosphate vibrations. We identify βγ-bidentate and αβγ-tridentate modes as the preferential coordination modes of Zn2+, as was proposed in the literature for Mg2+, although this conclusion is reached by a different spectral interpretation.

Cyclic RGD conjugated PEG-PLGA nanoparticle enhances preventative effect of bilirubin on the development of ultraviolet-B (UVB)-induced cataract

Age related cataract (ARC) is characterized by protein conformational disorder with aging stands out as an independent risk factor. Therefore, mitigation of oxidative stress and DNA damage within the lens emerges as a potential therapeutic strategy. While topical administration remains the most common treatment modality for ocular disorder, drug bioavailability is hindered by the cornea epithelium barrier. In this study, we developed a novel cyclic Arg-Gly-Asp (cRGD)-conjugated nanoparticle encapsulating bilirubin (cRNM@BR), an endogenous antioxidant, to combat against cellular senescence and lens opacity associated with ARC. Immunofluorescence staining assay confirmed that cRGD modification significantly prolonged nanoparticle retention on the ocular surface by targeting integrin expressed on corneal epithelium. Moreover, through LC-MS/MS analysis, we demonstrated the enhanced transcorneal penetration efficacy of cRGD-modified nanodrugs both in vivo and in vitro. Our mechanistic investigations revealed that cRNM entered human corneal epithelial cells (HCECs) by clathrin and micropinocytosis-mediated pathways, with the ER/Golgi pathway facilitating its exocytosis. In a mouse model of ultraviolet B (UVB)-induced cataract, topical application of cRNM@BR effectively alleviated intracellular reactive oxygen species (ROS) levels and DNA damage in lens epithelial cells (LECs), thereby preventing cellular senescence and lens opacity. Transcriptomics analysis of LECs in UVB-exposed group and cRNM@BR pretreated group indicated significant enrichment of the cGAS/STING pathway. Further experiments determined that cRNM@BR prevented cellular senescence and lens opacity by ameliorating the cGAS/STING pathway. In conclusion, our findings underscore the therapeutic potential of cRNM@BR in ARC management and highlight the efficacy of cRGD-conjugated nanoplatform for intraocular delivery.

A Long-Range Planar Polymer with Efficient π-Electron Delocalization for Superior Proton Storage.

Due to the unique "Grotthus mechanism", aqueous proton batteries (APBs) are promising energy devices with intrinsic safety and sustainability. Although polymers with tunable molecular structures are ideal electrode materials, their unsatisfactory proton-storage redox behaviors hinder the practical application in APB devices. Herein, a novel planar phenazine (PPHZ) polymer with a robust and extended imine-rich skeleton is synthesized and used for APB application for the first time. The long-range planar configuration achieves ordered molecular stacking and reduced conformational disorder, while the high conjugation with strong π-electron delocalization optimizes energy bandgap and electronic properties, enabling the polymer with low proton diffusion barriers, high redox activity, and superior electron affinity. As such, the PPHZ polymer as an electrode material exhibits fast, stable, and unrivaled proton-storage redox behaviors with a large capacity of 273.3 mAh g-1 at 0.5 A g-1 (1 C) in 1M H2SO4 electrolyte, which is the highest value among proton-inserted electrodes in aqueous acidic electrolytes. Dynamic in situ techniques confirm the high redox reversibility upon proton uptake/removal, and the corresponding protonation pathways are elucidated by theoretical calculations. Moreover, a pouch-type APB cell using PPHZ electrode exhibits an ultralong lifespan over 30000 cycles, further verifying its promising application prospect.

Conformational disorder in the crystal structure of methyl 2-acetamido-2-deoxy-β-D-glucopyranosyl-(1→4)-2-acetamido-2-deoxy-β-D-glucopyranoside (methyl β-chitobioside) methanol monosolvate.

Methyl 2-acetamido-2-deoxy-β-D-glucopyranosyl-(1→4)-2-acetamido-2-deoxy-β-D-glucopyranoside (methyl β-chitobioside), (IV), crystallizes from aqueous methanol at room temperature to give a structure (C17H30N2O22·CH3OH) containing conformational disorder in the exocyclic hydroxymethyl group of one of its βGlcNAc residues. As observed in other X-ray structures of disaccharides containing β-(1→4) O-glycosidic linkages, inter-residue hydrogen bonding between O3H of the βGlcNAc bearing the OCH3 aglycone and O5 of the adjacent βGlcNAc is observed based on the 2.79 Å internuclear distance between the O atoms. The structure of (IV) was compared to that determined previously for 2-acetamido-2-deoxy-β-D-glucopyranosyl-(1→4)-2-acetamido-2-deoxy-β-D-glucopyranose (β-chitobiose), (III). The O-glycosidic linkage torsion angles, phi (φ) and psi (ψ), in (III) and (IV) differ by 6-8°. The N-acetyl side chain conformation in (III) and (IV) shows some context dependence, with the C1-C2-N-Ccar torsion angle 10-15° smaller for the βGlcNAc residue involved in the internal O-glycosidic linkage. In (IV), conformational disorder is observed in the exocyclic hydroxymethyl (-CH2OH) group in the βGlcNAc residue bearing the OCH3 aglycone, and a fitting of the electron density indicates an approximate 50:50 distribution of the gauche-gauche (gg) and gauche-trans (gt) conformers in the lattice. Similar behavior is not observed in (III), presumably due to the different packing structure in the vicinity of the -CH2OH substituent that affects its ability to hydrogen bond to proximal donors/acceptors. Unlike (IV), a re-examination of the previously reported electron density of (III) revealed conformational disorder in the N-acetyl side chain attached to the reducing-end βGlcNAc residue caused by rotation about the C2-N bond.

Low temperature aging induced conjugated polymers aggregation by UV–Vis spectroscopy

AbstractMultiscale structural evolution of conjugated polymer (CP) solutions from disorder to aggregation via environmental perturbations is a universal phenomenon in condensed matter physics. Here, we take poly(3‐hexylthiophene‐2,5‐diyl) (P3HT) as a model material and use Ultraviolet–Visible (UV–Vis) spectroscopy to study the hierarchical structure evolution during prolonged aging at relatively low temperature. Using in‐situ UV–Vis spectroscopy and the Franck‐Condon (FC) method, the dynamics of multiscale structural transitions in P3HT were elucidated. Hierarchical structural details can be extracted from the UV–Vis spectra, including the overall percentage of aggregates, conjugation length, degree of H‐/J‐type molecular packing, and site energetic disorder. Through covariance analysis of conformational disorder to aggregation transitions of conjugated polymers obtained under multiple conditions, we find that the trends of the above four key parameters are not consistent, which informs the unique evolution of the degree of ordering at different length scales within the aggregates. This work facilitates the scrutiny of the hierarchical structural transition from multi‐length scale perspective.

B-Factor Rescaling for Protein Crystal Structure Analyses

The B-factor, also known as the atomic displacement parameter, is a fundamental metric in crystallography for quantifying the positional flexibility of atoms within crystal lattices. In structural biology, various developments have expanded the use of B-factors beyond conventional crystallographic analysis, allowing for a deeper understanding of protein flexibility, enzyme manipulation, and an improved understanding of molecular dynamics. However, the interpretation of B-factors is complicated by their sensitivity to various experimental and computational factors, necessitating rigorous rescaling methods to ensure meaningful comparisons across different structures. This article provides an in-depth description of rescaling approaches used for B-factors. It includes an examination of several methods for managing conformational disorder and selecting the atom types required for the analysis.

Boosting Reverse Intersystem Crossing of TADF Emitter through Molecular Geometry Adaptation to Crystalline Host

AbstractRapid reverse intersystem crossing (RISC) is one of the prime concerns for blue thermally activated delayed fluorescence (TADF) emitters, as it reduces triplet exciton population, the root cause of detrimental triplet‐mediated annihilation processes that accelerate device efficiency roll‐off and degradation. This work introduces a new concept to tailor the RISC of TADF emitters through their molecular geometry adaptation to crystalline hosts bearing a similar donor‐acceptor structure. A meticulously designed crystalline host comprising isophthalonitrile acceptor (A) and carbazole‐derived donor (D) units, characterized by nearly orthogonal D‐A arrangement, has been demonstrated to alleviate singlet‐triplet energy gap (ΔEST) of the TADF dopant by forcing it to adopt a more twisted D‐A configuration, as corroborated by X‐ray diffraction (XRD) measurements. The approach not only significantly reduces the RISC activation energy, resulting in a remarkable tenfold boost of the RISC rate (above 107 s−1) and fourfold shortening of delayed FL lifetime (down to 1.5 µs), but also offers the additional benefit of suppressing conformational disorder of TADF dopant, producing a narrower emission bandwidth. The presented concept, based on crystalline host‐driven RISC engineering, is anticipated to have a profound impact on the development of high‐performance, stable blue‐emitting TADF organic light‐emitting diodes (OLEDs).

Self-powered piezoelectric sensor based on BaTiO3/MWCNTs/PVDF electrospun nanofibers for wireless alarm system

Abstract The piezoelectric constant of polyvinylidene fluoride (PVDF) is inferior to that of piezoelectric ceramics, which will impede the efficient application in smart systems. In this work, we modulated the content of BaTiO3/multi-wall carbon nanotubes (MWCNTs) in the BaTiO3/MWCNTs/PVDF electrospun nanofibers to facilitate the β phase formation in the PVDF to enhance the piezoelectric properties of BaTiO3/MWCNTs/PVDF films. The BaTiO3 combined with MWCNTs through chemical bands can enhance the electrostatic interaction at the vicinity of BaTiO3-PVDF interface to induce augmentation of the local conformational disorder and result in the enhanced nucleation and stabilization of β phase in the BaTiO3/MWCNTs/PVDF films. When the ratio between BaTiO3 and MWCNTs is about 3:1, the PVDF-BM-3 can deliver the output voltage of 39.5 V under 250 kPa with a frequency of 10 Hz. The PVDF-BM-3 electrospun nanofibers as triggers used in the wireless alarm system can achieve comparable sensitivity under different external stresses. This work paves a new promising pathway for self-powered piezoelectric sensors in the Internet of Things.

Visible Light Induced Exciton Dynamics and trans-to-cis Isomerization in Azobenzene Aggregates: Insights from Surface Hopping/Semiempirical Configuration Interaction Molecular Dynamics Simulations.

Assemblies of photochromic molecules feature exciton states, which govern photochemical and photophysical processes in multichromophoric systems. Understanding the photoinduced dynamics of the assemblies requires nonadiabatic treatment involving multiple exciton states and numerous nuclear degrees of freedom, thus posing a challenge for simulations. In this work, we address this challenge for aggregates of azobenzene, a prototypical molecular switch, performing on-the-fly surface hopping calculations combined with semiempirical configuration interaction electronic structure and augmented with transition density matrix analysis to characterize exciton evolution. Specifically, we consider excitation of azobenzene tetramers in the nπ* absorption band located in the visible (blue) part of the electromagnetic spectrum, thus extending our recent work on dynamics after ππ* excitation corresponding to the ultraviolet region [Titov, J. Phys. Chem. C2023, 127, 13678-13688]. We find that the nπ* excitons, which are initially strongly localized by ground-state conformational disorder, undergo further (very strong) localization during short-time photodynamics. This excited-state localization process is extremely ultrafast, occurring within the first 10 fs of photodynamics. We observe virtually no exciton transfer of the localized excitons in the nπ* manifold. However, the transfer may occur via secondary pathways involving ππ* states or the ground state. Moreover, we find that the nπ* quantum yields of the trans-to-cis isomerization are reduced in the aggregated state.

Harnessing Conformational Disorder of Organic Cations for Efficient Blue Quasi‐2D Perovskite LEDs

AbstractDespite quasi‐2D perovskite offering great control over the optoelectronic properties, disordered organic cations are often perceived as detrimental to device performance, primarily affecting charge carrier mobility. However, it is proposed that such disordered organic cations‐enabled excellent excitonic properties can be beneficial for fabricating high‐efficiency perovskite light‐emitting diodes (PeLEDs) facilitated by reduced dielectric screening effect. Here, by incorporating acetamidinium bromide additives, the conformational disorder of organic cation is precisely manipulated and meticulously probed using sum frequency generation vibrational spectroscopy. Finally, a distinctive inverse relationship is elucidated between the degree of conformational order, characterized as relative structure ordering , and key performance metrics such as photoluminescence quantum yield and external quantum efficiency (EQE). By optimizing the configurational disorder, sky‐blue (485 nm) PeLEDs achieve a noteworthy EQE of 14.42% and exhibit significantly prolonged operational stability in open‐air conditions. This finding underscores the potential advantages of disordered organic cations in enhancing exciton properties and radiative recombination efficiency.

Polymorphism and Stretch-Induced Transformations of Sustainable Polyethylene-Like Materials.

Herein we demonstrate that polyethylene-like bioderived, biodegradable, and fully recyclable unbranched aliphatic polyesters, such as PE-2,18, develop hexagonal crystal structures upon quenching from the melt to temperatures <∼50 °C and orthorhombic-like packing at higher quenching temperatures or after isothermal crystallization. Both crystal types are layered. While all-trans CH2 packing characterizes the structure of the orthorhombic-like form, there is significant conformational disorder in the staggered long CH2 sequences of the hexagonal crystals. On heating, the hexagonal crystals transform to the orthorhombic type at ∼60 °C via melt recrystallization, but no change is apparent during heating samples with the orthorhombic form up to the melting point (∼95 °C). The hexagonal structure is of interest not only because it develops under very rapid quenching from the melt but also because under uniaxial tensile deformation it undergoes a stretch-induced transformation to the orthorhombic structure. Compared to deformation of orthorhombic specimens that maintain the same crystal type, such transformation results in larger strains and enhanced strain hardening, thus representing a desired toughening mechanism for this type of polyethylene-like materials.

Shedding light on thermally-activated delayed fluorescence.

Thermally activated delayed fluorescence (TADF) is a hot research topic in view of its impressive applications in a wide variety of fields from organic LEDs to photodynamic therapy and metal-free photocatalysis. TADF is a rare and fragile phenomenon that requires a delicate equilibrium between tiny singlet-triplet gaps, sizable spin-orbit couplings, conformational flexibility and a balanced contribution of charge transfer and local excited states. To make the picture more complex, this precarious equilibrium is non-trivially affected by the interaction of the TADF dye with its local environment. The concurrent optimization of the dye and of the embedding medium is therefore of paramount importance to boost practical applications of TADF. Towards this aim, refined theoretical and computational approaches must be cleverly exploited, paying attention to the reliability of adopted approximations. In this perspective, we will address some of the most important issues in the field. Specifically, we will critically review theoretical and computational approaches to TADF rates, highlighting the limits of widespread approaches. Environmental effects on the TADF photophysics are discussed in detail, focusing on the major role played by dielectric and conformational disorder in liquid solutions and amorphous matrices.

Temperature-dependent excited states for detecting reversible phase transitions in 2D lead(II) iodide perovskites.

Significant interest exists in water-tolerant 2D lead iodide perovskites owing to their stability and proven potential in photovoltaic and photonic applications. These materials have solid-state phase transitions that are accessible below 100 °C. Here, the study witnesses the multiple phase transitions of the last members of a series of organic-inorganic hybrid materials, [(CnH2n+1NH3)2PbI4], with even n as n = 14, 16, and 18, once again. By employing temperature-dependent steady-state photoluminescence (PL) and temperature-dependent time-resolved photoluminescence (TRPL) spectroscopy in the temperature range of -18 to +90 °C and at -196 °C, we explore the thermal responses of these materials. The investigation reveals reversible phase transitions occurring between room temperature (RT) and elevated temperatures, impacting the optical properties and emitting colors of the perovskite compounds. The longer the alkyl chain, the higher the phase transition temperature, attributed to increased conformational disorder and enhanced perovskite symmetry. The decay constants for all compounds are very close in value, which confirms the underlying excited-state dynamics, pointing to contributions primarily from inorganic components across different phases. We anticipate that our results on the detection of phase transitions in 2D perovskites will not only motivate the use of these techniques for detecting phase transitions but also would help to understand their excited states in more details to selectively use them for solar cell and next-generation display technologies.

Crystallization kinetics of (S)-4'-(1-methylheptyloxycarbonyl)biphenyl-4-yl 4-[4-(2,2,3,3,4,4,4-heptafluorobutoxy)but-1-oxy]-2-fluorobenzoate.

Chiral liquid crystalline compounds belonging to the homologous series of (S)-4'-(1-methylheptyloxycarbonyl)biphenyl-4-yl 4-[m-(2,2,3,3,4,4,4-heptafluorobutoxy)alk-1-oxy]-2-fluorobenzoates show various behaviors on cooling depending on the length of the CmH2m chain. The homologue with m = 2 crystallizes, while for m = 5, 6, 7, and presumably also for m = 3, the glass of the anticlinic smectic CA* phase is formed. The previous results for m = 4 suggest that this homologue may also be a glassformer. This paper presents the study of the crystallization kinetics for the compound with m = 4 in isothermal conditions (by polarizing optical microscopy) and for the 5-40 K min-1 cooling rates (by differential scanning calorimetry). Microscopic observations enable estimation of the energy barrier for nucleation, which equals 409 kJ mol-1. The threshold cooling rate necessary for complete vitrification of the smectic CA* phase, obtained by extrapolating the enthalpy change during crystallization to zero, is equal to 81 K min-1 or 64 K min-1 for the linear and parabolic fits, respectively. The structural studies by X-ray diffraction show that crystal phases have lamellar structures both in the pristine sample and after crystallization from the melt but with different layer spacing. A weak relaxation process is detected in the sample after melt crystallization, revealing the presence of the conformational disorder. The dynamic glass transition temperature of the SmCA* phase, estimated from the relaxation time of the PH process (as the α-relaxation time could not be registered in a wide enough temperature range), is 244 K.

Structural architecture of the acidic region of the B domain of coagulation factor V

BackgroundCoagulation factor (F)V features an A1-A2-B-A3-C1-C2 domain organization and functions as the inactive precursor of FVa, a component of the prothrombinase complex required for rapid thrombin generation in the penultimate step of the coagulation cascade. An intramolecular interaction within the large B domain (residues 710-1545) involves the basic region (BR, residues 963-1008) and acidic region (AR, residues 1493-1537) and locks FV in its inactive state. However, structural information on this important regulatory interaction or on the separate architecture of the AR and BR remains elusive due to conformational disorder of the B domain. ObjectivesTo reveal the structure of the BR-AR interaction or of its separate components. MethodsThe structure of FV is solved by cryogenic electron microscopy. ResultsA new 3.05 Å resolution cryogenic electron microscopy structure of FV confirms the overall organization of the A and C domains but resolves the segment 1507 to 1545 within a largely disordered B domain. The segment contains most of the AR and is organized as recently reported in FV short, a spliced variant of FV with a significantly shorter and less disordered B domain. ConclusionThe similar architecture of the AR in FV and FV short provides structural context for physiologically important interactions of this region with the BR in FV and with the basic C-terminal end of tissue factor pathway inhibitor α in FV short.

Comparative cytotoxic activity of lutein or cisplatin doped with liposomes against breast cancer cell lines after radiotherapy

Interactions of the anticancer drug cisplatin or the antioxidant drug lutein with liposomes as model membranes were characterized. All liposomes had the almost spherical shape, taking into account that lyposomes without the said drugs were more evenly dispersed and tended to aggregate less. The mean size diameter of empty liposomal samples was 617.90 ± 75.64 nm, while liposomes loaded with cisplatin, lutein and a cisplatin+lutein combination were 425.60 ± 64.74 nm, 877.85 ± 93.90 nm and 189.91 ± 136.84 nm, respectively, in diameter. The incorporation of cisplatin or lutein into liposome membranes resulted in an increase in the zeta potential values. The lowest zeta potential value was achieved in lyposomes containing cisplatin in combination with lutein. The addition of cisplatin to liposomes caused a shift in the melting temperature towards higher values than those of the main peak of empty liposomes indicating a conformational disorder within the phospholipids. Encapsulation of lutein into liposomes resulted in the disappearance of the main characteristic endothermic peak of pure liposomes. FTIR spectroscopy confirmed the interaction of lutein or cisplatin with functional groups in liposomes. In the absence of external gamma-irradiation, the IC50 value for free lutein in the cytotoxic assay with MCF-7 treated cells was 10.62 gg/ml, while free cisplatin showed the IC50 value of 41.02 gg/ml. IC50 was 65.84 gg/ml and 34.29 gg/ml for nanoliposomal lutein and cisplatin, respectively. Using the combined therapy of gamma irradiation at dose rate 5 Gray followed by 10 Gray, the IC50 value for free lutein changed from 17.0 to 9.5 gg/ml. IC50 for free cisplatin changed from 51.00 to 43.09 gg/ml. This study showed that cytotoxic effect of a standard form of lutein is stronger than that of nanoliposomal lutein. The current evidence reveals a new regimen for the treatment during which replacing cisplatin with free lutein increases anticancer activity against the MCF-7 cancer cell line.

Conformational Disorder in a Hybrid 2D Perovskite with a Long Aliphatic Chain under Pressure

Conformational Disorder in a Hybrid 2D Perovskite with a Long Aliphatic Chain under Pressure

The Influence of Regiochemistry on the Performance of Organic Mixed Ionic and Electronic Conductors.

Thiophenes functionalised in the 3-position are ubiquitous building blocks for the design and synthesis of organic semiconductors. Their non-centrosymmetric nature has long been used as a powerful synthetic design tool exemplified by the vastly different properties of regiorandom and regioregular poly(3-hexylthiophene) owing to the repulsive head-to-head interactions between neighbouring side chains in the regiorandom polymer. The renewed interest in highly electron-rich 3-alkoxythiophene based polymers for bioelectronic applications opens up new considerations around the regiochemistry of these systems as both the head-to-tail and head-to-head couplings adopt near-planar conformations due to attractive intramolecular S-O interactions. To understand how this increased flexibility in the molecular design can be used advantageously, we explore in detail the geometrical and electronic effects that influence the optical, electrochemical, structural, and electrical properties of a series of six polythiophene derivatives with varying regiochemistry and comonomer composition. We show how the interplay between conformational disorder, backbone coplanarity and polaron distribution affects the mixed ionic-electronic conduction. Ultimately, we use these findings to identify a new conformationally restricted polythiophene derivative for p-type accumulation-mode organic electrochemical transistor applications with performance on par with state-of-the-art mixed conductors evidenced by a μC* product of 267 F V-1 cm-1 s-1 .

The Influence of Regiochemistry on the Performance of Organic Mixed Ionic and Electronic Conductors.

Thiophenes functionalised in the 3-position are ubiquitous building blocks for the design and synthesis of organic semiconductors. Their non-centrosymmetric nature has long been used as a powerful synthetic design tool exemplified by the vastly different properties of regiorandom and regioregular poly(3-hexylthiophene) owing to the repulsive head-to-head interactions between neighbouring side chains in the regiorandom polymer. The renewed interest in highly electron-rich 3-alkoxythiophene based polymers for bioelectronic applications opens up new considerations around the regiochemistry of these systems as both the head-to-tail and head-to-head couplings adopt near-planar conformations due to attractive intramolecular S-O interactions. To understand how this increased flexibility in the molecular design can be used advantageously, we explore in detail the geometrical and electronic effects that influence the optical, electrochemical, structural, and electrical properties of a series of six polythiophene derivatives with varying regiochemistry and comonomer composition. We show how the interplay between conformational disorder, backbone coplanarity and polaron distribution affects the mixed ionic-electronic conduction. Ultimately, we use these findings to identify a new conformationally restricted polythiophene derivative for p-type accumulation-mode organic electrochemical transistor applications with performance on par with state-of-the-art mixed conductors evidenced by a μC* product of 267 F V-1 cm-1 s-1.

Fold Surfaces of Polymer Crystals Are Nucleation Sites: The Link between Polymer Decoration, Secondary Crystallization, and the Rigid Amorphous Fraction (RAF)

The fold surfaces of polymer crystals may become suitable nucleating sites for uncrystallized material left over during the primary crystallization process. This “nucleation by the folds surface” (NFS) ability is highlighted in the so-called polymer decoration technique in which vapors of polyethylene condense and crystallize on a cold fold surface substrate to form edge-on lamellae that reveal the folds and loops orientations in different growth sectors. In bulk materials, the primary crystallization leaves confined and uncrystallized material between lamellae. NFS, based on epitaxy-type interactions, is expected to take place in these confined and supercooled melt fractions before “true” homogeneous nucleation sets in. The insights provided help elucidate the structural features of the interlamellar layers of crystalline polymers, which overcomes the limits of global, indirect investigation techniques (e.g., differential scanning calorimetry (DSC)) used in attempts to analyze their structure in situ. The interlamellar layer is known to be divided into a rigid amorphous fraction (RAF) located in contact with the fold surfaces and a mobile amorphous fraction (MAF) at its center. The nature of the RAF─amorphous but rigid above its Tg, or crystalline─is still debated. The NFS provides a structural identity for the RAF that associates conformation disorder with stem orientation: the RAF is actually a “condis oriented” fraction. On heating, the small endotherm observed in DSC curves corresponds to its isotropization. The RAF is also a protonucleus for secondary crystallization and induces the growth of edge-on lamellae on top and in the interlamellar spaces of the primary crystals. As such, the RAF has also a layered lamellar structure. Polymer decoration, the “condis oriented” RAF, and the specific edge-on lamellar secondary crystallization are manifestations of the nucleation by the fold surfaces.