Lycopene destabilizes preformed Aß fibrils: Mechanistic insights from all-atom molecular dynamics simulation.

The therapeutic strategy employing destabilization of the preformed Aß fibril by various natural compounds, as studied by experimental and computational methods, has been reported significant in curing Alzheimer's disease (AD). However, lycopene (a carotenoid), from terpenes family, needs investigation for its destabilization potential of Aß fibril. The highest antioxidant potential and ability to cross blood brain barrier makes lycopene a preferred choice as drug lead for treating AD. The current study focuses on investigating the destabilization potential and underpinning mechanism of lycopene on different polymorphic forms of Aß fibril via Molecular Dynamics (MD) simulation. The key findings highlight binding of lycopene to the outer surface of the chain F of the fibril (2NAO). Herein G9, K16 and V18 residues were found to be involved in van der Waals with the methyl groups of the lycopene. Additionally, Y10 and F20 residues were observed to interact via π-π interactions with CC bonds of the lycopene. The surface mediated binding of lycopene to the fibril is attributed to the large size and structural rigidity of lycopene along with the bulky size of 2NAO and narrow space of fibrillar cavity. The destabilization of the fibril is evident by breakage of inherent H-bonds and hydrophobic interactions in the presence of one lycopene molecule. The lesser ß-sheet content explains disorganization of the fibril and bars the higher order aggregation curbing neurotoxicity of the fibril. The higher concentration of the lycopene is not found to be linearly correlated with the extent of destabilization of the fibril. Lycopene is also observed to destabilize the other polymorphic form of Aß fibril (2BEG), by accessing the fibrillar cavity and lowering the ß-sheet content. The destabilization observed by lycopene on two major polymorphs of Aß fibril explains its potency towards developing an effective therapeutic approach in treating AD.

Enhanced stability of a disaggregated Aß fibril on removal of ligand inhibits refibrillation: An all atom Molecular Dynamics simulation study.

The extraneuronally deposited senile plaques, composed of neurotoxic aggregates of Aß fibril, define Alzheimer's disease (AD). Natural compounds have been tested for their destabilization potential on Aß fibril, thereby curing AD. However, the resultant destabilized Aß fibril, needs to be checked for its irreversibility to the native organized state after removal of the ligand. Herein, we assessed the stability of a destabilized fibril after the ligand (ellagic acid represented as REF) is removed from the complex. The study has been conducted via Molecular Dynamics (MD) simulation of 1 µs for both Aß-Water (control) and Aß-REF″ (test or REF removed) system. The increased value of RMSD, Rg, SASA, lower ß-sheet content and reduced number of H-bonds explains enhanced destabilization observed in Aß-REF″ system. The increased inter-chain distance demonstrates breaking of the residual contacts, testifying the drift of terminal chains from the pentamer. The increased SASA along with the ∆Gps(polar solvation energy) accounts for the reduced interaction amongst residues, and more with solvent molecules, governing irreversibility to native state. The higher Gibb's free energy of the misaligned structure of Aß-REF″ ensures irreversibility to the organized structure due to its inability to cross such high energy barrier. The observed stability of the disaggregated structure, despite ligand elimination, establishes the effectiveness of the destabilization technique as a promising therapeutic approach towards treating AD.

Destabilization of Aß fibrils by omega-3 polyunsaturated fatty acids: a molecular dynamics study.

The senile plaques of neurotoxic aggregates of Aß protein, deposited extraneuronally, mark the pathological hallmark of Alzheimer's disease (AD). The natural compounds such as omega-3 (ω-3) polyunsaturated fatty acids (PUFAs), which can access blood-brain barrier, are believed to be potential disruptors of preformed Aß fibrils to cure AD with unknown mechanism. Herein, we present the destabilization potential of three ω-3 PUFAs, viz. Eicosapentaenoic acid (EPA), Docosahexaenoic acid (HXA), and α-linolenic acid (LNL) by molecular dynamics simulation. After an initial testing of 300 ns, EPA and HXA have been considered further for extended production run time, 500 ns. The increased value of root mean square deviation (RMSD), radius of gyration, and solvent-accessible surface area (SASA), the reduced number of H-bonds and ß-sheet content, and disruption of salt bridges and hydrophobic contacts establish the binding of these ligands to Aß fibril leading to destabilization. The polar head was found to interact with positively charged lysine (K28) residue in the fibril. However, the hydrophobicity of the long aliphatic tail competes with the intrinsic hydrophobic interactions of Aß fibril. This amphiphilic nature of EPA and HXA led to the breaking of inherent hydrophobic contacts and formation of new bonds between the tail of PUFA and hydrophobic residues of Aß fibril, leading to the destabilization of fibril. The Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) results explain the binding of EPA and HXA to Aß fibril by interacting with different residues. The destabilization potential of EPA and HXA establishes them as promising drug leads to cure AD, and encourages prospecting of other fatty acids for therapeutic intervention in AD.Communicated by Ramaswamy H. Sarma.

Self-Organized Liquid Crystal Droplets as Phototunable Softmasks.

A single-step self-organized pathway is harnessed to generate large-area and high-density liquid-crystal (LC) microdroplets via rapid spreading of an LC-laden volatile liquid film on an aqueous surfactant bath. The surfactant loading on the water bath and LC loading in the solvent fluid help in tuning the size, periodicity, and ordering of LC microdroplets. Remarkably, the experiments reveal a transition from a spinodal to heterogeneous nucleation pathway of dewetting when the surfactant loading is modulated from below to beyond the critical micellar concentration in the aqueous phase. In the process, a host of unprecedented drop formation modes, such as dewetting and contact-line instability, random ejection, and "fire cracker" toroid splitting, have been uncovered. Subsequently, the LC microdroplets on the air-water interface are employed as photomasks suitable for soft-photolithography applications. Such masks help in the decoration of a host of mesoscale three-dimensional features on the films of photoresists when photons are guided through the LC droplets. In such a scenario, phase transition of LC droplets under solvent vapor annealing is employed to control the movement of photons through drops and subsequently modulate the light exposure on the photoresist surface. Such a simple soft-photolithography setup leads to an array of flattened droplets on a positive resist, while donut features are observed on the negative tone. Remarkably, the orientation of nematogens within 4-cyano-4'-pentylbiphenyl droplets and at the three-phase contact-line provides additional handles in controlling the transmission of photons, which facilitates such a unique pattern formation. A number of low-cost and simple strategies are also discussed to order such soft-photolithography patterns. Importantly, with a minor modification to the same experimental setup, we could also measure the variation in the order parameter of the LC droplet during its phase transitions from the nematic to isotropic state.

Destabilization of the Alzheimer's amyloid-ß peptide by a proline-rich ß-sheet breaker peptide: a molecular dynamics simulation study.

The amyloid-ß peptide exists in the form of fibrils in the plaques found in the brains of patients with Alzheimer's disease. One of the therapeutic strategies is the design of molecules which can destabilize these fibrils. We present a designed peptide KLVFFP5 with two segments: the self-recognition sequence KLVFF and a ß-sheet breaker proline pentamer. Molecular dynamics simulations and docking results showed that this peptide could bind to the protofibrils and destabilize them by establishing hydrophobic contacts and hydrogen bonds with a higher affinity than the KLVFF peptide. In the presence of the KLVFFP5 peptide, the ß-sheet content of the protofibrils was reduced significantly; the hydrogen bonding network and the salt bridges were disrupted to a greater extent than the KLVFF peptide. Our results indicate that the KLVFFP5 peptide is an effective ß-sheet disruptor which can be considered in the therapy of Alzheimer's disease.

Functional liquid droplets for analyte sensing and energy harvesting.

Over the past century, rapid miniaturization of technologies has helped in the development of efficient, flexible, portable, robust, and compact applications with minimal wastage of materials. In this direction, of late, the usage of mesoscale liquid droplets has emerged as an alternative platform because of the following advantages: (i) a droplet is incompressible and at the same time deformable, (ii) interfacial area of a spherical droplet is minimum for a given amount of mass; and (iii) a droplet interface allows facile mass, momentum, and energy transfer. Subsequently, such attributes have aided towards the design of diverse droplet-based microfluidic technologies. For example, the microdroplets have been utilized as micro-reactors, colorimetric or electrochemical (EC) sensors, drug-delivery vehicles, and energy harvesters. Further, a number of recently reported lab-on-a-chip technologies exploit the motility, storage, and mixing capacities of the microdroplets. In view of this background, the review initiates discussion by highlighting the different attributes of the microdroplets such as size, shape, surface to volume ratio, wettability, and contact line. Thereafter, the effects of the surface or body forces on the properties of the droplets have been elaborated. Finally, the different aspects of such liquid droplet systems towards technological adaptations in health care, sensing, and energy harvesting have been presented. The review concludes with a tight summary on the potential avenues for further developments.

Destabilization of the Alzheimer's amyloid-ß protofibrils by THC: A molecular dynamics simulation study.

Alzheimer's disease is a leading cause of dementia in the elderly population for which there is no cure at present. Deposits of neurotoxic plaques are found in the brains of patients which are composed of fibrils of the amyloid-ß peptide. Molecules which can disrupt these fibrils have gained attention as potential therapeutic agents. Δ-tetrahydrocannabidiol (THC) is a cannabinoid, which can bind to the receptors in the brain, and has shown promise in reducing the fibril content in many experimental studies. In our present study, by employing all atom molecular dynamics simulations, we have investigated the mechanism of the interaction of the THC molecules with the amyloid-ß protofibrils. Our results show that the THC molecules disrupt the protofibril structure by binding strongly to them. The driving force for the binding was the hydrophobic interactions with the hydrophobic residues in the fibrils. As a result of these interactions, the tight packing of the hydrophobic core of the protofibrils was made loose, and salt bridges, which were important for stability were disrupted. Hydrogen bonds between the chains of the protofibrils which are important for stability were disrupted, as a result of which the ß-sheet content was reduced. The destabilization of the protofibrils by the THC molecules leads to the conclusion that THC molecules may be considered for the therapy in treating Alzheimer's disease.

Enhancing the binding of the ß-sheet breaker peptide LPFFD to the amyloid-ß fibrils by aromatic modifications: A molecular dynamics simulation study.

Alzheimer's is a fatal neurodegenerative disease for which there is no cure at present. The disease is characterized by the presence of plaques in the brains of a patient, which are composed mainly of aggregates of the amyloid-ß peptide in the form of ß-sheet fibrils. Here, we investigated the possibility of exploiting the superior binding ability of aromatic amino acids to a particular model of the amyloid-ß fibrils. which is a difficult target for drug design. The ß-sheet breaker peptide LPFFD was modified with aromatic amino acids and its binding to these fibrils was studied. We found that the orientation and the electrostatic complementarity of the modified peptide with respect to the fibrils played a crucial role in determining whether its binding was improved by the aromatic amino acids. The modified LPFFD peptides were able to bind to those fibril residues. which are important in the aggregation of amyloid-ß peptides and thus can potentially inhibit the further aggregation of the amyloid-beta peptides by blocking their interactions. We found that the tryptophan modified LPFFD peptides had the best binding affinities. In most cases, the aromatic amino acids in the N-terminus of the modified peptides made more contacts with the fibrils than those in the C-terminus. We also found that increasing the aromatic content did not significantly improve the binding of the LPFFD peptide to the fibrils. Our study can serve as a basis for the design of novel peptide-based drugs for Alzheimer's disease in which aromatic interactions play an important role.

Destabilization potential of phenolics on Aß fibrils: mechanistic insights from molecular dynamics simulation.

The clinical signature of Alzheimer's disease (AD) is the deposition of aggregated Aß fibrils that are neurotoxic to the brain. It is the major form of dementia affecting older people worldwide, impeding their normal function. Finding and testing various natural compounds to target and disrupt stable Aß fibrils seems to be a promising and attractive therapeutic approach. Four phenolic compounds from plant sources were taken into consideration for the present work, and were initially screened by docking. Ellagic acid (REF) came out to be the best binder of the Aß oligomer from docking studies. To test the destabilization effect of REF on the Aß oligomer, MD simulation was conducted. The simulation outcome obtained clearly indicates a drift of terminal chains from the Aß oligomer, leading to the disorganization of the characteristically organized cross ß structure of the Aß fibrils. Increased values of RMSD, Rg, RMSF, and SASA are indicative of the destabilization of the Aß fibril in the presence of REF. The disruption of salt bridges and a notable decline in the number of hydrogen bonds and ß-sheet content explain the conformational changes in the Aß fibril structure, ceasing their neurotoxicity. The MM-PBSA results revealed the binding of REF to chain A of the Aß oligomer. The destabilization potential of ellagic acid, as explained by the MD simulation study, establishes it as a promising drug for curing AD. The molecular-level details about the destabilization mechanism of ellagic acid encourage the intensive mining of other natural compounds for therapeutic intervention for AD.

Self-organized spreading of droplets to fluid toroids.

HYPOTHESIS: Mixing of a chemical trigger of lower surface tension into a microdroplet with relatively higher surface tension can cause a rapid spreading of the droplet on a liquid-sublayer to form a host of metastable liquid morphologies such as sheets, toroids, threads, or droplets. Subsequently, such metastable fluidic objects break into a collection of droplets to form microemulsions. EXPERIMENTS: Introduction of surfactant loaded water or long-chain alcohols into an oleic acid microdroplet stimulate a rapid spreading of the same on a water sublayer, which helps in the formation of a metastable liquid sheet connected to a liquid toroid. Much like slipping films, the liquid sheet dewets the water underlayer through the formation of holes before they grow and coalesce to form liquid ribbons. While such liquid structures eventually break into an array of microdroplets, the liquid toroid expands before undergoing a Plateau-Rayleigh instability to form microdroplets. FINDINGS: A single step self-organization process in which a chemical trigger can convert a microdroplet into a liquid-toroid on a water surface, in absence of any rotational influence. A symmetric to asymmetric transition in toroid morphology is observed due to the changeover of laminar to turbulent flow regimes with the reduction in viscosity of fluid-sublayer or variation in chemical triggers. The toroid cross-section and droplet spacing after the toroid breakup follow a length scale evaluated from a linear stability analysis.

Microdroplet photofuel cells to harvest high-density energy and dye degradation.

In this study, a membraneless photofuel cell, namely, µ-DropFC, was designed and developed to harvest chemical and solar energies simultaneously. The prototypes can also perform environmental remediation to demonstrate their multitasking potential as a sustainable hybrid device in a single embodiment. A hydrogen peroxide (H2O2) microdroplet at optimal pH and salt loading was utilized as a fuel integrated with Al as an anode and zinc phthalocyanine (ZnPC)-coated Cu as a cathode. The presence of n-type semiconductor ZnPC in between the electrolyte and metal enabled the formation of a photo-active Schottky junction suitable for power generation under light. Concurrently, the oxidation and reduction of H2O2 on the electrodes helped in the conversion of chemical energy into the electrical one in the same membraneless setup. The suspension of Au nanoparticles (Au NPs) in the droplet helped in enhancing the overall power density under photonic illumination through the effects of localized surface plasmon resonance (LSPR). Furthermore, the presence of photo-active n-type CdS NPs enabled the catalytic photo-degradation of dyes under light in the same embodiment. A 40 µL µ-DropFC could show a significantly high open circuit potential of ∼0.58 V along with a power density of 0.72 mW cm-2. Under the same condition, the integration of ten such µ-DropFCs could produce a power density of ∼7 mW cm-2 at an efficiency of 3.4%, showing the potential of the prototype for a very large scale integration (VLSI). The µ-DropFC could also degrade ∼85% of an industrial pollutant, rhodamine 6G, in 1 h while generating a power density of ∼0.6 mW cm-2. The performance parameters of µ-DropFCs were found to be either comparable or superior to the existing prototypes. In a way, the affordable, portable, membraneless, and high-performance µ-DropFC could harvest energy from multiple resources while engaging in environmental remediation.

Polyproline chains destabilize the Alzheimer's amyloid-ß protofibrils: A molecular dynamics simulation study.

Alzheimer's is a fatal neurodegenerative disease for which there is no cure at present. The disease is characterized by the presence of plaques, principally comprising the amyloid-ß peptide (viz., ß-sheet) in the brains of a patient. In our present work, we study the interaction of these ß-sheets with a different number of repeating units of proline (ß-sheet breaker) by docking and all atom molecular dynamics simulations. Our results indicate that proline can break the amyloid protofibrils apart, cause them to break their ß-sheet structure, and in some cases even induce the formation of 310 helices, which may be intermediates in the unfolding of these ß-sheets. We have also observed that some of the important hydrogen bonds and salt bridges between chains were disrupted by proline and the tight interatomic packing of atoms in the fibrils was made relatively loose. Proline chains had a tendency to make several contacts with charged residues. Proline chains binded well to the fibrils by strong electrostatic interactions while hydrophobic interactions played a less important role. This leads to the conclusion that proline can break the amyloid fibrils apart and can be considered in the design of novel peptide-based drugs to treat Alzheimer's disease and potentially other diseases caused by the misfolding of proteins into ß-sheets.

Caffeine destabilizes preformed Aß protofilaments: insights from all atom molecular dynamics simulations.

The aggregation and deposition of neurotoxic Aß fibrils are key in the etiology of Alzheimer's disease (AD). It has been clinically recognized as a major form of dementia across the globe. Finding and testing various natural compounds to target Aß fibrils to disrupt their stable structures seems to be a promising and attractive therapeutic strategy. The destabilization effects of caffeine on Aß fibrils are investigated via in silico studies, where a series of molecular dynamics (MD) simulations, each of 100 ns, was conducted. The simulation outcomes obtained henceforth clearly indicated the drift of the terminal chains from the protofibrils, leading to disorganization of the characteristically organized cross-ß structures of Aß fibrils. The structural instability of Aß17-42 protofibrils is explained through enhanced fluctuations in the RMSD, radius of gyration and RMSF values in the presence of caffeine. The key interactions providing stability, comprising D23-K28 salt bridges, intra- and inter-chain hydrogen bonding and hydrophobic interactions involving interchain A21-V36 and F19-G38 and intrachain L34-V36, were found to be disrupted due to increases in the distances between the participating components. The loss of ß-sheet structure with the introduction of turns and α-helices in terminal chains may further inhibit the formation of higher order aggregates, which is necessary to stop the progression of the disease. The atomistic details obtained via MD studies relating to the mechanism behind the underlying destabilization of Aß17-42 protofibrils by caffeine encourage further investigations exploring the potency of natural compounds to treat AD via disrupting preformed neurotoxic Aß protofibrils.

Effect of Composition Asymmetry on the Phase Separation and Crystallization in Double Crystalline Binary Polymer Blends: A Dynamic Monte Carlo Simulation Study.

Polymer blends offer an exciting material for various potential applications due to their tunable properties by varying constituting components and their relative composition. Our simulation results unravel an intrinsic relationship between crystallization behavior and composition asymmetry. We report simulation results for nonisothermal and isothermal crystallization with weak and strong segregation strength to elucidate the composition dependent crystallization behavior. With increasing composition of low melting B-polymer, macrophase separation temperature changes nonmonotonically, which is attributed to the nonmonotonic change in diffusivity of both polymers. In weak segregation strength, however, at high enough composition of B-polymer, A-polymer yields relatively thicker crystals, which is attributed to the dilution effect exhibited by B-polymer. When B-polymer composition is high enough, it acts like a "solvent" while A-polymer crystallizes. Under this situation, A-polymer segments become more mobile and less facile to crystallize. As a result, A-polymer crystallizes at a relatively low temperature with the formation of thicker crystals. At strong segregation strength, the dilution effect is accompanied by the strong A-B repulsive interaction, which is reflected in a nonmonotonic trend of the mean square radius of gyration with the increasing composition of the B-polymer. Isothermal crystallization also reveals a strong nonmonotonic relationship between composition and crystallization behavior. Two-step, compared to one-step, isothermal crystallization yields better crystals for both polymers.

Multi-scale molecular dynamics study of cholera pentamer binding to a GM1-phospholipid membrane.

The AB5 type toxin produced by the Vibrio cholerae bacterium is the causative agent of the cholera disease. The cholera toxin (CT) has been shown to bind specifically to GM1 glycolipids on the membrane surface. This binding of CT to the membrane is the initial step in its endocytosis and has been postulated to cause significant disruption to the membrane structure. In this work, we have carried out a combination of coarse-grain and atomistic simulations to study the binding of CT to a membrane modelled as an asymmetrical GM1-DPPC bilayer. Simulation results indicate that the toxin binds to the membrane through only three of its five B subunits, in effect resulting in a tilted bound configuration. Additionally, the binding of the CT can increase the area per lipid of GM1 leaflet, which in turn can cause the membrane regions interacting with the bound subunits to experience significant bilayer thinning and lipid tail disorder across both the leaflets.

Coarse-grain molecular dynamics study of fullerene transport across a cell membrane.

The study of the ability of drug molecules to enter cells through the membrane is of vital importance in the field of drug delivery. In cases where the transport of the drug molecules through the membrane is not easily accomplishable, other carrier molecules are used. Spherical fullerene molecules have been postulated as potential carriers of highly hydrophilic drugs across the plasma membrane. Here, we report the coarse-grain molecular dynamics study of the translocation of C60 fullerene and its derivatives across a cell membrane modeled as a 1,2-distearoyl-sn-glycero-3-phosphocholine bilayer. Simulation results indicate that pristine fullerene molecules enter the bilayer quickly and reside within it. The addition of polar functionalized groups makes the fullerenes less likely to reside within the bilayer but increases their residence time in bulk water. Addition of polar functional groups to one half of the fullerene surface, in effect creating a Janus particle, offers the most promise in developing fullerene models that can achieve complete translocation through the membrane bilayer.

Effect of block asymmetry on the crystallization of double crystalline diblock copolymers.

Monte Carlo simulation on the crystallization of double crystalline diblock copolymer unravels an intrinsic relationship between block asymmetry and crystallization behaviour. We model crystalline A-B diblock copolymer, wherein the melting temperature of A-block is higher than that of the B-block. We explore the composition dependent crystallization behaviour by varying the relative block length with weak and strong segregation strength between the blocks. In weak segregation limit, we observe that with increasing the composition of B-block, its crystallization temperature increases accompanying with higher crystallinity. In contrast, A-block crystallizes at a relatively low temperature along with the formation of thicker and larger crystallites with the increase in B-block composition. We attribute this non-intuitive crystallization trend to the dilution effect imposed by B-block. When the composition of the B-block is high enough, it acts like a "solvent" during the crystallization of A-block. A-block segments are more mobile and hence less facile to crystallize, resulting depression in crystallization temperature with the formation of thicker crystals. At strong segregation limit, crystallization and morphological development are governed by the confinement effect, rather than block asymmetry. Isothermal crystallization reveals that the crystallization follows a homogeneous nucleation mechanism with the formation of two-dimensional crystals. Two-step, compared to one-step isothermal crystallization leads to the formation of thicker crystals of A-block due to the dilution effect of the B-block.

Conformational transition of H-shaped branched polymers.

We report dynamic Monte Carlo simulation on conformational transition of H-shaped branched polymers by varying main chain (backbone) and side chain (branch) length. H-shaped polymers in comparison with equivalent linear polymers exhibit a depression of theta temperature accompanying with smaller chain dimensions. We observed that the effect of branches on backbone dimension is more pronounced than the reverse, and is attributed to the conformational heterogeneity prevails within the molecule. With an increase in branch length, backbone is slightly stretched out in the coil and globule state. However, in the pre-collapsed (cf. crumpled globule) state, backbone size decreases with the increase of branch length. We attribute this non-monotonic behavior as the interplay between excluded volume interaction and intra-chain bead-bead attractive interaction during collapse transition. Structural analysis reveals that the inherent conformational heterogeneity promotes the formation of a collapsed structure with segregated backbone and branch units (resembles to "sandwich" or "Janus" morphology) rather an evenly distributed structure consisting of all the units. The shape of the collapsed globule becomes more spherical with increasing either backbone or branch length.

Polymer crystallization in the presence of "sticky" additives.

The effect of "sticky" additives (viz., those that have attractive interactions with the polymer) on polymer crystallization, has been investigated by dynamic Monte Carlo (DMC) simulations. Additive-polymer attractive interactions result in a slowing down of the polymer chain diffusivity in the melt state. Our results show that with increasing additive stickiness, polymer crystallinity decreases monotonically, and thinner crystallites form, viz., crystallization is inhibited by the presence of sticky additives. Unusually, the observed "specific heat" peak at the phase transition shows nonmonotonic behavior with additive stickiness, and exhibits a maximum for intermediate values of additive stickiness. While the origins of this unexpected behavior are not clear, we show that it correlates with a large interchange between crystalline and amorphous states of the monomers, in the vicinity of the additives. At this intermediate additive stickiness, we also find that crystallization follows a qualitatively different route--crystallinity shows a non-Avrami-like evolution, unlike the case at low or high additive stickiness.

Pathway to copolymer collapse in dilute solution: uniform versus random distribution of comonomers.

Monte Carlo simulations show that copolymers with uniformly (or periodically) distributed sticky comonomers collapse "cooperatively," abruptly forming a compact intermediate comprising a monomer shell surrounding a core of the aggregated comonomers. In comparison, random copolymers collapse through a relatively less-compact intermediate comprising a comonomer core surrounded by a fluffy monomer shell that densifies over a wide temperature range. This difference between the collapse pathways for random and uniform copolymers persists to higher chain lengths, where uniform copolymers tend to form multiple comonomer cores. In this paper, we describe the formation of such an intermediate state, and the subsequent collapse, by recognizing that these arise from the expected balance between comonomer aggregation enthalpy and loop formation entropy dictated by the chain microstructure.