Chain Order Research Articles

Deciphering Lipid Arrangement in Phosphatidylserine/Phosphatidylcholine Mixed Membranes: Simulations and Experiments.

Phosphatidylserine (PS) exposure on the plasma membrane is crucial for many cellular processes including apoptotic cell recognition, blood clotting regulation, cellular signaling, and intercellular interactions. In this study, we investigated the arrangement of PS headgroups in mixed PS/phosphatidylcholine (PC) bilayers, serving as a simplified model of the outer leaflets of mammalian cell plasma membranes. Combining atomistic-scale molecular dynamics (MD) simulations with Langmuir monolayer experiments, we unraveled the mutual miscibility of POPC and POPS lipids and the intricate intermolecular interactions inherent to these membranes as well as the disparities in position and orientation of PC and PS headgroups. Our experiments revealed micrometer-scale miscibility at all mole fractions of POPC and POPS, marked by modest deviations from ideal mixing with no apparent microscale phase separation. The MD simulations, meanwhile, demonstrated that these deviations were due to strong electrostatic interactions between like-lipid pairs (POPC-POPC and POPS-POPS), culminating in lateral segregation and nanoscale clustering. Notably, PS headgroups profoundly affect the ordering of the lipid acyl chains, leading to lipid elongation and subtle PS protrusion above the zwitterionic membrane. In addition, PC headgroups are more tilted with respect to the membrane normal, while PS headgroups align at a smaller angle, making them more exposed to the surface of the mixed PC/PS membranes. These findings provide a detailed molecular-level account of the organization of mixed PC/PS membranes, corroborated by experimental data. The insights gained here extend our comprehension of the physiological role of PSs.

Molecular Design of Multifunctional Integrated Polymer Semiconductors with Intrinsic Stretchability, High Mobility, and Intense Luminescence.

Multifunctional semiconductors integrating unique optical, electrical, mechanical, and chemical characteristics are critical to advanced and emerging manufacturing technologies. However, due to the trade-off challenges in design principles, fabrication difficulty, defects in existing materials, etc., realizing multiple functions through multistage manufacturing is quite taxing. Here, an effective molecular design strategy is established to prepare a class of multifunctional integrated polymer semiconductors. The pyridal[1,2,3]triazole-thiophene co-structured tetrapolymers with full-backbone coplanarity and considerable inter/intramolecular noncovalent interactions facilitate short-range order and excellent (re)organization capability of polymer chains, providing stress-dissipation sites in the film state. The regioregular multicomponent conjugated backbones contribute to dense packing, excellent crystallinity, high crack onset strain over 100%, efficient carrier transport with mobilities exceeding 1cm2 V-1 s-1 , and controllable near-infrared luminescence. Furthermore, a homologous blending strategy is proposed to further enhance the color-tunable luminescent properties of polymers while effectively retaining mechanical and electrical properties. The blended system exhibits excellent field-effect mobility (µ) and quantum yield (Φ), reaching a record Φ · µ of 0.43cm2 V-1 s-1 . Overall, the proposed strategy facilitates a rational design of regioregular semicrystalline intrinsically stretchable polymers with high mobility and color-tunable intense luminescence, providing unique possibilities for the development of multifunctional integrated semiconductors in organic optoelectronics.

Retail Price of Imatinib Negotiated By Medicare Part D Plans with National or Regional Coverage at Large Chain and Mail Order Pharmacies

Title Retail price of imatinib negotiated by Medicare Part D plans with national or regional coverage at large chain and mail order pharmacies Background Direct-to-consumer pharmacies or websites such as Cost Plus or GoodRx has made imatinib more affordable even without prescription drug coverage. Wholesale acquisition cost (WAC) or list price is often used to compare drug prices. However, the pharmacy retail price negotiated by prescription drug plans and pharmacies is more relevant to patient as it directly impacts out-of-pocket costs and affects decisions on how to acquire oral cancer medications. The price of imatinib for Medicare beneficiaries through different Part D prescription drug plans is variable and not well known. Methods Part D Plan Finder was used to identify Medicare drug' plans offered in Portland, OR at zip code 97239. The monthly retail price of imatinib 400 mg was compared for all available Part D plans for a representative list of nationwide and regional large chain pharmacies (Walgreens, CVS, Rite Aid, Safeway) and for mail order pharmacy. The premium and deductible for each drug plan was extracted. The highest and lowest retail price available for each drug plan and the drug cost for first, second and third fill for each retail price was extracted. This drug cost of imatinib was compared to the out-of-pocket cost of imatinib available from Cost Plus pharmacy and GoodRx in zip code 97239. Results Nine insurance companies offered 24 drug plans in July, 2023. The premium ranged from $1.6 to $113 and the deductible was $0 to $505. All insurance companies offered 2-3 plans with low premium/high deductible or high premium/low deductible. Plans were categorized to low deductible plans (less than $100), medium deductible plans ($100 to $300) and high deductible plans (more than $300). There were 19 high deductible plans. The median retail price was $4340 (IQR 945-5467). The median drug cost for the patient at first fill was $1464 (IQR 583-1745). There were 4 low deductible plans with median retail price of $823 (IQR 187-6419) and median drug cost at first fill of $275 (IQR 61-1971). There was one medium deductible plan and the retail price was $4374 and patient drug cost at first fill was $1425. The lowest retail price was $77 for Asuris Medicare Script Enhanced (PDP) if prescription was filled at Safeway. The highest retail price was $8881 for Elixir RxPlus (PDP) if prescription was filled at Safeway, CVS or Rite Aid. The monthly imatinib from Cost Plus is $33 (+$5 shipping). GoodRx offered coupons for Walgreens at $150, Rite Aid at $64, CVS at $789 and Safeway $90. Conclusions The retail price of imatinib for patients with Medicare Part D drug plan is highly variable depending on the drug plan and filling pharmacy and the out-of-pocket drug cost is often higher than the cost of buying imatinib at Cost Plus by mail order or at the same pharmacy using a GoodRx coupon.

Simulations of naïve and KLA-activated macrophage plasma membrane models

Macrophages (MAs), which play vital roles in human immune responses and lipid metabolisms, are implicated in the development and progression of atherosclerosis, a major contributor to cardiovascular diseases. Specifically, the abnormal lipid metabolism of oxidized low-density lipids (oxLDLs) in MAs is believed to be a crucial factor. However, the precise mechanism by which the MA membrane contributes to this altered lipid metabolism remains unclear. Lipidomic studies have revealed significant differences in membrane composition between various MA phenotypes. This study serves to provide and characterize complex realistic computational models for naïve (M0) and Kdo2-lipid A-activated (M1) state MA. Analyses of surface area per lipid (SA/lip), area compressibility modulus (KA), carbon‑hydrogen order parameter (SCH), electron density profile (EDP), tilt angles, two-dimension radial distribution functions (2D RDFs), mean squared displacement (MSD), hydrogen bonds (H-bonds), lipid clustering, and lipid wobble were conducted for both models. Results indicate that the M1 state MA membrane is more tightly packed, with increased chain order across lipid species, and forms PSM-DOPG-CHOL and PSM-SLPC-CHOL clusters. Importantly, the bilayer thicknesses reported for the models are in good agreement with experimental data for the thicknesses of transmembrane regions for MA integral proteins. These findings validate the described models as physiologically accurate for future computational studies of MA membranes and their residing proteins.

The rise of FTIR spectroscopy in the characterization of asymmetric lipid membranes

In contrast to symmetric unilamellar liposomes (sLUVs) prepared from a mixture of different lipids, asymmetric ones (aLUVs) with different lipid composition in the inner and outer membrane leaflets are more suitable model systems of eukaryotic plasma membranes. However, apart from the challenging preparation of asymmetric liposomes and small amounts of obtained asymmetric unilamellar liposomes (aLUVs), a major drawback is the qualitative characterization of asymmetry, as each of the techniques used so far has certain limitations. In this regard, we prepared aLUVs composed dominantly of DPPC(out)/DPPS(in) lipids and, along with 1H NMR and DSC characterization, we showed for the first time how FTIR spectroscopy can be used in the presence of (a)symmetry between DPPC/DPPS lipid bilayers. Using second derivative FTIR spectra we demonstrated not only that the hydration of lipids glycerol backbone and choline moiety of DPPC differs in s/aLUVs, but in addition that the lateral interactions between hydrocarbon chains during the phase change display different trend in s/aLUVs. Molecular dynamics simulations confirmed different chain ordering and packing between s/a bilayers, with a significant influence of temperature, i.e. membrane phase.

Analysis of Program Representations Based on Abstract Syntax Trees and Higher-Order Markov Chains for Source Code Classification Task

In this paper we consider the research and development of classifiers that are trained to predict the task solved by source code. Possible applications of such task detection algorithms include method name prediction, hardware–software partitioning, programming standard violation detection, and semantic code duplication search. We provide the comparative analysis of modern approaches to source code transformation into vector-based representations that extend the variety of classification and clustering algorithms that can be used for intelligent source code analysis. These approaches include word2vec, code2vec, first-order and second-order Markov chains constructed from abstract syntax trees (AST), histograms of assembly language instruction opcodes, and histograms of AST node types. The vectors obtained with the forementioned approaches are then used to train such classification algorithms as k-nearest neighbor (KNN), support vector machine (SVM), random forest (RF), and multilayer perceptron (MLP). The obtained results show that the use of program vectors based on first-order AST-based Markov chains with an RF-based classifier leads to the highest accuracy, precision, recall, and F1 score. Increasing the order of Markov chains considerably increases the dimensionality of a vector, without any improvements in classifier quality, so we assume that first-order Markov chains are best suitable for real world applications. Additionally, the experimental study shows that first-order AST-based Markov chains are least sensitive to the used classification algorithm.

Molecular dynamics simulations of an antifreeze protein at the lipid / water interface

The ability of antifreeze proteins (AFP's) and glycoproteins (AFGP's) to prevent damage to certain organisms under cold stress is well established. These molecules have also been shown to prevent chilling damage in some biological membranes and interaction between membranes and AF(G)P's has been observed during chilling events; however, the exact mechanism of membrane stabilization is still not well understood. Molecular modelling is an ideal technique for probing atomistic information in these systems although modelling studies to date have focused on peptide structure and the site and mode, e.g., insertion, of the peptide-membrane interaction. To provide insight into how AF(G)P's may act to stabilize (or destabilize) membranes during phase transitions, we have conducted molecular dynamics (MD) simulations of a solvated dimyristoylphosphatidylcholine (DMPC) lipid bilayer containing an AFP Type I at the lipid/water interface at several temperatures. We present the analysis of several properties of the phospholipid bilayer that are relevant when considering phase transitions. Possible areas for concentrating future research efforts have been highlighted; namely the acyl chain order and the polar headgroups, both of which have been implicated in experimental studies of the stabilization of model membranes by AF(G)P's.

Cytotoxic effect of polyvinyl alcohol-magnetite composite

Polymeric hydrogel is a promising candidate for drug delivery applications due to its ability to encapsulate and release drugs. Incorporating magnetic particles enables controlled and specific release, providing sustained and targeted delivery. This study aimed to assess the cytotoxicity of the magnetite-polyvinyl alcohol (MPVA) hydrogel, specifically its magnetite content, using 3T3 fibroblast cells. The findings indicate that the MPVA hydrogel with magnetite nanoparticles was compatible with the cells and did not induce cell death. Incorporating magnetite nanoparticles into the PVA hydrogel improved its thermal stability and degradation temperature, disrupting the chain order, decreasing melting behavior, and fractional crystallinity of the hydrogel. The MPVA hydrogel demonstrated a higher gel fraction and crosslink density compared to the PVA hydrogel due to the presence of magnetite nanoparticles. The interaction between PVA and magnetite nanoparticles occurred through non-covalent forces, allowing for reversible interactions and dispersion of the nanoparticles within the PVA matrix. Although the cytotoxicity of the MPVA gel was similar to that of the PVA gel, the viability of fibroblast cells within the MPVA gel varied depending on the concentration. The MPVA hydrogel exhibited stronger attachment and induced irregular changes on the cell surface compared to the PVA hydrogel. Furthermore, the MPVA gel displayed paramagnetic behavior and controllable magnetization, as demonstrated by the hysteresis loop. These magnetic properties make the MPVA gel suitable for potential biomedical applications, including drug delivery, tissue engineering, and magnetic resonance imaging (MRI) contrast agents.

Cluster-based test vector re-ordering for reduced power dissipation in digital circuits

Optimizing testing power is a paramount concern in modern digital circuit design, particularly as the intricacy of circuits continues to rise. This issue becomes even more pronounced with the scaling down of feature sizes due to advancements in process technology. The increase in testing power dissipation, beyond the regular operational state, raises red flags for both designers and test engineers. This paper introduces a novel cluster-based approach, shedding light on the efficient reordering of test vectors to mitigate the heightened switching activity. This technique aims to reduce the power consumption during testing, while still ensuring efficient error detection, maintaining the test period, and preserving the original order of the scan chain. Importantly, this reordering method does not introduce any additional area or test time overhead, minimizing the risks associated with these factors. The potential impact of this approach is demonstrated through concrete examples drawn from ISCAS’89 benchmark circuits. The results showcase a notable 11% reduction in switching activity, all while preserving fault coverage levels.

Puncturing lipid membranes: onset of pore formation and the role of hydrogen bonding in the presence of flavonoids

Products of lipid peroxidation induce detrimental structural changes in cell membranes, such as the formation of water pores, which occur in the presence of lipids with partially oxidized chains. However, the influence of another class of products, dicarboxylic acids, is still unclear. These products have greater mobility in the lipid bilayer, which enables their aggregation and the formation of favorable sites for the appearance of pores. Therefore, dodecanedioic acid (DDA) was selected as a model product. Additionally, the influence of several structurally different flavonoids on DDA aggregation via formation of hydrogen bonds with carboxyl groups was investigated. The molecular dynamics of DDA in DOPC lipid bilayer revealed the formation of aggregates extending over the hydrophobic region of the bilayer and increasing its polarity. Consequently, water penetration and the appearance of water wires was observed, representing a new step in the mechanism of pore formation. Furthermore, DDA molecules were found to interact with lipid polar groups, causing them to be buried in the bilayer. The addition of flavonoids to the system disrupted aggregate formation, resulting in the displacement of DDA molecules from the center of the bilayer. The placement of DDA and flavonoids in the lipid bilayer was confirmed by small-angle X-ray scattering. Atomic force microscopy and electron paramagnetic resonance were used to characterize the structural properties. The presence of DDA increased bilayer roughness and decreased the ordering of lipid chains, confirming its detrimental effects on the membrane surface, while flavonoids were found to reduce or reverse these changes.

Characterization of conformational states of POPC and DPPCd62 in POPC/DPPCd62/cholesterol mixtures using Raman spectroscopy

Conformational states of phospholipid chains in ternary mixtures of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), deuterated 1,2-dipalmitoyl-d62-sn-glycero-3-phosphocholine (DPPCd62), and cholesterol (Chol) were studied by Raman spectroscopy. Parameters of Raman peaks sensitive to conformational order have been used to determine chain order for mixtures over a wide range of compositions. A ternary diagram of fractions of phospholipid chains in conformationally ordered and disordered states has been constructed. It was found that the addition of POPC and cholesterol increases the fraction of DPPC chains in disordered conformations. The so-called liquid-ordered phase includes DPPC molecules in both ordered and disordered states in comparable proportions. It was found that POPC chains are partially ordered in mixtures with DPPC and cholesterol, in contrast to the case of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). This maybe the underlying reason why ternary mixtures with POPC have different miscibility behavior compared to DOPC.

First passage times in portfolio optimization: A novel nonparametric approach

This paper introduces a portfolio optimization procedure that aims to minimize the intra-horizon (IH) risk subject to a minimum expected time to achieve a target cumulative return. To estimate the first passage probabilities and the expected time a novel nonparametric method and a new Markov chain order determination approach are developed. The optimization framework proposed allows us to include novel path-dependent measures of risk and return in the asset allocation problem. An empirical application to S&P 100 companies, a risk-free asset and stock indices is provided. Our empirical results suggest that the proposed framework exhibits more consistency between in-sample and out-of-sample performance than the mean-variance model and an alternative optimization problem that minimizes the MaxVaR measure of Boudoukh et al. (2004). Overall, the portfolio optimization approach we introduce results in higher out-of-sample annualized returns for relatively low levels of IH risk.

Exploring the Molecular Dynamics of a Lipid-A Vesicle at the Atom Level: Morphology and Permeation Mechanism.

Lipid-A was previously shown to spontaneously aggregate into a vesicle via the hybrid particle field approach. We assess the validity of the proposed vesiculation mechanism by simulating the resulting lipid-A vesicle at the atom level. The spatial confinement imposed by the vesicle geometry on the conformation and packing of lipid-A induces significant heterogeneity of physical properties in the inner and outer leaflets. It also induces tighter molecular packing and lower acyl chain order compared to the lamellar arrangement. Around 5% of water molecules passively permeates the vesicle membrane inward and outward. The permeation is facilitated by interactions with water molecules that are transported across the membrane by a network of electrostatic interactions with the hydrogen bond donors/acceptors in the N-acetylglucosamine ring and upper region of the acyl chains of lipid-A. The permeation process takes place at low rates but still at higher frequencies than observed for the lamellar arrangement of lipid-A. These findings not only substantiate the proposed lipid-A vesiculation mechanism but also reveal the complex structural dynamics of an important nonlamellar arrangement of lipid-A.

Bioinspired nanoarchitectonics at the air-water interface to understand the interaction of lipids with a Europium-coordinated quinoline derivative

5SO3H-8-hydroxyquinoline coordinated to Europium (Eu-5SO3-HQ) was incorporated in biomembrane models using Langmuir monolayers. Dipalmitoyl phosphatidylcholine (DPPC) and dipalmitoyl phosphatidylserine (DPPS) were employed, representing mammalian cells and dioctadecyldimethylammonium bromide (DODAB) as a positively charged lipid to study the contrast with negatively charged lipids. Tensiometric, rheological and spectroscopic techniques were employed to characterize Eu-5SO3-HQ- lipid monolayer interactions. The complex condenses all the monolayer indicating interactions with the lipids' polar heads, but with distinctive effects on the mechanical and rheological properties. While the complex decreases the compression and elastic moduli of DPPC and DPPS monolayers, it increases for DODAB, also decreasing its lateral viscosity. Infrared spectroscopy shows that the interaction of Eu-5-SO3-HQ alters the ordering of the lipids' alkyl chains, impacting the monolayer's molecular packing. These results show that the interaction of Eu-5SO3-HQ with lipid monolayers at the air-water is modulated by the composition of the polar head, which can be supportive in the preparation of nanodevices for molecular probing.

Appropriateness of serum free light chain orders in an academic medical institution.

Appropriateness of serum free light chain orders in an academic medical institution.

Ekstraksi Fitur Rantai Markov untuk Klasifikasi Famili Protein

As complex molecules, proteins have various roles for living things. Proteins are organic molecules formed from twenty amino acid combinations with various functions for living things, such as transportation systems, a catalyst of chemical reactions for metabolism, and food reserves. This research aims to classify proteins family based on sequences of amino acids as the primary structure. There are 300 amino acid fragments obtained from the Pfam database. The proteins family database subset with three sub-sample classes was obtained, including 1-cysPrx_C, 4HBT, and ABC_Tran. In this research, the first and second order of the Markov chain for extracting features were applied. Moreover, we use a Probabilistic Neural Network (PNN) as a classifier compared to the joint probability technique with Markov assumptions. We evaluate the results by comparing the sensitivity and specificity of both classification techniques. The evaluation results show that overall, PNN has slightly better performance than the joint probability technique for classifying protein families.

Morphological Transitions in Solutions of Macromolecules with Solvophilic Backbone and Orientationally Mobile Solvophobic Side Groups

A theoretical model describing the self-assembly in dilute solutions of amphiphilic macromolecules containing the backbone built of the solvophilic units (the P groups) and the solvophobic side chains (the H groups) possessing orientational mobility relative to the backbone units has been elaborated. In the framework of strong segregation limit (The size of the insoluble regions of the formed micelles is on the order of the hydrophobic side chains), state diagrams of the solution have been calculated with and without accounting for the orientational entropy contribution of the side groups to the total free energy of the solution at different thermodynamic qualities of solvent for the macromolecules and the grafting density of the H groups; the regions of stability of spherical and cylindrical micelles as well as planar bilayers (vesicles) have been revealed. It has been found that the contribution of the orientational entropy significantly affects the view of the state diagrams. In the case of considering the orientational mobility, the conditions of the cylindrical micelle stability are very sensitive to the change in the grafting density of the side groups. This sensitivity can be the reason why the formation of long cylindrical (wormlike) micelles is not observed in experiments and computer simulations. As earlier demonstrated at a qualitative level, the orientational mobility of the side groups can lead to the emergence of the orientation-induced attraction between the polymer micelles (A. I. Buglakov, D. E. Larin, and V. V. Vasilevskaya, Polymer 232, 124160 (2021)). In this study, exact analytical calculations of the energy of orientation-induced attraction for the case of the interaction between two planar bilayer micelles has been performed. At distances being of the order of the size of the side H group, the orientation-induced attraction forces are much stronger than the van der Waals forces and, hence, the orientation-induced attraction can be decisive in the formation of large aggregates observed in experiments.

Effects of antimicrobial peptides on membrane dynamics: A comparison of fluorescence and NMR experiments

Antimicrobial peptides (AMPs) represent a promising class of compounds to fight resistant infections. They are commonly thought to kill bacteria by perturbing the permeability of their cell membranes. However, bacterial killing requires a high coverage of the cell surface by bound peptides, at least in the case of cationic and amphipathic AMPs. Therefore, it is conceivable that peptide accumulation on the bacterial membranes might interfere with vital cellular functions also by perturbing bilayer dynamics, a hypothesis that has been termed “sand in the gearbox”. Here we performed a systematic study of such possible effects, for two representative peptides (the cationic cathelicidin PMAP-23 and the peptaibol alamethicin), employing fluorescence and NMR spectroscopies. These approaches are commonly applied to characterize lipid order and dynamics, but sample different time-scales and could thus report on different membrane properties. In our case, fluorescence anisotropy measurements on liposomes labelled with probes localized at different depths in the bilayer showed that both peptides perturb membrane fluidity and order. Pyrene excimer-formation experiments showed a peptide-induced reduction in lipid lateral mobility. Finally, laurdan fluorescence indicated that peptide binding reduces water penetration below the headgroups region. Comparable effects were observed also in fluorescence experiments performed directly on live bacterial cells. By contrast, the fatty acyl chain order parameters detected by deuterium NMR spectroscopy remained virtually unaffected by addition of the peptides. The apparent discrepancy between the two techniques confirms previous sporadic observations and is discussed in terms of the different characteristic times of the two approaches. The perturbation of membrane dynamics in the ns timescale, indicated by the multiple fluorescence approaches reported here, could contribute to the antimicrobial activity of AMPs, by affecting the function of membrane proteins, which is strongly dependent on the physicochemical properties of the bilayer.

Polymer Films with Metal‐Like Thermal Conductivity, Excellent Stability, and Flame Retardancy

AbstractPolymers often have thermal conductivities that are too low to be used directly in thermal management applications. In this study, a poly(p‐phenylene‐2,6‐benzobisoxazole) (PBO) film is prepared through a sol–gel‐film conversion and annealing method that utilizes PBO nanofibers as building blocks. The polymer film shows an in‐plane thermal conductivity of 36.7 W mK−1, which is two orders of magnitude higher than those of most polymers (<0.5 W mK−1) and 2.4 times that of 304‐stainless steel. The high thermal conductivity is attributed to the highly oriented 3D interconnected nanofiber network resulting from the fine‐tuning sol‐gel‐film conversion, and the annealing that further enhances the ordering of the PBO chains and the interactions between the nanofibers. Moreover, the PBO films exhibit excellent mechanical strength, thermal/chemical stability, electrical insulation, flame retardance, and improved UV resistance. The lightweight, robust, and easily processed PBO film with a metal‐like thermal conductivity has promising potential thermal management applications.

Exploring the Role of Anionic Lipid Nanodomains in the Membrane Disruption and Protein Folding of Human Islet Amyloid Polypeptide Oligomers on Lipid Membrane Surfaces Using Multiscale Molecular Dynamics Simulations.

The aggregation of human Islet Amyloid Polypeptide (hIAPP) on cell membranes is linked to amyloid diseases. However, the physio-chemical mechanisms of how these hIAPP aggregates trigger membrane damage are unclear. Using coarse-grained and all-atom molecular dynamics simulations, we investigated the role of lipid nanodomains in the presence or absence of anionic lipids, phosphatidylserine (PS), and a ganglioside (GM1), in the membrane disruption and protein folding behaviors of hIAPP aggregates on phase-separated raft membranes. Our raft membranes contain liquid-ordered (Lo), liquid-disordered (Ld), mixed Lo/Ld (Lod), PS-cluster, and GM1-cluster nanosized domains. We observed that hIAPP aggregates bound to the Lod domain in the absence of anionic lipids, but also to the GM1-cluster- and PS-cluster-containing domains, with stronger affinity in the presence of anionic lipids. We discovered that L16 and I26 are the lipid anchoring residues of hIAPP binding to the Lod and PS-cluster domains. Finally, significant lipid acyl chain order disruption in the annular lipid shells surrounding the membrane-bound hIAPP aggregates and protein folding, particularly beta-sheet formation, in larger protein aggregates were evident. We propose that the interactions of hIAPP and both non-anionic and anionic lipid nanodomains represent key molecular events of membrane damage associated with the pathogenesis of amyloid diseases.