Harmonic and anharmonic studies on THz spectra of two vanillin polymorphs.

Polymorphism commonly exists in organic molecular crystals. The fingerprint features in low-frequency vibrational range are important information reflecting different intermolecular interactions of polymorphs. Interpreting these features is very helpful to understand vibrational property of polymorphs and reveal the thermodynamic stability. In this work, the low-frequency vibrations of form I and II of vanillin are investigated using terahertz time-domain spectroscopy. Static DFT calculation and ab initio molecular dynamics (AIMD) are employed to interpret their low-frequency vibrations of both forms in harmonic and anharmonic ways, respectively. Their low-frequency vibration characteristics in harmonic calculations are discussed, and anharmonic mode couplings between OH bond stretch and the stretching and bending motion of hydrogen bonds are uncovered. Moreover, the thermodynamic energies including electronic potential energy and vibrational/kinetic energy arising from nuclear motions are calculated. The result reveals that the stability order of the two forms is mainly dependent on their electric potential energy difference.

Nonreciprocal reflection based on asymmetric graphene metasurfaces.

We propose a scheme to achieve controllable nonreciprocal behavior in asymmetric graphene metasurfaces composed of a continuous graphene sheet and a poly crystalline silicon slab with periodic grooves of varying depths on each side. The proposed structure exhibits completely asymmetric reflection in opposite directions in the near-infrared range, which is attributed to the pronounced structural asymmetry and its accompanying nonlinear effects. The obtained nonreciprocal reflection ratio, reaching an impressive value of 21.27 dB, combined with a minimal insertion loss of just -0.76 dB, highlights the remarkable level of nonreciprocal efficiency achieved by this design compared to others in its category. More importantly, the proposed design can achieve dynamic tunability by controlling the incident field intensity and the graphene Fermi level. Our design highlights a potential means for creating miniaturized and integratable nonreciprocal optical components in reflection mode, which can promote the development of the integrated isolators, optical logic circuits, and bias-free nonreciprocal photonics.

Molecular Insights into the Self-Assembly of a Full-Length hIAPP Trimer: ß-Protofibril Formed by ß-Hairpin Lateral or Longitudinal Association.

The fibrillar protein deposits of the human islet amyloid polypeptide (hIAPP) in the pancreatic islet of Langerhans are pathological hallmark of type II diabetes. Extensive experimental studies have revealed that the oligomeric formations of the hIAPP are more toxic than the mature fibrils. Exploring the oligomeric conformations in the early aggregation state is valuable for effective therapeutics. In this work, using the all-atom explicit-solvent replica exchange molecular dynamic (REMD) simulations, we investigated the structural features and the assembly mechanisms of the full-length hIAPP trimer in solution. The hIAPP trimer adopted more ß-sheets than a-helix conformations, and three types of ordered conformations including open ß-barrel, single-layer, and double-layer U-shaped ß-sheet structures with five ß-strands were captured in our simulations. A representative single-layer ß-sheet conformation with a CCS value of 1400 Å2 in our simulations matches exactly the experimentally ESI-IMS-MS-derived hIAPP trimer sample. These five ß-strand conformations formed via the ß-hairpin lateral and longitudinal association, respectively, showing two ß-protofibril formation models. To the best of our knowledge, it is the first time to reveal two routes to ß-sheet formation in the hIAPP trimers on the atomic level. The contact probabilities between pairs of the ß-stranded residue show that the hydrophobic interactions between the residues F15 ∼ V17 and A25 ∼ L27 are responsible for the inter- and intra-peptide ß-hairpin formations. All of these results indicate that the ß-sheet formation is the first step in the conformational changes toward pathological aggregation and provides evidence of the ß-sheet assembly mechanism into hIAPP aggregation.

Dehydration kinetics and mechanism of the stable isonicotinamide hydrate revealed by terahertz spectroscopy and DFT calculation.

The dehydration behavior of pharmaceutical hydrates has a great influence on its physiochemical properties such as stability, dissolution rate and bioavailability. However, how the intermolecular interactions vary during dehydration process remains elusive. In this work, we employed terahertz time-domain spectroscopy (THz-TDS) to probe the low-frequency vibrations and the dehydration process of isonicotinamide hydrate I (INA-H I). Theoretical solid-state DFT calculation was conducted to reveal its mechanism. Vibrational modes which are responsible for the THz absorption peaks were decomposed for better understanding the characters of these low-frequency modes. The result suggests translational motion is the dominant component for water molecules in THz region. Evolution of the THz spectrum of INA-H I during dehydration provides direct evidence of the variations of crystal structure. Based on the THz measurements, a two-step kinetics mode including first-rate reaction and three-dimensional nuclei growth is proposed. And we figure that the low-frequency vibrations of water molecules are the origin of dehydration process of hydrate.

Insights into Allosteric Mechanisms of the Lung-Enriched p53 Mutants V157F and R158L.

Lung cancer is a leading fatal malignancy in humans. p53 mutants exhibit not only loss of tumor suppressor capability but also oncogenic gain-of-function, contributing to lung cancer initiation, progression and therapeutic resistance. Research shows that p53 mutants V157F and R158L occur with high frequency in lung squamous cell carcinomas. Revealing their conformational dynamics is critical for developing novel lung therapies. Here, we used all-atom molecular dynamics (MD) simulations to investigate the effect of V157F and R158L substitutions on the structural properties of the p53 core domain (p53C). Compared to wild-type (WT) p53C, both V157F and R158L mutants display slightly lesser ß-sheet structure, larger radius of gyration, larger volume and larger exposed surface area, showing aggregation-prone structural characteristics. The aggregation-prone fragments (residues 249-267 and 268-282) of two mutants are more exposed to water solution than that of WT p53C. V157F and R158L mutation sites can affect the conformation switch of loop 1 through long-range associations. Simulations also reveal that the local structure and conformation around the V157F and R158L mutation sites are in a dynamic equilibrium between the misfolded and properly folded conformations. These results provide molecular mechanistic insights into allosteric mechanisms of the lung-enriched p53 mutants.

Deciphering the mechanisms of HPV E6 mutations in the destabilization of E6/E6AP/p53 complex.

In epithelial tumors, oncoprotein E6 binds with the ubiquitin ligase E6AP to form E6/E6AP heterodimer; then this heterodimer recruits p53 to form E6/E6AP/p53 heterotrimer and induces p53 degradation. Recent experiments demonstrated that three E6 single-site mutants (F47R, R102A, and L50E) can inhibit the E6/E6AP/p53 heterotrimer formation and rescue p53 from the degradation pathway. However, the molecular mechanism underlying mutation-induced heterotrimer inhibition remains largely elusive. Herein, we performed extensive molecular dynamics simulations (totally ∼13 µs) on both heterodimer and heterotrimer to elucidate at an atomic level how each p53-degradation-defective HPV16 E6 mutant reduces the structural stabilities of the two complexes. Our simulations reveal that the three E6 mutations destabilize the structure of E6/E6AP/p53 complex through distinct mechanisms. Although F47RE6 mutation has no effect on the structure of E6/E6AP heterodimer, it results in an electrostatic repulsion between R47E6 and R290p53, which is unfavorable for E6-p53 binding. R102AE6 mutation destabilizes the structure of E6/E6AP heterodimer and significantly disrupts hydrophobic and cation-π interactions between F47E6 and E286p53/L298p53/R290p53. L50EE6 mutation impairs both E6 interdomain interactions (especially F47-K108 cation-π interaction) and E6-E6AP intermolecular interactions important for the stabilization of E6/E6AP heterodimer. This study identifies the intra- and intermolecular interactions crucial for the complex stability, which may provide mechanistic insights into the inhibition of complex formation by the three HPV16 E6 mutations.

Temperature-Dependent Terahertz Spectra of Isonicotinamide in the Form I Studied Using the Quasi-Harmonic Approximation.

Anharmonicity of molecular vibrational motions is closely associated with the thermal property of crystals. However, the origin of anharmonicity is still not fully understood. Low-frequency vibrations, which are usually defined in the terahertz (THz) range, show excellent sensitivity to anharmonicity. In this work, anharmonicity of isonicotinamide in the form I was investigated by using temperature-dependent terahertz time-domain spectroscopy and the quasi-harmonic approximation (QHA) approach at PBE-D3 and PBE-MBD levels. Both DFT calculations suggest the variation of π-π stacking conformation dominates in the thermal expansion of the unit cell. Frequency shifts of the modes in THz range obtained by QHA approach are found to be qualitatively consistent with experimental observations, demonstrating QHA approach is a useful tool for the interpretation of frequency shifts of modes induced by temperature.

Molecular dynamics study on the inhibition mechanisms of ReACp53 peptide for p53-R175H mutant aggregation.

p53 mutant aggregation can lead to loss-of-function (LoF), dominant-negative (DN) and gain-of-function (GoF) effects, involving in tumor growth. Finding inhibition methods of p53 mutant aggregation is a key step for developing new therapeutics against aggregation-associated cancers. Recent studies have shown that a cell-permeable peptide, ReACp53, can inhibit aggregation of the p53 mutant and restore p53 nuclear function as a transcriptional factor, showing extraordinary therapeutic potential. However, the molecular mechanism underlying the inhibition of p53 mutant aggregation by the ReAp53 peptide is unclear. In this work, we used all-atom molecular dynamics (MD) simulations to investigate the effect of ReACp53 peptide on the structural and dynamic properties of the p53 core domain (p53C) of the aggregation-prone R175H mutant. Our simulations revealed that the ReACp53 peptide can stabilize the ordered secondary structure and decrease the flexibility of disordered loops of the R175H mutant through increasing the intra-interactions of p53C. Moreover, we found that ReACp53 peptide specifically binds to the fragment (residues 180-233) of the R175H mutant through strong hydrophobic interactions with residues L188 and L201 and a salt bridge or hydrogen bond formation with residues D186, E198, D204, E221 and E224. The specific binding pattern protects the aggregation-prone fragment (residues 182-213) from exposure to water. Hence, we suggested that the ReACp53 peptide inhibits aggregation of the R175H mutant by restoring the wild-type conformation from an aggregation-prone state and reducing the exposure of the aggregation-prone segment. These results provide molecular mechanistic insight into inhibition of the ReACp53 peptide on amyloid aggregation of the R175H mutant.

Common cancer mutations R175H and R273H drive the p53 DNA-binding domain towards aggregation-prone conformations.

The p53 protein is a tumor suppressor and the most often mutated protein in human cancers. Recent studies reported that p53 mutants, including two of the common cancer mutants (R175H and R273H), are more prone to aggregation than wild type (WT) p53 and their pathological aggregation can lead to diverse cancers. However, the underlying molecular mechanism is poorly understood. Herein, we investigated the structural and dynamic properties of R175H and R273H mutants of the p53 core domain (p53C) by performing extensive all-atom molecular dynamics simulations. We found that both R175H and R273H mutants exhibit a well preserved ß-sheet structure, but a larger hydrophobic surface area and higher loop flexibility than WT p53C. These conformational properties are consistent with the structural features of aggregation-prone molten-globule states. Our data also provide the details on how the two mutations lead to an increased flexibility of loop2. Moreover, using dynamic network analysis, we identified the allosteric path through which the R273H mutation induces an increased flexibility of the distant N-terminal region of loop2. These results provide mechanistic insights into the high aggregation propensities of R175H and R273H mutants.

Investigation of the Dissociation Mechanism of Single-Walled Carbon Nanotube on Mature Amyloid-ß Fibrils at Single Nanotube Level.

Amyloid fibrils originating from the fibrillogenesis of misfolded amyloid proteins are associated with the pathogenesis of many neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's diseases. Carbon nanotubes have been extensively applied in our life and industry due to their unique chemical and physical properties. Nonetheless, the details between carbon nanotubes and mature amyloid fibrils remain elusive. In this study, we explored the interplay between single-walled carbon nanotubes (SWCNTs) and preformed amyloid-ß (Aß) fibrils by atomic force microscopy at the single SWCNT level, together with ThT fluorescence, cellular viability assays, infrared spectroscopy, and molecular dynamics (MD) simulations. The results demonstrated that SWCNTs could partially destroy the preformed Aß fibrils and form the Aß-surrounded-SWCNTs conjugates, as well as reduce the ß-sheet structures. Peak force quantitative nanomechanical measurements revealed that the conjugates have lower Young's modulus than fibrils. Furthermore, our MD simulation demonstrated that the dissociation ability was dependent on the binding sites of Aß fibrils. Overall, this study provides an insight into the dissociation mechanism between SWCNT and Aß fibrils, which could be beneficial for the study of bionanomaterials and the development of other potential drug candidates for amyloidosis.

Expanding the Functional Scope of the Fmoc-Diphenylalanine Hydrogelator by Introducing a Rigidifying and Chemically Active Urea Backbone Modification.

Peptidomimetic low-molecular-weight hydrogelators, a class of peptide-like molecules with various backbone amide modifications, typically give rise to hydrogels of diverse properties and increased stability compared to peptide hydrogelators. Here, a new peptidomimetic low-molecular-weight hydrogelator is designed based on the well-studied N-fluorenylmethoxycarbonyl diphenylalanine (Fmoc-FF) peptide by replacing the amide bond with a frequently employed amide bond surrogate, the urea moiety, aiming to increase hydrogen bonding capabilities. This designed ureidopeptide, termed Fmoc-Phe-NHCONH-Phe-OH (Fmoc-FuF), forms hydrogels with improved mechanical properties, as compared to those formed by the unmodified Fmoc-FF. A combination of experimental and computational structural methods shows that hydrogen bonding and aromatic interactions facilitate Fmoc-FuF gel formation. The Fmoc-FuF hydrogel possesses properties favorable for biomedical applications, including shear thinning, self-healing, and in vitro cellular biocompatibility. Additionally, the Fmoc-FuF, but not Fmoc-FF, hydrogel presents a range of functionalities useful for other applications, including antifouling, slow release of urea encapsulated in the gel at a high concentration, selective mechanical response to fluoride anions, and reduction of metal ions into catalytic nanoparticles. This study demonstrates how a simple backbone modification can enhance the mechanical properties and functional scope of a peptide hydrogel.

Mechanistic insight into E22Q-mutation-induced antiparallel-to-parallel ß-sheet transition of Aß16-22 fibrils: an all-atom simulation study.

Alzheimer's disease is associated with the abnormal self-assembly of amyloid-ß (Aß) peptide into toxic oligomers and fibrils. Recent experiments reported that Aß16-22, containing the central hydrophobic core (CHC) of Aß, formed antiparallel ß-sheet fibrils, while its E22Q mutant self-assembled into parallel ß-sheet fibrils. However, the molecular mechanisms underlying E22Q-mutation-induced parallel ß-sheet fibril formation are not well understood. Herein, we performed molecular dynamics (MD) simulations to study the dimerization processes of Aß16-22 and Aß16-22E22Q peptides. ß-Sheet dimers with diverse hydrogen bond arrangements were observed and they exhibited highly dynamic and interconverting properties. An antiparallel-to-parallel ß-sheet transition occurred in the assembly process of the E22Q mutant, but not in that of Aß16-22. During this conformational transformation process, the inter-molecular Q22-Q22 hydrogen bonds were first formed and acted as a binder to facilitate the two chains forming a parallel orientation, then the hydrophobic interactions between residues in the CHC region consolidated this arrangement and drove the main-chain H-bond formation, hence resulting in parallel ß-sheet formation. However, parallel ß-sheets were less populated than antiparallel ß-sheets of Aß16-22E22Q dimers. In order to explore whether parallel ß-sheets became dominant in larger size oligomers, we investigated the conformational ensembles of Aß16-22 and Aß16-22E22Q octamers by conducting replica exchange molecular dynamics (REMD) simulations. The REMD simulations revealed that the population of parallel ß-strand alignment increased with an increase of the size of ordered Aß16-22E22Q ß-sheet oligomers, implying that the formation of full parallel ß-sheets requires larger sized oligomers. Our findings provide a mechanistic explanation for the E22Q-mutation-induced formation of parallel ß-sheet fibrils observed experimentally.

Molecular dynamics simulations reveal the mechanism of graphene oxide nanosheet inhibition of Aß1-42 peptide aggregation.

The aggregation of the amyloid-beta (Aß) peptides into toxic ß-sheet-rich oligomers, protofibrils and mature fibrils is the major pathological hallmark of Alzheimer's disease (AD). Inhibiting the ß-sheet formation and fibrillization of Aß peptides is considered an important treatment strategy for AD. Graphene oxide (GO) has attracted particular interest in the anti-aggregation of amyloid proteins due to its good ability of crossing the blood-brain barrier (BBB), low cytotoxicity and good biocompatibility. Recent experiments reported that GO nanosheets could strongly inhibit the fibril formation of Aß1-42 and reduce its cytotoxicity. However, the mechanism of suppressing Aß1-42 fibrillization by GO nanosheets is not well understood. Aß1-42 dimer is the smallest toxic oligomer of Aß1-42 aggregation. As a starting step to understand the inhibitory effect of GO nanosheets towards Aß1-42 aggregation, we investigated the conformational distribution of the Aß1-42 dimer with or without GO nanosheets by performing explicit-solvent replica exchange molecular dynamics simulations. Our simulations showed that Aß1-42 peptides could form diverse ß-sheet rich dimeric conformations, whereas those conformations were significantly inhibited after the addition of GO nanosheets. We found that GO suppressed the ß-sheet formation of Aß1-42 mostly by weakening inter-peptide interactions mostly via salt bridge, hydrogen bonding and cation-π interactions with charged residues D1, E3, R5, D7, E11, K16, E22, K28 and A42. The π-π and hydrophobic interactions between GO and Aß1-42 also play a role in the inhibition of Aß aggregation. This study provides mechanistic insights into Aß1-42 aggregation and amyloid inhibition by GO nanosheets, which may provide new clues for the development of therapeutic candidates against AD.

Influence of fullerenol on hIAPP aggregation: amyloid inhibition and mechanistic aspects.

Fullerenols have garnered significant scientific interest in nano-technology and biomedicine. A detailed understanding of their interactions with proteins is fundamentally important for their biomedical applications. Human islet amyloid polypeptide (hIAPP) is an intrinsically disordered protein and its aggregation is associated with type 2 diabetes. Here, we investigated the nano-bio-interactions of fullerenol with hIAPP and focused on the effect of C60(OH)24 on hIAPP aggregation by replica-exchange molecular dynamic simulations. Our simulations show that isolated hIAPP dimers transiently populated amyloid-precursor (ß-hairpin) containing ß-sheet structure, whereas C60(OH)24 completely suppressed this fibril-prone structure, thus inhibiting hIAPP aggregation. The simulation-predicted inhibitory effect of fullerenols was validated by atom force microscopy and thioflavin T fluorescence experiments. We find C60(OH)24 binds to hIAPP via hydrogen bonding interactions with polar residues T9, Q10, N14, N21, N22, N31, N35 and T36 as well as the collective van der Waals and hydrogen-bonding interaction with Y37. Molecular dynamic simulations show that C60(OH)24 destabilized the hIAPP protofibril by mostly binding to the 20SNNFGAILSS29 amyloid core region. This study not only helps to understand the mechanisms involved in hIAPP aggregation and amyloid inhibition, but also provides new clues for the development of therapeutic candidates against type 2 diabetes.

Conformational stability and dynamics of the cancer-associated isoform Δ133p53ß are modulated by p53 peptides and p53-specific DNA.

p53 is a tumor suppressor protein that maintains genome stability, but its Δ133p53ß and Δ160p53ß isoforms promote breast cancer cell invasion. The sequence truncations in the p53 core domain raise key questions related to their physicochemical properties, including structural stabilities, interaction mechanisms, and DNA-binding abilities. Herein, we investigated the conformational dynamics of Δ133p53ß and Δ160p53ß with and without binding to p53-specific DNA by using molecular dynamics simulations. We observed that the core domains of the 2 truncated isoforms are much less stable than wild-type (wt) p53ß, and the increased solvent exposure of their aggregation-triggering segment indicates their higher aggregation propensities than wt p53. We also found that Δ133p53ß stability is modulable by peptide or DNA interactions. Adding a p53 peptide (derived from truncated p53 sequence 107-129) may help stabilize Δ133p53. Most importantly, our simulations of p53 isomer-DNA complexes indicate that Δ133p53ß dimer, but not Δ160p53ß dimer, could form a stable complex with p53-specific DNA, which is consistent with recent experiments. This study provides physicochemical insight into Δ133p53ß, Δ133p53ß-DNA complexes, Δ133p53ß's pathologic mechanism, and peptide-based inhibitor design against p53-related cancers.-Lei, J., Qi, R., Tang, Y., Wang, W., Wei, G., Nussinov, R., Ma, B. Conformational stability and dynamics of the cancer-associated isoform Δ133p53ß are modulated by p53 peptides and p53-specific DNA.

The Inhibitory Effect of Hydroxylated Carbon Nanotubes on the Aggregation of Human Islet Amyloid Polypeptide Revealed by a Combined Computational and Experimental Study.

Fibrillar deposits formed by the aggregation of the human islet amyloid polypeptide (hIAPP) are the major pathological hallmark of type 2 diabetes mellitus (T2DM). Inhibiting the aggregation of hIAPP is considered the primary therapeutic strategy for the treatment of T2DM. Hydroxylated carbon nanoparticles have received great attention in impeding amyloid protein fibrillation owing to their reduced cytotoxicity compared to the pristine ones. In this study, we investigated the influence of hydroxylated single-walled carbon nanotubes (SWCNT-OHs) on the first step of hIAPP aggregation: dimerization by performing explicit solvent replica exchange molecular dynamics (REMD) simulations. Extensive REMD simulations demonstrate that SWCNT-OHs can dramatically inhibit interpeptide ß-sheet formation and completely suppress the previously reported ß-hairpin amyloidogenic precursor of hIAPP. On the basis of our simulation results, we proposed that SWCNT-OH can hinder hIAPP fibrillation. This was further confirmed by our systematic turbidity measurements, thioflavin T fluorescence, circular dichroism (CD), transmission electron microscope (TEM), and atomic force microscopy (AFM) experiments. Detailed analyses of hIAPP-SWCNT-OH interactions reveal that hydrogen bonding, van der Waals, and π-stacking interactions between hIAPP and SWCNT-OH significantly weaken the inter- and intrapeptide interactions that are crucial for ß-sheet formation. Our collective computational and experimental data reveal not only the inhibitory effect but also the inhibitory mechanism of SWCNT-OH against hIAPP aggregation, thus providing new clues for the development of future drug candidates against T2DM.

Dihydrochalcone molecules destabilize Alzheimer's amyloid-ß protofibrils through binding to the protofibril cavity.

Alzheimer's disease (AD) is associated with the aggregation of amyloid-ß (Aß) peptides into toxic fibrillar aggregates. Finding effective inhibitors of Aß aggregation is a crucial step for the development of drugs against AD. Recent experiments reported that dihydrochalcone (Dih), a compound extracted from the daemonorops draco tree, could effectively inhibit Aß fibrillization and reduce Aß cytotoxicity. However, the influence of Dih molecules on preformed Aß fibrils and the atomic-level details of interactions between Dih and Aß fibrils are largely unknown. In this work, we performed multiple molecular dynamics (MD) simulations for 1.2 µs in total on the Aß17-42 protofibrils with and without Dih molecules. We found that Dih molecules mostly bind to three different sites of the protofibril: the exterior central hydrophobic core (CHC) spanning residues 17LVFFA21 in the ß1 region, the protofibril cavity and the C-terminal hydrophobic-groove spanning residues 31IIGLM35 in the ß2 region. Binding to the C-terminal hydrophobic-groove slightly affects the structures of Aß17-42 protofibrils, while binding to the exterior CHC and the cavity strongly destabilizes the protofibrils by mostly disrupting the D23-K28 salt bridges and the inter-peptide ß-sheet in the ß1 region. The dynamic process of Dih molecules entering the cavity of Aß17-42 protofibrils is also investigated. We also examined the effect of Dih molecules on both U-shaped Aß40/Aß42 protofibrils and S-shaped Aß42 protofibrils by carrying out multiple MD simulations. Our simulations show that Dih molecules can destabilize both U-shaped and S-shaped Aß protofibrils by binding to the protofibril cavity. This study reveals the mechanism by which Dih molecules disrupt Aß protofibrils, which may offer new clues for the development of drug candidates for the treatment of AD.

Mechanistic insights into the inhibition and size effects of graphene oxide nanosheets on the aggregation of an amyloid-ß peptide fragment.

The aggregation of amyloid-ß (Aß), which involves the formation of small oligomers and mature fibrils, has received considerable attention in the past few decades due to its close link with Alzheimer's disease (AD). The inhibition of ß-sheet formation has been considered as the primary therapeutic strategy for AD. In this respect, graphene oxide (GO) has gained significant attention because of its high solubility, good biocompatibility and inhibitory effect on the aggregation of Aß and the 33-42 fragment (Aß33-42). However, the inhibitory mechanism at the atomic level remains elusive. Herein, we investigated the oligomerization of Aß33-42 by performing replica exchange molecular dynamics simulations on four Aß33-42 peptide chains in the absence and presence of two different sizes of GO. Our simulations show that isolated Aß33-42 can form fibril-prone extended ß-sheets and barrel-like structures, whereas they are suppressed in the presence of GO nanosheets. Our data reveal that GO inhibits Aß33-42 oligomerization by making Aß33-42 peptides separate from each other through strong interactions with M35. With the same total number of atoms, GO120 displays better inhibitory effect than GO60 by providing a larger effective contact surface area. This study provides the molecular mechanism of GO in inhibiting the aggregation of Aß33-42, which might offer a theoretical insight into the design of drugs against AD at the atomic level.

Structural Polymorphism in a Self-Assembled Tri-Aromatic Peptide System.

Self-assembly is a process of key importance in natural systems and in nanotechnology. Peptides are attractive building blocks due to their relative facile synthesis, biocompatibility, and other unique properties. Diphenylalanine (FF) and its derivatives are known to form nanostructures of various architectures and interesting and varied characteristics. The larger triphenylalanine peptide (FFF) was found to self-assemble as efficiently as FF, forming related but distinct architectures of plate-like and spherical nanostructures. Here, to understand the effect of triaromatic systems on the self-assembly process, we examined carboxybenzyl-protected diphenylalanine (z-FF) as a minimal model for such an arrangement. We explored different self-assembly conditions by changing solvent compositions and peptide concentrations, generating a phase diagram for the assemblies. We discovered that z-FF can form a variety of structures, including nanowires, fibers, nanospheres, and nanotoroids, the latter were previously observed only in considerably larger or co-assembly systems. Secondary structure analysis revealed that all assemblies possessed a ß-sheet conformation. Additionally, in solvent combinations with high water ratios, z-FF formed rigid and self-healing hydrogels. X-ray crystallography revealed a "wishbone" structure, in which z-FF dimers are linked by hydrogen bonds mediated by methanol molecules, with a 2-fold screw symmetry along the c-axis. All-atom molecular dynamics (MD) simulations revealed conformations similar to the crystal structure. Coarse-grained MD simulated the assembly of the peptide into either fibers or spheres in different solvent systems, consistent with the experimental results. This work thus expands the building block library for the fabrication of nanostructures by peptide self-assembly.

Conformational Ensemble of hIAPP Dimer: Insight into the Molecular Mechanism by which a Green Tea Extract inhibits hIAPP Aggregation.

Small oligomers formed early along human islet amyloid polypeptide (hIAPP) aggregation is responsible for the cell death in Type II diabetes. The epigallocatechin gallate (EGCG), a green tea extract, was found to inhibit hIAPP fibrillation. However, the inhibition mechanism and the conformational distribution of the smallest hIAPP oligomer - dimer are mostly unknown. Herein, we performed extensive replica exchange molecular dynamic simulations on hIAPP dimer with and without EGCG molecules. Extended hIAPP dimer conformations, with a collision cross section value similar to that observed by ion mobility-mass spectrometry, were observed in our simulations. Notably, these dimers adopt a three-stranded antiparallel ß-sheet and contain the previously reported ß-hairpin amyloidogenic precursor. We find that EGCG binding strongly blocks both the inter-peptide hydrophobic and aromatic-stacking interactions responsible for inter-peptide ß-sheet formation and intra-peptide interaction crucial for ß-hairpin formation, thus abolishes the three-stranded ß-sheet structures and leads to the formation of coil-rich conformations. Hydrophobic, aromatic-stacking, cation-π and hydrogen-bonding interactions jointly contribute to the EGCG-induced conformational shift. This study provides, on atomic level, the conformational ensemble of hIAPP dimer and the molecular mechanism by which EGCG inhibits hIAPP aggregation.