Many fatal neurodegenerative diseases such as Alzheimer's, Parkinson, the prion-related diseases, and non-neurodegenerative disorders such as type II diabetes are characterized by abnormal amyloid fiber aggregates, suggesting a common mechanism of pathogenesis. We have discovered that a class of systematically designed natural tri-to hexapeptides with a characteristic sequential motif can simulate the process of fiber assembly and further condensation to amyloid fibrils, probably via unexpected dimeric α-helical intermediate structures. The characteristic sequence motif of the novel peptide class consists of an aliphatic amino acid tail of decreasing hydrophobicity capped by a polar head. To our knowledge, the investigated aliphatic tripeptides are the shortest ever reported naturally occurring amino acid sequence that can adopt α-helical structure and promote amyloid formation. We propose the stepwise assembly process to be associated with characteristic conformational changes from random coil to α-helical intermediates terminating in cross-β peptide structures. Circular dichroism and X-ray fiber diffraction analyses confirmed the concentrationdependent conformational changes of the peptides in water. Molecular dynamics simulating peptide behavior in water revealed monomer antiparallel pairing to dimer structures by complementary structural alignment that further aggregated and stably condensed into coiled fibers. The ultrasmall size and the dynamic facile assembly process make this novel peptide class an excellent model system for studying the mechanism of amyloidogenesis, its evolution and pathogenicity. The ability to modify the properties of the assembled structures under defined conditions will shed light on strategies to manipulate the pathogenic amyloid aggregates in order to prevent or control aggregate formation.self-assembly mechanism | ultrasmall peptides | supramolecular peptide scaffolds | fiber diffraction | molecular dynamics simulation

The self-assembly of abnormally folded proteins into amyloid fibrils is a hallmark of many debilitating diseases, from Alzheimer's and Parkinson diseases to prion-related disorders and diabetes type II. However, the fundamental mechanism of amyloid aggregation remains poorly understood. Core sequences of four to seven amino acids within natural amyloid proteins that form toxic fibrils have been used to study amyloidogenesis. We recently reported a class of systematically designed ultrasmall peptides that self-assemble in water into cross-β-type fibers. Here we compare the self-assembly of these peptides with natural core sequences. These include core segments from Alzheimer's amyloid-β, human amylin, and calcitonin. We analyzed the self-assembly process using circular dichroism, electron microscopy, X-ray diffraction, rheology, and molecular dynamics simulations. We found that the designed aliphatic peptides exhibited a similar self-assembly mechanism to several natural sequences, with formation of α-helical intermediates being a common feature. Interestingly, the self-assembly of a second core sequence from amyloid-β, containing the diphenylalanine motif, was distinctly different from all other examined sequences. The diphenylalanine-containing sequence formed β-sheet aggregates without going through the α-helical intermediate step, giving a unique fiberdiffraction pattern and simulation structure. Based on these results, we propose a simplified aliphatic model system to study amyloidosis. Our results provide vital insight into the nature of early intermediates formed and suggest that aromatic interactions are not as important in amyloid formation as previously postulated. This information is necessary for developing therapeutic drugs that inhibit and control amyloid formation.

The impact of five different imidazolium-based ionic liquids (ILs) diluted in water on the properties of a bacterial plasma membrane is investigated using molecular dynamics (MD) simulations. Cations considered are 1-octyl-3-methylimidazolium (OMIM), 1-octyloxymethyl-3-methylimidazolium (OXMIM), and 1-tetradecyl-3-methylimidazolium (TDMIM), as well as the anions chloride and lactate. The atomistic model of the membrane bilayer is designed to reproduce the lipid composition of the plasma membrane of Gram-negative Escherichia coli. Spontaneous insertion of cations into the membrane is observed in all ILs. Substantially more insertions of OMIM than of OXMIM occur and the presence of chloride reduces cation insertions compared to lactate. In contrast, anions do not adsorb onto the membrane surface nor diffuse into the bilayer. Once inserted, cations are oriented in parallel to membrane lipids with cation alkyl tails embedded into the hydrophobic membrane core, while the imidazolium-ring remains mostly exposed to the solvent. Such inserted cations are strongly associated with one to two phospholipids in the membrane. The overall order of lipids decreased after OMIM and OXMIM insertions, while on the contrary the order of lipids in the vicinity of TDMIM increased. The short alkyl tails of OMIM and OXMIM generate voids in the bilayer that are filled by curling lipids. This cation induced lipid disorder also reduces the average membrane thickness. This effect is not observed after TDMIM insertions due to the similar length of cation alkyl chain and the fatty acids of the lipids. This lipid-mimicking behavior of inserted TDMIM indicates a high membrane affinity of this cation that could lead to an enhanced accumulation of cations in the membrane over time. Overall, the simulations reveal how cations are inserted into the bacterial membrane and how such insertions change its properties. Moreover, the different roles of cations and anions are highlighted and the fundamental importance of cation alkyl chain length and its functionalization is demonstrated.

The study of crystal growth using molecular dynamics is very difficult due to the slow rate of growth and the complex intermolecular interactions involved. In order to perform molecular dynamics simulations of crystal growth from aqueous solution accurately, both interactions within the crystal and interactions between the crystal molecules and water need to be described correctly. In this study, we have investigated and compared various force fields for their applicability in the molecular dynamics study of R-glycine crystallization. The force fields that have been investigated include Charmm27, general AMBER, OPLS-AA/L, and Gromos53a6. As the electrostatic interactions are expected to play a significant role in the properties of bulk glycine crystal and solution, five other charge sets obtained from first principles calculations have also been investigated. Simulations in the bulk crystal and aqueous solution environments have been carried out, and results for the R-glycine lattice energy, solution densities, and self-diffusivities are compared to available experimental results. The solution enthalpy has also been determined and is found to be a good indicator of the applicability of the force field for crystal growth studies. The general AMBER force field, coupled with charges derived from calculations using the Complete Neglect of Differential Overlap method, is found to be the optimal force field, resulting in significant crystal growth at the (010) face of the R-glycine crystal from a slightly supersaturated glycine solution. Such simulations provide insights into the mechanism of crystal growth at the molecular level. We observe that R-glycine crystal growth involves monomeric growth units that attach to the existing crystal face in the correct molecular orientation. This work also opens up possibilities to systematically investigate the various factors that affect crystal growth through simulations, such as temperature, concentration, solvent, impurities, etc., so as to gain a better overall understanding of the crystal growth process.

The phase behavior of charge-and size-asymmetric primitive model electrolytes has been investigated using reservoir grand canonical Monte Carlo simulations. The simulations rely on the insertion and removal of neutral ion clusters from a reservoir of possible configurations. We first validated our approach by investigating the effect of R c , the maximum allowable distance between the central cation and its associated anions, on the critical parameters of 2:1 and 3:1 electrolytes. We have shown that the effect of R c is weak and does not change the qualitative dependence of the critical parameters on size and charge asymmetry. The critical temperature for 2:1 and 3:1 electrolytes shows a maximum at R c Ϸ3, while the critical volume fraction decreases more or less monotonically, consistent with previous results for 1:1 electrolytes by Romero-Enrique et al. ͓Phys.Rev. E 66, 041204 ͑2002͔͒. We have used the reservoir method to obtain the critical parameters for 5:1 and 10:1 electrolytes. The critical temperature decreases with increasing charge asymmetry and shows a maximum as a function of ␦, the size asymmetry parameter. The critical volume fraction however, defined as the volume occupied by ions divided by the total volume of the simulation box, increases with increasing charge asymmetry and exhibits a minimum as a function of ␦. This trend is contrary to what is generally predicted by theories, although more recent approaches based on the Debye-Hückel theory reproduce this observed trend. Our results deviate somewhat from the predictions of Linse ͓Philos. Trans. R. Soc. London, Ser. A 359, 853 ͑2001͔͒ for the scaling of the critical temperature for a system of macroions with point counterions.

A lattice model for ionic surfactants with explicit counterions is proposed for which the micellization behavior can be accurately determined from grand canonical Monte Carlo simulations. The model is characterized by a few parameters that can be adjusted to represent various linear surfactants with ionic headgroups. The model parameters have a clear physical interpretation and can be obtained from experimental data unrelated to micellization, namely, geometric information and solubilities of tail segments. As a specific example, parameter values for sodium dodecyl sulfate were obtained by optimizing for the solubility of hydrocarbons in water and the structural properties of dodecane. The critical micelle concentration (cmc), average aggregation number, degree of counterion binding, and their dependence on temperature were determined from histogram reweighting grand canonical Monte Carlo simulations and were compared to experimental results. The model gives the correct trend and order of magnitude for all quantities but underpredicts the cmc and aggregation number. We suggest ways to modify the model that may improve agreement with experimental values.

The epicuticle is the outermost layer of the human hair, and consists of a monolayer of fatty acids that is predominantly 18-methyleicosanoic acid (18-MEA) covalently bound to a protein matrix. Surprisingly, despite the clear scientific and industrial importance, the detailed molecular structure of this fatty acid layer is still poorly understood. In this work, we aim to gain insight into the structure of this socalled F-layer by performing molecular dynamics simulations on a simplified hair surface model consisting of a monolayer of 18-MEA covalently attached to graphene sheets at various separation distances. The relative free energy of the fatty acid layer was calculated as a function of separation distance in order to obtain the optimal packing density of the fatty acids. Conformational properties such as the thickness, tilt angle, and order parameter of the fatty acid layers were also calculated to characterize the structure of the F-layer. Simulations of the structurally similar eicosanoic acid (EA) were also performed as a comparison and to investigate the role of the anteiso-methyl side chain at the 18th position of 18-MEA. The degree of water penetration into the fatty acid layer at the various separation distances was also investigated. Our simulations suggest that the optimal spacing for the fatty acids is between 0.492 and 0.651 nm, in contrast to the generally accepted literature value of around 0.9−1.0 nm. This results in a packing density of between 0.21 and 0.37 nm 2 per fatty acid molecule and a thickness of around 2.01−2.64 nm. We also show that, at larger separation distances, the 18-MEA fatty acid provides a slightly better hydrophobic layer than the EA fatty acid, suggesting that the 18-MEA fatty acid may have been naturally selected to provide better protection for the hair when it loses some of the fatty acids due to daily wear and tear. To our knowledge, this is the first attempt to systematically investigate the hair surface structure and properties with molecular simulations.

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