Pathways of hLL-3717-29 Aggregation Give Insight into the Mechanism of α-Amyloid Formation.

α-amyloids present a novel self-assembly principle that can be utilized to prepare functional biomaterials. Evidence of α-amyloid formation in the active core of the human LL-37 protein (comprising residues 17 to 29) was associated with this peptide's membranolytic property. Though mechanistic pathways of ß-amyloid formation are known, such studies are scarce in α-amyloids. Modern computational techniques allow such mechanistic studies in molecular detail. Here, we propose aggregation pathways in hLL-3717-29 through molecular dynamics simulations. We first identified oligomers among peptides based on a distance criterion. The distribution of oligomers was then used to build Markov state models from which pathways were obtained using the framework of transition path theory. We checked the structural stability of the peptides during oligomerization, which is crucial from their functional point of view. We also investigated the key residues that participate in oligomer formation, the interactions between them, and the effect of residue mutations on the binding free energy of the peptides. Our findings suggest that larger oligomers are produced from the association of smaller and intermediate oligomers. The peptides retain their helical structure during aggregation with transient occurrences of 3-10 helix and turns. Hydrophobic interactions are vital in the aggregation of these peptides with Ile24 playing a crucial role. Mutation of this residue to alanine decreases the peptides' binding free energy, resulting in reduced aggregation tendency.

Hydrophobic Deep Eutectic Solvents as Greener Substitutes for Conventional Extraction Media: Examples and Techniques.

Deep eutectic solvents (DESs) are multicomponent designer solvents that exist as stable liquids over a wide range of temperatures. Over the last two decades, research has been dedicated to developing noncytotoxic, biodegradable, and biocompatible DESs to replace commercially available toxic organic solvents. However, most of the DESs formulated until now are hydrophilic and disintegrate via dissolution on coming in contact with the aqueous phase. To expand the repertoire of DESs as green solvents, hydrophobic DESs (HDESs) were prepared as an alternative. The hydrophobicity is a consequence of the constituents and can be modified according to the nature of the application. Due to their immiscibility, HDESs induce phase segregation in an aqueous solution and thus can be utilized as an extracting medium for a multitude of compounds. Here, we review literature reporting the usage of HDESs for the extraction of various organic compounds and metal ions from aqueous solutions and absorption of gases like CO2. We also discuss the techniques currently employed in the extraction processes. We have delineated the limitations that might reduce the applicability of these solvents and also discussed examples of how DESs behave as reaction media. Our review presents the possibility of HDESs being used as substitutes for conventional organic solvents.

Elucidating the Hydrotropic Mechanism of the Antagonistic Salt PPh4Cl.

PPh4Cl is an antagonistic salt that recently showed promise as a hydrotropic agent. Here, we give mechanistic insights into the PPh4Cl-assisted solubility of a dye molecule using molecular dynamics simulations. Our findings reveal that dye molecules aggregate into a cluster which leads to an accumulation of PPh4+ ions in its vicinity and subsequent exclusion of water molecules from the region. The structural organization is attributed to the preferential interaction of dye molecules and PPh4Cl. The origin of such preference arises from the difference in π-π and CH-π interaction among the pairs. The hydrodynamic radius of PPh4Cl indicates a low propensity for cluster formation, which enhances its hydrotropic behavior. The process of dye dissolution is thermodynamically favored and occurs through a cooperative mechanism. Our studies provide molecular insight into experimental observations crucial for the design of novel hydrotropes with enhanced solubilizing properties.

A computational approach on the stereoselective binding of peptides from aqueous medium with endo-functionalized molecular tubes.

The need to obtain enantiomerically pure isomers of amino acids and peptides is often realized in the field of biology and in the pharmaceutical industry. Research is underway to devise simple methods for the chiral resolution of amino acids from their racemic mixtures. Inspired by this objective, in our present work, we have computationally shown the possibility of chiral separation of the enantiomeric pairs of two model peptides, namely, (D,L)-aspargine and (D,L)-phenylalanine, in the presence of water. For this purpose, we have used two synthetic supramolecular receptors named host-1a and host-1b, respectively. Molecular dynamics simulations and quantum chemical methods are employed to analyze the structural features and the energy aspects involved in the separation process. The information obtained at the molecular level helps us gain better insights into the key interactions that operate to produce such enantioselectivity. We have also investigated the dynamics and changes in the water structure in the vicinity of the host molecules, both in the presence and absence of the model peptides. The D- and L-isomers of the same peptide undergo complexation with a particular host molecule registering a difference of more than 1.5 kcal mol-1 (obtained from PMF and MM-PBSA analyses) in their respective energies. This indicates that the chiral separation of the peptides with the help of these endo-fuctionalized molecular tube receptors may be energetically feasible. The connection between the peptide stereochemistry and its interaction with the endo-functionalized hosts would be instrumental in designing novel segregation techniques that can be further extended to separate larger model peptides or proteins.

Phase separation property of a hydrophobic deep eutectic solvent-water binary mixture: A molecular dynamics simulation study.

Over the past decade, deep eutectic solvents (DESs) have earned applicability in numerous fields as non-flammable, non-volatile, and greener alternatives to conventional organic solvents. In a first of its kind, a hydrophobic DES composed of a 1:1 mixture of oleic acid and lidocaine was recently reported, possessing a lower critical solution temperature in water. The thermoreversible phase property of this DES-water system was utilized to sequester out dye molecules from their aqueous solutions. In this article, we explore the phase separation phenomena for this particular DES in its aqueous solution using an all-atom molecular dynamics simulation. A 50 wt. % solution of the DES in water was studied at three different temperatures (253, 293, and 313 K) to understand the various molecular interactions that dictate the phase segregation property of these systems. In this work, we have elaborated on the importance of hydrogen bonding interactions and the non-bonding interactions between the components and the competition between the two that leads to phase separation. Overall, we observe that the increase in unfavorable interaction between the DES components and water with increasing temperature determines the phase separation behavior. We have also studied the modification in the dynamical properties of water molecules close to the phase boundary. Such molecular insights would be beneficial for designing novel solvent systems that can be used as extraction-based media in industries.