Structure-function analysis of plant G-protein regulatory mechanisms identifies key Gα-RGS protein interactions.

Heterotrimeric GTP-binding protein alpha subunit (Gα) and its cognate regulator of G-protein signaling (RGS) protein transduce signals in eukaryotes spanning protists, amoeba, animals, fungi, and plants. The core catalytic mechanisms of the GTPase activity of Gα and the interaction interface with RGS for the acceleration of GTP hydrolysis seem to be conserved across these groups; however, the RGS gene is under low selective pressure in plants, resulting in its frequent loss. Our current understanding of the structural basis of Gα:RGS regulation in plants has been shaped by Arabidopsis Gα, (AtGPA1), which has a cognate RGS protein. To gain a comprehensive understanding of this regulation beyond Arabidopsis, we obtained the x-ray crystal structures of Oryza sativa Gα, which has no RGS, and Selaginella moellendorffi (a lycophyte) Gα that has low sequence similarity with AtGPA1 but has an RGS. We show that the three-dimensional structure, protein-protein interaction with RGS, and the dynamic features of these Gα are similar to AtGPA1 and metazoan Gα. Molecular dynamic simulation of the Gα-RGS interaction identifies the contacts established by specific residues of the switch regions of GTP-bound Gα, crucial for this interaction, but finds no significant difference due to specific amino acid substitutions. Together, our data provide valuable insights into the regulatory mechanisms of plant G-proteins but do not support the hypothesis of adaptive co-evolution of Gα:RGS proteins in plants.

Phenylpropanoids on the Inhibition of ß-Amyloid Aggregation and the Movement of These Molecules through the POPC Lipid Bilayer.

Alzheimer's disease (AD), caused by Aß aggregation, is a major concern in medical research. It is a neurodegenerative disorder, leading to a loss of cognitive abilities, which is still claiming the lives of many people all over the world. This poses a challenge before the scientific community to discover effective drugs which can prevent such toxic aggregation. Recent experimental findings suggest the potency of two naturally-occurring phenylpropanoids, Schizotenuin A (SCH) and Lycopic Acid B (LAB) which can effectively combat the deleterious effects of Aß aggregation, although nothing is known about their mechanism of inhibition. In this work, we deal with an extensive computational study on the inhibitory effects of these inhibitors by using an all-atom molecular dynamics simulation to interpret the underlying mechanism of their inhibitory processes. A series of investigations is carried out while studying the various structural and conformational changes of the peptide chains in the absence and presence of inhibitors. To investigate the details of the interactions between the peptide residues and inhibitors, nonbonding energy calculations, the radial distribution function, the coordination number of water and inhibitor molecules around the peptide residues, and hydrogen-bonding interactions are calculated. The potential of mean force (PMF) is calculated to estimate aggregate formation from their free-energy profiles. It is seen that the hydrophobic core of the KLVFFAE undergoes aggregation and that these inhibitors show great promise in preventing the onset of AD in the future by preventing Aß aggregation. Also, the translocation studies on these inhibitors through a model POPC lipid bilayer shed light on their permeation properties and biocompatibility.

Inhibition of Aß16-22 Peptide Aggregation by Small Molecules and Their Permeation through POPC Lipid Bilayer: Insight from Molecular Dynamics Simulation Study.

Alzheimer's Disease is a rapidly progressing irreversible neurodegenerative disorder characterized by neuronal cell deterioration that endangers human health. With its proper therapeutic treatment being unavailable, several research groups throughout the world are involved in designing efficient drug molecules. However, the elusive mechanism of action of the drugs as well as their debilitating side effects pose major challenges in this regard. In the present article, we investigated the inhibitory effect of an indanone-carbamate-based molecule on Aß16-22 peptide aggregation by employing a series of all-atom molecular dynamics simulation study. To gain explicit insights, we studied the role of inhibitor molecules on the disruption of highly arranged ß-sheet of peptides by various types of analyses such as structural analysis, Cα-Cα-atom distance, residue-wise contact map, and solvent accessible surface area. The results obtained from various analyses revealed that the inhibitor molecules interacted with Aß16-22 peptides to destabilize its arranged ß-sheet conformer via hydrophobic interaction. To further comprehend the effect of inhibitors on amyloid aggregation, we also determined interaction energy, hydration number, radial distribution function, hydrogen bonding, and potential of mean forces. In addition, the permeability of the inhibitors through model POPC lipid bilayer via passive diffusion was also analyzed. Our study is noteworthy in that it elucidates the strong interaction between inhibitors and the central hydrophobic core of peptides comprising aromatic phenylalanine residues, as well as the passive translocation of inhibitors across POPC lipid bilayers.

Exploration on the drug solubility enhancement in aqueous medium with the help of endo-functionalized molecular tubes: a computational approach.

One major problem in the pharmaceutical industry is the aqueous solubility of newly developed orally administered drug candidates. More than 50% of newly developed drug molecules suffer from low aqueous solubility. The therapeutic effects of drug molecules are majorly dependent on the bioavailability and, in essence, on the solubility of the used drug molecules. Thus, enhancement of drug solubility of sparingly soluble drug molecules is a need of modern times. Considering the high importance of drug solubility, we have computationally shown the enhancement of drug solubility for seven class II (poorly water-soluble) drug molecules in a water medium. The uses of supramolecular macrocycles have immense importance in the same field. Thus, we have used two synthetic supramolecular receptors named host-1a and host-1b to enhance the water solubility of fluorouracil, albendazole, camptothecin, clopidogrel, indomethacin, melphalan, and tolfenamic acid drug molecules. Biomedical engagements of a supramolecular receptor commence with the formation of stable host-drug complexes. These complexations enhance the water solubility of drug molecules and sustain the release rate and bioavailability of drug molecules. Thus, in this work, we focus on the formation of stable host-drug complexes in water medium. Molecular dynamics simulation is applied to analyze the structural features and the energetics involved in the host-drug complexation process. The information obtained at the atomistic level helps us gain better insights into the key interactions that operate to produce such highly stable complexes. Thus, we can propose that these two supramolecular receptors may be used as drug solubilizing agents, and patients will benefit from this theragnostic application shortly.

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.

Translocation of Endo-Functionalized Molecular Tubes across Different Lipid Bilayers: Atomistic Molecular Dynamics Simulation Study.

Various artificial receptors, such as calixarenes, cyclodextrins, cucurbit[n]urils, and their acyclic compounds, pliiar[n]arenes, deep cavitands, and molecular tweezers, can permeate the lipid membranes and they are used as drug carriers to improve the drug solubility, stability, and bioavailability. Inspired by these, we have employed atomistic molecular dynamics simulation to examine the effects of endo-functionalized molecular tubes or naphthotubes (host-1a and host-1b) on seven different types of model lipid bilayers and the permeation properties of these receptors through these model lipid bilayers. Lipid types include six model lipid bilayers (POPC, POPE, DOPC, POPG, DPPE, POPE/POPG) and one realistic membrane (Yeast). We observe that these receptors are spontaneously translocated toward these model lipid bilayer head regions and do not proceed further into these lipid bilayer tail regions (reside at the interface between lipid head and lipid tail region), except for the DPPE-containing systems. In the DPPE model lipid bilayer-containing systems (1a-dppe and 1b-dppe), receptor molecules are only adsorbed on the bilayer surface and reside at the interface between lipid head and water. This finding is also supported by the biased free-energy profiles of these translocation processes. Passive transport of these receptors may be possible through these model lipid bilayers (due to low barrier height), except for DPPE bilayer-containing systems (that have a very high energy barrier at the center). The results from these simulations provide insight into the biocompatibility of host-1a or host-1b in microscopic detail. Based on this work, more research is needed to fully comprehend the role of these synthesized receptors as a prospective drug carrier.

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.

Role of Hydrotropes in Sparingly Soluble Drug Solubilization: Insight from a Molecular Dynamics Simulation and Experimental Perspectives.

Drug molecules' therapeutic efficacy depends on their bioavailability and solubility. But more than 70% of the formulated drug molecules show limited effectiveness due to low water solubility. Thus, the water solubility enhancement technique of drug molecules becomes the need of time. One such way is hydrotropy. The solubilizing agent of a hydrophobic molecule is generally referred to as a hydrotrope, and this phenomenon is termed hydrotropy. This method has high industrial demand, as hydrotropes are noninflammable, readily available, environmentally friendly, quickly recovered, cost-effective, and not involved in solid emulsification. The endless importance of hydrotropes in industry (especially in the pharmaceutical industry) motivated us to prepare a feature article with a clear introduction, detailed mechanistic insights into the hydrotropic solubilization of drug molecules, applications in pharma industries, and some future directions of this technique. Thus, we believe that this feature article will become an adequate manual for the pharmaceutical researchers who want to explore all of the past perspectives of the hydrotropic action of hydrotropes in pharmaceutics.

Switching of Self-Assembly to Solvent-Assisted Assembly of Molecular Motor: Unveiling the Mechanisms of Dynamic Control on Solvent Exchange.

Natural biological molecular motors are capable of performing several biological functions, such as fuel production, mobility, transport, and many other dynamic features. Inspired by these biological motors, scientists effectively synthesized artificial molecular motors to mimic several biological functionalities. Several molecular systems, from sensitive materials to molecular motors, are essential for controlling dynamic processes in larger assemblies. In this work, we discuss the self-assembly of molecular motors in water and how this self-assembly switches to the solvent-assisted assembly as solvent changes to a water-THF (tetrahydrofuran) mixture. We present an elaborate description of the morphological changes of molecular motor assemblies from pure water to a water-THF mixture to pure THF. Under the influence of THF solvent, molecular motors form an assembled structure by taking a sufficient number of THF molecules in between themselves, resulting in an assembled molecular motor with a softened core. So, molecular motor assembly swells in the water-THF mixture, and in pure water, it shrinks. This solvent-assisted assembled structure has a specific shape. We have confirmed this assembly as a solvent-assisted assembly with the help of molecular dynamics simulation and quantum chemical analysis. Molecular motor-THF and THF-THF interactions are the main responsible interactions for solvent-assisted assembly over self-assembly. This work is a perfect example of conversion between self-assembly (shrinking) and solvent-assisted assembly (swelling) of molecular motors by adding THF into water or vice versa. A spectacular check on the shrinking and swelling by merely altering solvents illustrates so many intriguing possibilities for an alteration of dynamic processes at the nanoscale.

Computational Study of Encapsulation of Polyaromatic Hydrocarbons by Endo-Functionalized Receptors in Nonpolar Medium.

Polycyclic aromatic hydrocarbons (PAHs) constitute a large group of organic pollutants produced from either natural or artificial sources during the incomplete combustion of fossil fuels or derived from various industrial processes (such as refinery processes of crude petroleum). They are seriously hazardous to human health, and removing them is of major importance. The complexation likeliness with and selective recognition of PAH guests by endo-functionalized molecular tube hosts (host-abu and host-abtu) in a nonpolar medium are investigated using classical molecular dynamics simulation and quantum calculation to probe the factors and the molecular mechanism involved in complexation processes. We examine the role of different guest molecules in the structural changes of hosts, a prelude to van der Waals interactions and binding free energy in the complexation process. These types of host-guest interactions depend on various factors. We find that (i) both the host molecules (host-abtu and host-abu) interact with the guest π-electron cloud almost equally and (ii) these interactions also depend on the molecular size of PAHs. The larger the nonpolar surface area of PAHs, the greater the interactions with the host, and the more extensive the π-electron cloud of the guest, the stronger the interactions. The linear PAHs interact more strongly than isomeric branched/curved PAHs, and the presence of heteroatoms on PAHs decreases the interactions with the host by creating repulsion between the lone pairs of heteroatoms and the π-electron cloud of the host. Noncovalent van der Waals interactions and N-H···π interactions dominate the high affinities of PAHs toward host-abu and host-abtu. The potential of mean force and molecular mechanics Poisson-Boltzmann surface area calculations reveal that all host-guest complexes are energetically stable.

Synergistic host-guest hydrophobic and hydrogen bonding interactions in the complexation between endo-functionalized molecular tube and strongly hydrophilic guest molecules in aqueous solution.

The propensity of complex formation of a host, an endo-functionalized naphthotube that has bisnaphthalene cleft architecture (host-1b), with four different strongly neutral hydrophilic guest molecules, namely 1,4-dioxane (14D), acetone, DMSO and DMF, in water is examined using classical molecular dynamics simulations. This type of molecular tube has received significant attention recently due to its usefulness as a supramolecular catalyst and for its ability to selectively recognise biologically and environmentally important neutral molecules in aqueous solution. We sequentially address the role of the different guest molecules in the structural change of host-1b, the role of the host-inserted guest and the water-inserted guest hydrogen bond properties and the host-guest binding free energies in the complex. The derivatives of our findings are: (a) the host changes its shape upon the insertion of a guest molecule and the magnitude of the shape change depends on the type and the nature of the guest molecule; (b) the complete insertion of a guest into the cavity of host-1b is only observed for guest 14D; and (c) the complete removal of water molecules from the host cavity is observed for guest 14D and the presence of a single water molecule is observed for all other guest molecules. The PMF and MM-PBSA calculations reveal that host-1b/14D complexation is the most energetically stable and the synergistic host-guest hydrophobic and hydrogen bonding interactions play a profound role in the stability of these host-guest complexes. Specifically, as the host cavity contains a small hydrophilic part and a large hydrophobic part, guest molecules with both these parts can form hydrogen bonds with the hydrophilic part of the host as well as forming a favorable hydrophobic interaction with the hydrophobic part of the host at the time of complexation.