Synthesis of Thiazolidin-4-Ones Derivatives, Evaluation of Conformation in Solution, Theoretical Isomerization Reaction Paths and Discovery of Potential Biological Targets.

Thiazolin-4-ones and their derivatives represent important heterocyclic scaffolds with various applications in medicinal chemistry. For that reason, the synthesis of two 5-substituted thiazolidin-4-one derivatives was performed. Their structure assignment was conducted by NMR experiments (2D-COSY, 2D-NOESY, 2D-HSQC and 2D-HMBC) and conformational analysis was conducted through Density Functional Theory calculations and 2D-NOESY.

From structural polymorphism to structural metamorphosis of the coat protein of flexuous filamentous potato virus Y.

The structural diversity and tunability of the capsid proteins (CPs) of various icosahedral and rod-shaped viruses have been well studied and exploited in the development of smart hybrid nanoparticles. However, the potential of CPs of the wide-spread flexuous filamentous plant viruses remains to be explored. Here, we show that we can control the shape, size, RNA encapsidation ability, symmetry, stability and surface functionalization of nanoparticles through structure-based design of CP from potato virus Y (PVY).

Sub-THz acoustic excitation of protein motion.

The application of terahertz radiation has been shown to affect both protein structure and cellular function. As the key to such structural changes lies in the dynamic response of a protein, we focus on the susceptibility of the protein's internal dynamics to mechanical stress induced by acoustic pressure waves. We use the open-boundary molecular dynamics method, which allows us to simulate the protein exposed to acoustic waves.

Water-Aluminum Interaction as Driving Force of Linde Type A Aluminophosphate Hydration.

Linde type A (LTA) aluminophosphate is a promising candidate for an energy storage material used for low-temperature solar and waste-heat management. The mechanism of reversible water adsorption, which is the basis for potential industrial applications, is still not clear. In this paper, we provide mechanistic insight into various aspects of the hydration process using molecular modeling methods.

Rotational Dynamics of a Protein under Shear Flow Studied by the Eckart Frame Formalism.

Proteins are natural polymers that play an essential role in both living organisms and biotechnological applications. During certain bioprocessing steps, they can be exposed to significant mechanical stress induced by, for example, shear flow or sonication, resulting in reduced therapeutic efficacy, aggregation, or even a loss of activity. For this reason, there is a need to understand and determine the susceptibility of the protein activity to the experienced mechanical stress.

Surface plasmon resonance and microscale thermophoresis approaches for determining the affinity of perforin for calcium ions.

Perforin is a pore-forming protein that plays a crucial role in the immune system by clearing virus-infected or tumor cells. It is released from cytotoxic granules of immune cells and forms pores in targeted lipid membranes to deliver apoptosis-inducing granzymes. It is a very cytotoxic protein and is therefore adapted not to act in producing cells.

Influence of SGLT1 Sugar Uptake Inhibitors on Water Transport.

Sodium glucose cotransporters (SGLTs) are cotransporters located in the cell membrane of various epithelia that uptake glucose or galactose and sodium into the cell. Its founding member, SGLT1, represents a major pharmaceutically relevant target protein for development of new antidiabetic drugs, in addition to being the target protein of the oral rehydration therapy. Previous studies focused primarily on the transport of substrates and ions, while our study focuses on the effect of water transport.

Collective Domain Motion Facilitates Water Transport in SGLT1.

The human sodium-glucose cotransporter protein (SGLT1) is an important representative of the sodium solute symporters belonging to the secondary active transporters that are critical to the homeostasis of sugar, sodium, and water in the cell. The underlying transport mechanism of SGLT1 is based on switching between inward- and outward-facing conformations, known as the alternating access model, which is crucial for substrate transport, and has also been postulated for water permeation. However, the nature of water transport remains unclear and is disputed along the passive and active transport, with the latter postulating the presence of the pumping effect.

Molecular Dynamics-Derived Pharmacophore Model Explaining the Nonselective Aspect of K10.1 Pore Blockers.

The K10.1 voltage-gated potassium channel is highly expressed in 70% of tumors, and thus represents a promising target for anticancer drug discovery. However, only a few ligands are known to inhibit K10.

Endogenous modulators of neurotrophin signaling: Landscape of the transient ATP-NGF interactions.

The Nerve Growth Factor (NGF) neurotrophin acts in the maintenance and growth of neuronal populations. Despite the detailed knowledge of NGF's role in neuron physiology, the structural and mechanistic determinants of NGF bioactivity modulated by essential endogenous ligands are still lacking. We present the results of an integrated structural and advanced computational approach to characterize the extracellular ATP-NGF interaction.

Decoupling between the translation and rotation of water in the proximity of a protein molecule.

The interaction between water and biomacromolecules is of fundamental interest in biophysics, biochemistry and physical chemistry. By combining neutron scattering and molecular dynamics simulations on a perdeuterated protein at a series of hydration levels, we demonstrated that the translational motion of water is slowed down more significantly than its rotation, when water molecules approach the protein molecule. Further analysis of the simulation trajectories reveals that the observed decoupling results from the fact that the translational motion of water is more correlated over space and more retarded by the charged/polar residues and spatial confinement on the protein surface, than the rotation.

Nucleotide-Specific Autoinhibition of Full-Length K-Ras4B Identified by Extensive Conformational Sampling.

K-Ras is one of the most frequently mutated oncogenes in human tumor cells. It consists of a well-conserved globular catalytic domain and a flexible tail-like hypervariable region (HVR) at its C-terminal end. It plays a key role in signaling networks in proliferation, differentiation, and survival, undergoing a conformational switch between the active and inactive states.

Why do water molecules around small hydrophobic solutes form stronger hydrogen bonds than in the bulk?

Molecular solutes are known to have a strong effect on the structural and dynamical properties of the surrounding water. In our recent study (PNAS, 114, 322 (2017)) we have identified the presence of strengthened water hydrogen bonds near hydrophobic solutes by using both IR spectroscopy and ab-initio molecular dynamics simulations. The water molecules involved in the enhanced hydrogen bonding have been shown to display extensive structural ordering and restricted mobility.

Structural basis for the multitasking nature of the potato virus Y coat protein.

Potato virus Y (PVY) is among the most economically important plant pathogens. Using cryoelectron microscopy, we determined the near-atomic structure of PVY's flexuous virions, revealing a previously unknown lumenal interplay between extended carboxyl-terminal regions of the coat protein units and viral RNA. RNA-coat protein interactions are crucial for the helical configuration and stability of the virion, as revealed by the unique near-atomic structure of RNA-free virus-like particles.

Evaluation of Selected CYP51A1 Polymorphisms in View of Interactions with Substrate and Redox Partner.

Cholesterol is essential for development, growth, and maintenance of organisms. Mutations in cholesterol biosynthetic genes are embryonic lethal and few polymorphisms have been so far associated with pathologies in humans. Previous analyses show that lanosterol 14α-demethylase (CYP51A1) from the late part of cholesterol biosynthesis has only a few missense mutations with low minor allele frequencies and low association with pathologies in humans.

Origin of hydrophobicity and enhanced water hydrogen bond strength near purely hydrophobic solutes.

Hydrophobicity plays an important role in numerous physicochemical processes from the process of dissolution in water to protein folding, but its origin at the fundamental level is still unclear. The classical view of hydrophobic hydration is that, in the presence of a hydrophobic solute, water forms transient microscopic "icebergs" arising from strengthened water hydrogen bonding, but there is no experimental evidence for enhanced hydrogen bonding and/or icebergs in such solutions. Here, we have used the redshifts and line shapes of the isotopically decoupled IR oxygen-deuterium (O-D) stretching mode of HDO water near small purely hydrophobic solutes (methane, ethane, krypton, and xenon) to study hydrophobicity at the most fundamental level.

A novel synthetic luteinizing hormone-releasing hormone (LHRH) analogue coupled with modified β-cyclodextrin: insight into its intramolecular interactions.

Background: Cyclodextrins (CDs) in combination with therapeutic proteins and other bioactive compounds have been proposed as candidates that show enhanced chemical and enzymatic stability, better absorption, slower plasma clearance and improved dose-response curves or immunogenicity. As a result, an important number of therapeutic complexes between cyclodextrins and bioactive compounds capable to control several diseases have been developed.

Results: In this article, the synthesis and the structural study of a conjugate between a luteinizing hormone-releasing hormone (LHRH) analogue, related to the treatment of hormone dependent cancer and fertility, and modified β-cyclodextrin residue are presented.

An efficient synthetic method and theoretical calculations of olmesartan methyl ether: study of biological function of AT1 antagonism.

The dissolution of the antihypertensive AT1 antagonist olmesartan in methanol generates in situ a new highly bioactive methyl ether analogue via SN1 mechanism involving an intramolecular proton transfer from carboxyl to hydroxyl group. Theoretical calculations confirmed the thermodynamic control preference of methyl ether versus the antagonistic product methyl ester. Α facile synthetic method for olmesartan methyl ether from olmesartan or olmesartan medoxomil is also described.

Allostery and conformational dynamics in cAMP-binding acyltransferases.

Mycobacteria harbor unique proteins that regulate protein lysine acylation in a cAMP-regulated manner. These lysine acyltransferases from Mycobacterium smegmatis (KATms) and Mycobacterium tuberculosis (KATmt) show distinctive biochemical properties in terms of cAMP binding affinity to the N-terminal cyclic nucleotide binding domain and allosteric activation of the C-terminal acyltransferase domain. Here we provide evidence for structural features in KATms that account for high affinity cAMP binding and elevated acyltransferase activity in the absence of cAMP.

The amide III vibrational circular dichroism band as a probe to detect conformational preferences of alanine dipeptide in water.

The conformational preferences of blocked alanine dipeptide (ADP), Ac-Ala-NHMe, in aqueous solution were studied using vibrational circular dichroism (VCD) together with density functional theory (DFT) calculations. DFT calculations of three most representative conformations of ADP surrounded by six explicit water molecules immersed in a dielectric continuum have proven high sensitivity of amide III VCD band shape that is characteristic for each conformation of the peptide backbone. The polyproline II (PII ) and αR conformation of ADP are associated with a positive VCD band while β conformation has a negative VCD band in amide III region.

Polymorphisms of CYP51A1 from cholesterol synthesis: associations with birth weight and maternal lipid levels and impact on CYP51 protein structure.

We investigated the housekeeping cytochrome P450 CYP51A1 encoding lanosterol 14α-demethylase from cholesterol synthesis that was so far not directly linked to human disorders. By direct sequencing of CYP51A1 in 188 women with spontaneous preterm delivery and 188 unrelated preterm infants (gestational age <37 weeks) we identified 22 variants where 10 are novel and rare. In infants there were two novel CYP51A1 variants where damaging effects of p.

Quantitative structure-activation barrier relationship modeling for Diels-Alder ligations utilizing quantum chemical structural descriptors.

Background: In the present study, we show the correlation of quantum chemical structural descriptors with the activation barriers of the Diels-Alder ligations. A set of 72 non-catalysed Diels-Alder reactions were subjected to quantitative structure-activation barrier relationship (QSABR) under the framework of theoretical quantum chemical descriptors calculated solely from the structures of diene and dienophile reactants. Experimental activation barrier data were obtained from literature.

Soft collective fluctuations governing hydrophobic association.

The interaction between two associating hydrophobic particles has traditionally been explained in terms of the release of entropically frustrated hydration shell water molecules. However, this picture cannot account for the kinetics of hydrophobic association and is therefore not capable of providing a microscopic description of the hydrophobic interaction (HI). Here, Monte Carlo simulations of a pair of molecular-scale apolar solutes in aqueous solution reveal the critical role of collective fluctuations in the hydrogen bond (HB) network for the microscopic picture of the HI.

Physical origin underlying the entropy loss upon hydrophobic hydration.

The hydrophobic effect (HE) is commonly associated with the demixing of oil and water at ambient conditions and plays the leading role in determining the structure and stability of biomolecular assembly in aqueous solutions. On the molecular scale HE has an entropic origin. It is believed that hydrophobic particles induce order in the surrounding water by reducing the volume of configuration space available for hydrogen bonding.