9 research outputs found
Towards Understanding the Structure, Dynamics and Bio-activity of Diabetic Drug Metformin
Small molecules are often found to exhibit extraordinarily diverse biological
activities. Metformin is one of them. It is widely used as anti-diabetic drug
for type-two diabetes. In addition to that, metformin hydrochloride shows
anti-tumour activities and increases the survival rate of patients suffering
from certain types of cancer namely colorectal, breast, pancreas and prostate
cancer. However, theoretical studies of structure and dynamics of metformin
have not yet been fully explored. In this work, we investigate the
characteristic structural and dynamical features of three mono-protonated forms
of metformin hydrochloride with the help of experiments, quantum chemical
calculations and atomistic molecular dynamics simulations. We validate our
force field by comparing simulation results to that of the experimental
findings. Nevertheless, we discover that the non-planar tautomeric form is the
most stable. Metformin forms strong hydrogen bonds with surrounding water
molecules and its solvation dynamics show unique features. Because of an
extended positive charge distribution, metformin possesses features of being a
permanent cationic partner toward several targets. We study its interaction and
binding ability with DNA using UV spectroscopy, circular dichroism, fluorimetry
and metadynamics simulation. We find a non-intercalating mode of interaction.
Metformin feasibly forms a minor/major groove-bound state within a few tens of
nanoseconds, preferably with AT rich domains. A significant decrease in the
free-energy of binding is observed when it binds to a minor groove of DNA.Comment: 60 pages, 24 figure
Atom-efficient synthesis of a benchmark electrolyte for magnesium battery applications
The benchmark magnesium electrolyte, [Mg2Cl3]+ [AlPh4]−, can be prepared in a 100% atom-economic fashion by a ligand exchange reaction between AlCl3 and two molar equivalents of MgPh2. NMR and vibrational spectroscopy indicate that the reported approach results in a simpler ionic composition than the more widely adopted synthesis route of combining PhMgCl with AlCl3. Electrochemical performance has been validated by polarisation tests and cyclic voltammetry, which demonstrate excellent stability of electrolytes produced via this atom-efficient approach
Studying Hemoglobin and a Bare Metal-Porphyrin Complex Immobilized on Functionalized Silicon Surfaces Using Synchrotron X-ray Reflectivity
We evaluate here, using synchrotron X-ray reflectivity, hemoglobin adsorption characteristics on silicon substrates with varying chemical functionalities. Hemoglobin at isoelectronic point and at negative charge is immobilized on functionalized hydrophilic (hydroxyl, carboxylic, amine) and hydrophobic (alkylated) silicon surfaces for the study. As a control, the bare cofactor hemin (containing only the metal and porphyrin with no amino acid residues) is also studied under similar conditions. Ordered layers (grown using the Langmuir-Blodgett technique) are observed to be less affected by the surface chemistry compared to the multilayers formed by physical absorption. Surface chemistry and charge of the proteins are critical in controlling the protein adsorption characteristics on silicon, such as thickness (correlated to molecule size) and roughness. In this study, this is very well realized by varying both the hydrophobicity and hydrophilicity of the substrate. The fundamental studies discussed here provide us with a set of important guidelines as to how electrode surface functionalization can control molecular conformation/orientation, especially protein adsorption on the substrate. This in turn is expected to have a significant impact on the protein electrochemical function and response of biomolecular devices
Using porphyrin-amino acid pairs to model the electrochemistry of heme proteins: experimental and theoretical investigations
Quasi reversibility in electrochemical cycling between different oxidation states of iron is an often seen characteristic of iron containing heme proteins that bind dioxygen. Surprisingly, the system becomes fully reversible in the bare iron-porphyrin complex: hemin. This leads to the speculation that the polypeptide bulk (globin) around the iron-porphyrin active site in these heme proteins is probably responsible for the electrochemical quasi reversibility. To understand the effect of such polypeptide bulk on iron-porphyrin, we study the interaction of specific amino acids with the hemin center in solution. We choose three representative amino acids-histidine (a well-known iron coordinator in bio-inorganic systems), tryptophan (a well-known fluoroprobe for proteins), and cysteine (a redox-active organic molecule). The interactions of these amino acids with hemin are studied using electrochemistry, spectroscopy, and density functional theory. The results indicate that among these three, the interaction of histidine with the iron center is strongest. Further, histidine maintains the electrochemical reversibility of iron. On the other hand, tryptophan and cysteine interact weakly with the iron center but disturb the electrochemical reversibility by contributing their own redox active processes to the system. Put together, this study attempts to understand the molecular interactions that can control electrochemical reversibility in heme proteins. The results obtained here from the three representative amino acids can be scaled up to build a heme-amino acid interaction database that may predict the electrochemical properties of any protein with a defined polypeptide sequence
Methodologies for operando ATR-IR spectroscopy of magnesium battery electrolytes
We explore the suitability of operando attenuated total reflection infrared (ATR-IR) spectroscopy methodologies for the study of organoaluminate electrolytes for Mg battery applications. The "all-phenyl complex" in tetrahydrofuran (THF), with the molecular structure [Mg Cl ·6THF] [AlPh ] , is used as an exemplar electrolyte to compare two different spectroelectrochemical cell configurations. In one case, a Pt gauze is used as a working electrode, while in the second case, a thin (∼10 nm) Pt film working electrode is deposited directly on the surface of the ATR crystal. Spectroscopic measurements indicate substantial differences in the ATR-IR response for the two configurations, reflecting the different spatial arrangements of the working electrode with respect to the ATR sampling volume. The relative merits and potential pitfalls associated with the two approaches are discussed
Determination of Redox Sensitivity in Structurally Similar Biological Redox Sensors
Redox
stimuli govern a variety of biological processes. The relative
sensitivity of redox sensors plays an important role in providing
a calibrated response to environmental stimuli and cellular homeostasis.
This cellular machinery plays a crucial role in the human pathoge<i>n Mycobacterium tuberculosis</i> as it encounters diverse microenvironments
in the host. The redox sensory mechanism in <i>M. tuberculosis</i> is governed by two component and one-component systems, alongside
a class of transcription factors called the extra cytoplasmic function
(ECF) σ factors. ECF σ factors that govern the cellular
response to redox stimuli are negatively regulated by forming a complex
with proteins called zinc associated anti-σ factors (ZAS). ZAS
proteins release their cognate σ factor in response to oxidative
stress. The relative sensitivity of the ZAS sensors to redox processes
dictate the concentration of free ECF σ factors in the cell.
However, factors governing the redox threshold of these sensors remain
unclear. We describe here, the molecular characterization of three
σ factor/ZAS pairsσ<sup>L</sup>/RslA, σ<sup>E</sup>/RseA, and σ<sup>H</sup>/RshAusing a combination
of biophysical and electrochemical techniques. This study reveals,
conclusively, the differences in redox sensitivity in these proteins
despite apparent structural similarity and rationalizes the hierarchy
in the activation of the cognate ECF σ factors. Put together,
the study provides a basis for examining sequence and conformational
features that modulate redox sensitivity within the confines of a
conserved structural scaffold. The findings provide the guiding principles
for the design of intracellular redox sensors with tailored sensitivity
and predictable redox thresholds, providing a much needed biochemical
tool for understanding host–pathogen interaction
Unique Features of Metformin: A Combined Experimental, Theoretical, and Simulation Study of Its Structure, Dynamics, and Interaction Energetics with DNA Grooves
There
are certain small molecules that exhibit extraordinarily
diverse biological activities. Metformin is one of them. It is widely
used as an antidiabetic drug for type-two diabetes. Recent lines of
evidence of its role in antitumor activities and increasing the survival
rates of cancer patients (namely, colorectal, breast, pancreas, and
prostate cancer) are emerging. However, theoretical studies of the
structure and dynamics of metformin have not yet been fully explored.
In this work, we investigate the characteristic structural and dynamical
features of three monoprotonated forms of metformin hydrochloride
with the help of experiments, quantum chemical calculations, and atomistic
molecular dynamics simulations. We validate our force field by comparing
simulation results to those of the experimental findings. Energetics
of proton transfer between two planar monoprotonated forms reveals
a low energy barrier, which leads us to speculate a possible coexistence
of them. Nevertheless, among the protonation states, we find that
the nonplanar tautomeric form is the most stable. Our calculated values
of the self-diffusion coefficient agree quantitatively with NMR results.
Metformin forms strong hydrogen bonds with surrounding water molecules,
and its solvation dynamics shows unique features. Because of an extended
positive charge distribution, metformin possesses features of being
a permanent cationic partner toward several targets. We study its
interaction and binding ability with DNA using UV spectroscopy, circular
dichroism, fluorimetry, and metadynamics simulation. We find a nonintercalative
mode of interaction. Metformin feasibly forms a minor/major groove-bound
state within a few tens of nanoseconds, preferably with AT-rich domains.
A significant decrease in the free energy of binding is observed when
it binds to a minor groove of DNA
Differentiating between ion transport and plating–stripping phenomena in magnesium battery electrolytes using operando Raman spectroscopy
Understanding metal plating–stripping and mass transport processes is necessary for the development of new electrolytes for post-lithium energy storage applications. Operando vibrational spectroscopy is a valuable analytical tool for this purpose, enabling structural and chemical changes at electrode–electrolyte interfaces to be probed dynamically, under battery cycling conditions. In this work we apply operando Raman spectroscopy to characterize the behavior of the Mg based "all phenyl complex" [Mg2Cl3]+[AlPh4]− in tetrahydrofuran (THF), an exemplar electrolyte for emerging Mg battery technologies. We demonstrate that the observed electrolyte Raman band intensities vary reversibly with electrochemical cycling due to anion migration in response to the applied electric field, while Mg plating and stripping can be monitored independently through the broad background scattering intensity. Spectral measurements across different sites of the platinum working electrode indicate that the ion transport response is spatially heterogeneous, while the plating and stripping response is ubiquitous