This review presents a summary of seven noncovalent interactions (NCIs) that are prevalent in proteins and nucleic acids. These NCIs are belittled in the literature and need special attention.
The demand for long-term storage and stability of proteins
has
increased substantially in the pharmaceutical industries, yet the
sensitivity of proteins toward the environment has become a cardinal
task for researchers. To deal with this, we have selected a multifunctional
enzyme Cytochrome-c (Cyt-c) involved in many chemical and biochemical
reactions as model protein, which is very sensitive and loses structural
integrity on exposure to the environment. The remarkable features
of ionic liquids (ILs) have entitled them as alternatives to aqueous
and organic solvents for solubility, storage, and surrogate reaction
medium. Hence, we have adapted the biocompatible and nontoxic cation
and anion based amino acid ILs (CAAAILs) as potential solvents for
storage and stability of Cyt-c. Herein, we report the molecular insights
and thermodynamics of interaction between CAAAILs and Cyt-c with the
help of isothermal titration calorimetry (ITC), transmission electron
microscopy (TEM), UV–vis, CD, and fluorescence spectroscopy
as well as molecular docking and molecular dynamics (MD) simulations.
The structure and stability of Cyt-c remain unchanged in the presence
of CAAAILs. Both electrostatic and hydrophobic interactions are accountable
for the binding of CAAAILs in the region between terminal helices
and the loop of Cyt-c through nonspecific multiple binding sites,
which can be exploited for storage and stability of proteins and will
be helpful in designing new biobased ILs for biochemical applications.
Crystal structure analysis and quantum chemical calculations enabled us to discover a new non-covalent interaction, coined as carbo-hydrogen bond (CH-bond).
Ribonucleic acid (RNA) is exceedingly sensitive to degradation
compared to DNA. The current protocol for storage of purified RNA
requires freezing conditions below −20 °C. Recent advancements
in biological chemistry have identified amino acid-based ionic liquids
as suitable preservation media for RNA, even in the presence of degrading
enzymes. However, the mechanistic insight into the interaction between
ILs and RNA is unclear. To the best of our knowledge, no attempts
are made so far to provide a molecular view. This work aims to establish
a detailed understanding of how ILs enable structural stability to
RNA sourced from Torula yeast. Herein, we manifest the hypothesis
of multimodal binding of IL and its minimal perturbation to the macromolecular
structure, with several spectroscopic techniques such as time-resolved
fluorescence and fluorescence correlation spectroscopy (FCS) aided
with molecular dynamics at microsecond time scales. Relevant structural
and thermodynamic details from biophysical experiments confirm that
even long-term RNA preservation with ILs is a possible alternative
devoid of any structural deformation. These results establish a unifying
mechanism of how ILs are maintaining conformational integrity and
thermal stability. The atomistic insights are transferable for their
potential applications in drug delivery and biomaterials by considering
the advantages of having maximum structural retention and minimum
toxicity.
Ionic liquids (ILs) are useful in pharmaceutical industries and biotechnology as alternative solvents or sources for protein extraction and purification, preservation of biomolecules and for regulating the catalytic activity of enzymes. However, the binding mechanism, the non-covalent forces responsible for protein-IL interactions and dynamics of proteins in IL need to be investigated in depth for the effective use of ILs as alternatives. Herein, we disclose the molecular level understanding of the structural intactness and reactivity of a model protein cytochrome c (Cyt c) in biocompatible threonine-based ILs with the help of experimental techniques such as isothermal titration calorimetry (ITC), fluorescence spectroscopy, transmission electron microscopy (TEM) as well as molecular docking. Hydrophobic and electrostatic forces are responsible for the structural and conformational integrity of Cyt c in IL. The ITC experiments revealed the Cyt c-IL binding free energies are in the range of 10-14 kJ/mol and the molecular docking studies demonstrated that ILs interact at the surfaces of Cyt c. The results look promising as the ILs used here are non-toxic and biocompatible, and thus may find potential applications in structural biology and biotechnology.
The conceptual development of aromaticity is essential to rationalize and understand the structure and behavior of aromatic heterocycles. This work addresses for the first time, the interconnection between aromaticity and sulfur/selenium centered hydrogen bonds (S/SeCHBs) involved in representative heterocycle models of canonical nucleobases (2‐Pyridone; 2PY) and its sulfur (2‐Thiopyridone; 2TPY) and selenium (2‐Selenopyridone; 2SePY) analogs. The nucleus‐independent chemical shift (NICS) and gauge induced magnetic current density (GIMIC) values suggested significant reduction of aromaticity upon replacement of exocyclic carbonyl oxygen with sulfur and selenium. However, we observed two‐fold (57 %) and three‐fold (80 %) enhancement in the aromaticity for 2TPY dimer, and 2SePY dimer, respectively which are connected through S/SeCHBs. Aromaticity enhancement was also noticed in 1 : 1 H‐bonded complexes (heterodimers), micro hydrated clusters and for bulk hydration. It is expected that exocyclic S and Se incorporation into heterocycles without compromising aromatic loss would definitely reinforce to design new supramolecular building blocks via S/SeCH‐bonded complexes.
Finding appropriate photosensitizers (PSs) for daylight
photodynamic
therapy (dPDT) applications is extremely challenging, even though
heavy-atom-free photosensitizers (HAFPSs) such as thiocarbonyl-modified
nucleobases have shown a ray of hope. Few attempts have been made
to find alternative natural products for dPDT applications. Pteridine
heterocycles consisting of a pyrazine ring and a pyrimidine ring,
such as lumazine, which exhibit many structural similarities to the
alloxazine ring of the flavin molecule, could be an option for HAFPSs.
The photophysical and quantum mechanical studies of the thio-modified
lumazines revealed that sequential thiomodifications in lumazine result
in a bathochromic shift. Additionally, higher tissue penetration depths
were observed for thiolumazines. The fluorescence quenching in the
case of thiomodified lumazines was explained using triplet state formation,
whereas the contribution from the photoinduced electron transfer process
cannot be ignored. It was also noticed that a strong one-photon absorption
influenced the two-photon absorption (TPA) process, leading to a self-focusing
effect in the visible spectral region. The higher tissue penetration
and larger TPA cross section are the hallmark characteristics of the
thiolumazines to be considered as potential HAFPSs for dPDT applications.
Designing a potential protein–ligand pair is pivotal, not only to track the protein structure dynamics, but also to assist in an atomistic understanding of drug delivery. Herein, the potential of a small model thioamide probe being used to study albumin proteins is reported. By monitoring the Förster resonance energy transfer (FRET) dynamics with the help of fluorescence spectroscopic techniques, a twofold enhancement in the FRET efficiency of 2‐thiopyridone (2TPY), relative to that of its amide analogue, is observed. Molecular dynamics simulations depict the relative position of the free energy minimum to be quite stable in the case of 2TPY through noncovalent interactions with sulfur, which help to enhance the FRET efficiency. Finally, its application is shown by pairing thiouracils with protein. It is found that the site‐selective sulfur atom substitution approach and noncovalent interactions with sulfur can substantially enhance the FRET efficiency, which could be a potential avenue to explore in the design of FRET probes to study the structure and dynamics of biomolecules.
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