Entropy Balance in the Intercalation Process of an Anti-Cancer Drug Daunomycin

The interplay of entropy components in a molecular recognition process is complex but intriguing. In this study, we probed into the origin of this interplay among the drug, DNA, and water entropy in the intercalation process (free → minor groove-bound → intercalation) of an anticancer drug daunomycin, resulting in small entropy difference (+1.1 kcal/mol) in excellent agreement with experiment (−1.1 kcal/mol). Using extensive all-atom simulations (>0.6 μs in total), followed by quasi- harmonic entropy calculation (with prior permutation reduction for water) and rigorous anharmonic and mutual information corrections, this study captures differing trends of drug and DNA entropy in different bound states. Overall water entropy change is positive although somewhat controlled due to the formation of bigger solvation layer in the bound states. This study encompasses for the first time all of the different entropy contributions including water in a biomolecular recognition process depicting entropy compensation similar to the ubiquitous enthalpy/entropy compensation prevalent in chemistry

Molecular Mechanism of Direct Proflavine–DNA Intercalation: Evidence for Drug-Induced Minimum Base-Stacking Penalty Pathway

DNA intercalation, a biophysical process of enormous clinical significance, has surprisingly eluded molecular understanding for several decades. With appropriate configurational restraint (to prevent dissociation) in all-atom metadynamics simulations, we capture the free energy surface of direct intercalation from minor groove-bound state for the first time using an anticancer agent proflavine. Mechanism along the minimum free energy path reveals that intercalation happens through a minimum base stacking penalty pathway where nonstacking parameters (Twist→Slide/Shift) change first, followed by base stacking parameters (Buckle/Roll→Rise). This mechanism defies the natural fluctuation hypothesis and provides molecular evidence for the drug-induced cavity formation hypothesis. The thermodynamic origin of the barrier is found to be a combination of entropy and desolvation energy

Single Amino Acid Switch between a Flavin-Dependent Dehalogenase and Nitroreductase

A single mutation within a flavo­protein is capable of switching the catalytic activity of a dehalogenase into a nitro­reductase. This change in function correlates with a destabilization of the one-electron-reduced flavin semi­quinone that is differentially expressed in the nitro-FMN reductase super­family during redox cycling. The diversity of function within such a super­family therefore has the potential to arise from rapid evolution, and its members should provide a convenient basis for developing new catalysts with an altered specificity of choice

Single Water Entropy: Hydrophobic Crossover and Application to Drug Binding

Entropy of water plays an important role in both chemical and biological processes e.g. hydrophobic effect, molecular recognition etc. Here we use a new approach to calculate translational and rotational entropy of the individual water molecules around different hydrophobic and charged solutes. We show that for small hydrophobic solutes, the translational and rotational entropies of each water molecule increase as a function of its distance from the solute reaching finally to a constant bulk value. As the size of the solute increases (0.746 nm), the behavior of the translational entropy is opposite; water molecules closest to the solute have higher entropy that reduces with distance from the solute. This indicates that there is a crossover in translational entropy of water molecules around hydrophobic solutes from negative to positive values as the size of the solute is increased. Rotational entropy of water molecules around hydrophobic solutes for all sizes increases with distance from the solute, indicating the absence of crossover in rotational entropy. This makes the crossover in total entropy (translation + rotation) of water molecule happen at much larger size (>1.5 nm) for hydrophobic solutes. Translational entropy of single water molecule scales logarithmically (<i>S</i>_tr^QH = <i>C</i> + <i>k</i>_B ln <i>V</i>), with the volume <i>V</i> obtained from the ellipsoid of inertia. We further discuss the origin of higher entropy of water around water and show the possibility of recovering the entropy loss of some hypothetical solutes. The results obtained are helpful to understand water entropy behavior around various hydrophobic and charged environments within biomolecules. Finally, we show how our approach can be used to calculate the entropy of the individual water molecules in a protein cavity that may be replaced during ligand binding

Distribution of Residence Time of Water around DNA Base Pairs: Governing Factors and the Origin of Heterogeneity

Water dynamics in the solvation shell around biomolecules plays a vital role in their stability, function, and recognition processes. Although extensively studied through various experimental and computational methods, dynamical time scales of water near DNA is highly debated. The residence time of water is one such dynamical quantity that has been probed rarely around DNA using computational methods. Moreover, the effect of local DNA sequence variation in water residence time has also not been addressed. Using 20 DNA systems with different sequences, we capture here the mean residence time (MRT) of water molecules around 360 different sites in the major and minor grooves of DNA. Thus, we show that a distribution of time scales exists even for a regular structure of DNA, reflecting the effect of chemistry, topography, and other factors governing dynamics of water. We used the stable state picture (SSP) formalism to calculate MRT that avoids the effect of transient recrossing. Results obtained from simulations agree well with experiments done on a few specific systems at a similar temperature. Most importantly, we find that although the groove width and depth influence water time scale, MRT of water is always longer in the middle of the DNA, in agreement with NMR experiments. We propose a simple kinetic model of water escape from DNA where water molecules move along the DNA and perpendicular to it in both the first and second solvation shell before it escapes to bulk. We show that this simple kinetic model captures both the time scale and the position dependence of MRT of water around DNA. This study thus portrays the origin and a measure of heterogeneity in water dynamics around DNA and provides a fresh perspective in the ongoing debate on water dynamical time scales around DNA

Theoretical Study of Structural Changes in DNA under High External Hydrostatic Pressure

The study of DNA under high hydrostatic pressure provides fundamental insights into the nature of interactions responsible for its structure and its remarkable stability in extreme conditions. We have investigated the structural changes in DNA under 2000 bar external pressure using electronic structure calculations and molecular dynamics simulations. Both these methods predict very small distortions in the structure; notably, the change in hydrogen bond lengths is an order of magnitude smaller than previously reported experimental values using NMR. The large discrepancy suggests further investigation into the analysis of the experimental data obtained from NMR

Molecular Origin of DNA Kinking by Transcription Factors

Binding of transcription factor (TF) proteins with DNA may cause severe kinks in the latter. Here, we investigate the molecular origin of the DNA kinks observed in the TF-DNA complexes using small molecule intercalation pathway, crystallographic analysis, and free energy calculations involving four different transcription factor (TF) protein–DNA complexes. We find that although protein binding may bend the DNA, bending alone is not sufficient to kink the DNA. We show that partial, not complete, intercalation is required to form the kink at a particular place in the DNA. It turns out that while amino acid alone can induce the desired kink through partial intercalation, protein provides thermodynamic stabilization of the kinked state in TF-DNA complexes

Cu₂O Nanoparticles Anchored on Amine-Functionalized Graphite Nanosheet: A Potential Reusable Catalyst

Synthesis of Cu₂O–amine-functionalized graphite nanosheet (AFGNS) composite has been accomplished at room temperature. In the first step, AFGNS is synthesized by wet chemical functionalization where the −NH₂ groups formed on nanosheet surface help to anchor the Cu²⁺ ions homogeneously through coordinate bonds. Reduction of Cu²⁺ (3.4 × 10^–2 mmol) in the presence of NaBH₄ (1.8 mmol) can be restricted to Cu¹⁺ on AFGNS surface at room temperature. This leads to the formation of uniform Cu₂O nanoparticles (NP) on AFGNS. The role played by the −NH₂ groups in anchoring Cu²⁺ ions and followed by stabilizing the Cu₂O NP on AFGNS was understood by controlled reactions in the absence of −NH₂ groups and without any graphitic support, respectively. The prepared Cu₂O–AFGNS composite shows excellent catalytic activity toward degradation of an azo dye, methyl orange, which is an environmental pollutant. The dye degradation proceeds with high rate constant value, and the composite shows high stability and excellent reuse capability

One-Pot Synthesis and Transmembrane Chloride Transport Properties of <i>C</i>₃‑Symmetric Benzoxazine Urea

One-pot synthesis of a <i>C</i>₃-symmetric benzoxazine-based tris-urea compound is discussed. ¹H NMR titrations indicate a stronger Cl^– binding compared that of Br^– and I^– by the receptor. Effective Cl^– transport across liposomal membranes via a Cl^–/X^– antiport mechanism is confirmed. Theoretical calculation suggests that a few water molecules with N–H, CO, and the aromatic ring of the receptor create a H-bonded polar cavity where a Cl^– is recognized by O–H···Cl^– interactions from five bridged water molecules

Quantum yield and brightness of FbFPs.

<p>Brightness is quantified as the product of quantum yield and molar extinction coefficient of the fluorophore (flavin mononucleotide). Brightness values are reported for monomeric units of PpFbFP and EcFbFP, which exist as functional dimers.</p