Rajendra Prasad Ojha

Binding of berberine to human telomeric quadruplex – spectroscopic, calorimetric and molecular modeling studies

This study examines the characteristics of binding of berberine to the human telomeric d[AG3(T2AG3)3] quadruplex. By employing UV‐visible spectroscopy, fluorescence spectroscopy and isothermal titration calorimetry, we found that the binding affinity of berberine to the human telomeric quadruplex is 106. The complete thermodynamic profile for berberine binding to the quadruplex, at 25 °C, shows a small negative enthalpy (ΔH) of −1.7 kcal·mol−1, an entropy change with TΔS of +6.5 kcal·mol−1, and an overall favorable free energy (ΔG) of −8.2 kcal·mol−1 .Through the temperature dependence of ΔH, we obtained a heat capacity (ΔCp) of −94 (± 5) cal·mol−1·K−1. The osmotic stress method revealed that there is an uptake of 13 water molecules in the complex relative to the free reactants. Furthermore, the molecular modeling studies on different quadruplex–berberine complexes show that berberine stacking at the external G‐quartet is mainly aided by the π–π interaction and the stabilization of the high negative charge density of O6 of guanines by the positively charged N7 of berberine. The theoretical heat capacity (ΔCp) values for quadruplex–berberine models are −89 and −156 cal·mol−1·K−1.

Energetics of the human Tel-22 quadruplex-telomestatin interaction: a molecular dynamics study.

The formation and stabilization of telomeric quadruplexes has been shown to inhibit the activity of telomerase, thus establishing telomeric DNA quadruplex as an attractive target for cancer therapeutic intervention. In this context, telomestatin, a G-quadruplex-specific ligand known to bind and stabilize G-quadruplex, is of great interest. Knowledge of the three-dimensional structure of telomeric quadruplex and its complex with telomestatin in solution is a prerequisite for structure-based rational drug design. Here, we report the relative stabilities of human telomeric quadruplex (AG3[T2AG3]3) structures under K+ ion conditions and their binding interaction with telomestatin, as determined by molecular dynamics simulations followed by energy calculations. The energetics study shows that, in the presence of K+ ions, mixed hybrid-type Tel-22 quadruplex conformations are more stable than other conformations. The binding free energy for quadruplex-telomestatin interactions suggests that 1:2 binding is favored over 1:1 binding. To further substantiate our results, we also calculated the change in solvent-accessible surface area (DeltaSASA) and heat capacity (DeltaCp) associated with 1:1 and 1:2 binding modes. The extensive investigation performed for quadruplex-telomestatin interaction will assist in understanding the parameters influencing the quadruplex-ligand interaction and will serve as a platform for rational drug design.

Binding free energy calculation with QM/MM hybrid methods for Abl-Kinase inhibitor

We report a Quantum mechanics/Molecular Mechanics–Poisson-Boltzmann/ Surface Area (QM/MM-PB/SA) method to calculate the binding free energy of c-Abl human tyrosine kinase by combining the QM and MM principles where the ligand is treated quantum mechanically and the rest of the receptor by classical molecular mechanics. To study the role of entropy and the flexibility of the protein ligand complex in a solvated environment, molecular dynamics calculations are performed using a hybrid QM/MM approach. This work shows that the results of the QM/MM approach are strongly correlated with the binding affinity. The QM/MM interaction energy in our reported study confirms the importance of electronic and polarization contributions, which are often neglected in classical MM-PB/SA calculations. Moreover, a comparison of semi-empirical methods like DFTB-SCC, PM3, MNDO, MNDO-PDDG, and PDDG-PM3 is also performed. The results of the study show that the implementation of a DFTB-SCC semi-empirical Hamiltonian that is derived from DFT gives better results than other methods. We have performed such studies using the AMBER molecular dynamic package for the first time. The calculated binding free energy is also in agreement with the experimentally determined binding affinity for c-Abl tyrosine kinase complex with Imatinib.

Role of pH on dimeric interactions for DENV envelope protein: An insight from molecular dynamics study

The entry of dengue viruses is mediated by pH triggering in the host cells. Here we have studied the DENV E protein stability and binding of its units at low and normal pH using MD and MM-PB/SA method for the first time. To investigate the role of pH in dissociation of dimeric protein, we have performed a concise study of hydrogen bonding and other interactions between units of dimer at low and normal pH. The Generalized Born calculation connotes that dimeric unit was relatively less stable and less proned for dimerisation at low pH. Our results provide a theoretical verification for previous assumptions of pH triggering mechanism of dengue envelope protein. During the pH alteration, we found a large decrement in salt bridges which were observed at normal pH. We also compared the flexibility of each unit and found that they exhibit different fluctuations during molecular dynamics simulations.

Theoretical Study of Ordering in Liquid Crystals with the Help of Intermolecular Interaction Energy Calculations Part l-Anisaldehyde Azine

Abstract The ordering of mesogenic compounds in the liquid phase has been investigated using intermolecular interaction energy calculations taking Anisaldehyde azine (CH3 – O – C6H4 - CH = N – N = CH - C6H4 - O - CH3) as a specific example. The molecular structure has been taken from literature. Computations of atomic net charges and dipole moments have been carried out using CNDO/2 method. The multicentered-multipole expansion method has been employed to evaluate the various interaction energy terms viz. electrostatic, polarisation, dispersion, and repulsion. Distance as well as orientation has been changed with a view toward locating the minimum energy configuration. The large interaction energy value obtained through these calculations has been used to explain the liquid crystalline behaviour of this substance. The minimum energy configuration also supports the theoretical findings about the existence of the nematic phase and a high transition temperature.

Molecular basis of drug action of some antibiotics.

A molecular model for the role of nucleoside or nucleotide analogs in drug action has been developed. This model, an extension of our earlier model has been employed to examine the possibility of incorporation of the formycin class of antibiotics (formycin, formycin B and oxoformycin B) in the growing RNA chain. Interaction energy of the analogous bases has been computed for the entire available space inside the deep groove of the DNA double helix. The values of the interaction energy thus computed along with the location of the sites of possible association are compared with the recommended configuration for RNA during transcription. It has been found that only formycin which structurally and energy-wise fulfils the requirement of the model, can successfully replace adenosine during transcription. Results are in agreement with experimental findings.

Role of polarization in ligand docking and binding affinity prediction for inhibitors of dengue virus

Molecular docking methodology is useful in predicting comparative binding affinity of library of different ligands whose co-crystal structure in complex form is already known. However, scope of this methodology is not reliable for cross docking of different ligands due to incorrect prediction of binding pose if co-crystal structure is unknown. In the present work, we have studied the ligand polarization due to protein environment during the docking of seven ligands in envelope protein of dengue virus. We have used six kinase inhibitors which are active for dengue virus as well and a detergent molecule whose crystal structure is already known. We observed major change in docking scores due to polarization of ligands. The charges of the ligands were calculated by ab initio methods for the accuracy of our results. We observed increased hydrogen bonding due to polarization in protein environment. These results are more significant for inhibitors containing electronegative elements like chlorine and fluorine.

Interaction energy studies on pyrazolopyrimidine nucleoside antibiotics — A theoretical study: Oxoformycin B

The biological activity of oxoformycin B has been exafned on the basis of the model developed for the incorporation of nucleoside analogues during transcription. Claverie’s simplified formula has been employed for intermolecular interaction energy calculation. The pairing energy of oxoformycin B base with complementary bases as well as the association energy with nucleic acid base pairs have been calculated. The results are compared with those of similar computation with normal bases. In addition to the in-plane interaction the vertical interaction energy between the analogue and the normal bases has been computed to specify the particular position of the analogue in the chain. On the basis of the model an attempt has been made to explain the mechanism of the biological action of oxoformycin B and to compare the biological activity of pyrazolopyrimidine nucleoside analogues.

Recent Advances in Protein−Ligand Interactions: Molecular Dynamics Simulations and Binding Free Energy

Computational techniques are one of the most emerging topics in structural and molecular biology. Molecular dynamics (MD) simulations are used not only to explore the conformational aspects of biological systems but also to have significant scope in protein-ligand interactions. Then the binding free energy calculations are readily applied to the simulated systems in order to predict the binding affinities. The thermodynamic properties are directly related to protein-ligand interactions which are dependent upon a few specific parameters. In the present review, we highlight some facts related to protein-ligand complexes, by starting with a survey of MD simulations and binding free energy calculations and ending with some successful implementations of these computational techniques.

Stability and free energy calculation of LNA modified quadruplex: a molecular dynamics study

Telomeric ends of chromosomes, which comprise noncoding repeat sequences of guanine-rich DNA, which are the fundamental in protecting the cell from recombination and degradation. Telomeric DNA sequences can form four stranded quadruplex structures, which are involved in the structure of telomere ends. The formation and stabilization of telomeric quadruplexes has been shown to inhibit the activity of telomerase, thus establishing telomeric DNA quadrulex as an attractive target for cancer therapeutic intervention. Molecular dynamic simulation offers the prospects of detailed description of the dynamical structure with ion and water at molecular level. In this work we have taken a oligomeric part of human telomeric DNA, d(TAGGGT) to form different monomeric quadruplex structures d(TAGGGT)4. Here we report the relative stabilities of these structures under K+ ion conditions and binding interaction between the strands, as determined by molecular dynamic simulations followed by energy calculation. We have taken locked nucleic acid (LNA) in this study. The free energy molecular mechanics Poission Boltzman surface area calculations are performed for the determination of most stable complex structure between all modified structures. We calculated binding free energy for the combination of different strands as the ligand and receptor for all structures. The energetic study shows that, a mixed hybrid type quadruplex conformation in which two parallel strands are bind with other two antiparallel strands, are more stable than other conformations. The possible mechanism for the inhibition of the cancerous growth has been discussed. Such studies may be helpful for the rational drug designing.