Computational Sciences - Research Publications
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Item Understanding the principles of protein-protein interactions: Designing novel means for virtual proteomics(Central University of Punjab, 2020) Kumar, Vicky; Kulharia, Mahesh and Munshi, AnjanaProteins are the basic functional units in the cellular world of life. They are nano- machines programmed to associate with other biomolecules in order to enact an array of molecular functions in response to biological events at cellular and system levels. Understanding the biomolecular phenomenon governing such associations may provide insights into the principles of protein chemistry that have a wide-range of applications. In the current work, two databases (PPInS and NRDB) in which the information of interacting protein chains from the experimentally determined protein- protein complexes (PPCs) for which structural information in terms of SCOP superfamily was available, is demarcated in the form of protein-protein interaction interfaces (PPIIs) were developed. The PPIIs contained in these databases were made available on a web server for public use. These were analysed w.r.t. physicochemical and geometrical characteristics of PPI sites. With the belief that designing of computational tools with prediction ability must be trained and tested on real instances of the phenomenon for which it is designed, the analytical information obtained from the analysis of PPIIs from NRDB was incorporated in development of a computational tool, Anveshan, for prediction of putative protein-protein interaction (PPI) sites. The training and test datasets for Anveshan development were obtained from the PPInS. PPInS is a high-performance database of PPIIs in which atomic-level information of the molecular interactions amongst various protein chains in PPCs together with their evolutionary information in Structural Classification of Proteins (SCOPe release 2.06), is made available. Total 32,468 PDB files representing X-ray crystallized multimeric PPCs with structural resolution better than 2.5 Å were shortlisted to demarcate the PPIIs. Total 111,857 PPIIs with approximately 32.24 million atomic contact pairs were generated and made available on a web server, named PPInS, (http://www.cup.edu.in:99/ppins/home.php) for on-site analysis and downloading purpose. A non-redundant database (NRDB) of PPInS containing 2,265 PPIIs with over 1.8 million ACPs corresponding to the 1,931 PPCs was also designed by removing structural redundancies at the level of SCOP superfamily (SCOP release 1.75) was also designed to provide the foundation to the development of Anveshan. All the PPIIs and PPIPs involved in both these databases were analysed w.r.t. residues interface propensity (RIP), hydrophobic content, solvation free energy, compactness of interacting residue’ neighbourhood, planarity, and depth index. The PPIIs were also examined in the context of sequence similarity shared by the protein chains involved in the PPII formation which revealed the presence of homodimers in abundance in PDB. Therefore, prior to analysing the PPIIs w.r.t to other parameters, PPIIs from both the databases were categorized in three PPII classes depicting the low-sequence similarity (LSS), moderate-sequence similarity (MSS), and high- sequence similarity (HSS) between the protein chains involved in PPIIs. Analysis pertaining to RIP showed the presence of aliphatic and aromatic residues on interaction sites in abundance and the least occurrence of charged residues (except Arg). Physicochemical and structural analysis of PPIPs, initially, showed a significant difference between their parametric scores w.r.t. all three PPII classes from PPInS and NRDB. However, on removing less than 1% statistical outliers from each PPII class, the parametric scores from all three classes of PPInS and NRDB converged to a statistical indistinguishable common sub-range and followed the similar distribution trends. This indicates that the principles of molecular recognition among proteins are not driven by their sequence similarity and reinforces the importance of geometrical and electrostatic complementarity as the main determinants for PPIs. The parametric score obtained by analysing 4,530 PPIPs from NRDB w.r.t. their RIP, their hydrophobic content and the amount of solvation free energy associated with them provided the basis for the implementation of Anveshan. By applying Anveshan on another dataset of 4,290 PPIPs from 2,145 PPIIs, the optimal range of these parametric scores and protein-probe van der Waals energy of interaction was determined. Subsequently, taking the optimal range of PPIP parametric scores and threshold for protein-probe van derWaals energy of interaction into the consideration, the Anveshan was tested on a blind dataset of 554 protein chains. Predicting 10 sites for each protein chain and taking the best-predicted patch into account, Anveshan was successful in predicting 69.67% sites correctly with at least 50% accuracy in both precision and coverage separately. On predicting only one PPI site for each protein chain, sites predicted by Anveshan on an average covered 21.91% of actual sites in them. Analysing the sites predicted by SPPIDER, it was found that 22.7% of actual sites were covered in predicted sites. However, on predicting two sites for each protein chain, the percentage coverage of actual sites in the sites predicted by Anveshan exceeded two- fold (i.e. 41.81%), thus making Anveshan a superior approach.Item Synthesis and photophysics of new unsymmetrically substituted 5,5?-diaryl-2,2?-bypiridine-based “push-pull” fluorophores(Elsevier Ltd, 2019) Starnovskaya E.S.; Kopchuk D.S.; Khasanov A.F.; Tanya O.S.; Santra S.; Giri K.; Rahman M.; Kovalev I.S.; Zyryanov G.V.; Majee A.; Charushin V.N.New unsymmetrically substituted 5,5?-diaryl-2,2?-bypiridine “push-pull “ fluorophores were prepared in good yields via the “1,2,4-triazine method “/Suzuki coupling reaction sequence. The obtained fluorophores contain the “push-pull “ system with donor and acceptor moieties arranged in a D-?-A-?-D fashion, and that provides both the prospective photophysical properties and unique solvatocromic effects for the most representative compounds.Item Electronic spectroscopy of carbon chains (C2 n +1, n = 7-10) of astrophysical importance. I. Quantum chemistry(American Institute of Physics Inc., 2019) Reddy S.R.; Ghosh A.; Mahapatra S.Carbon chains have been predicted to be potential carriers of diffuse interstellar band features in astrophysical observations. Motivated by numerous predictions, we set out to carry out extensive ab initio quantum chemistry calculations to establish the ground and excited electronic potential energy surfaces and their coupling surfaces for carbon chains containing an odd number of carbon atoms (C2n+1, n = 7-10). Vibronic coupling models are established with the aid of the calculated electronic energies to investigate nuclear dynamics from first principles. The latter are reported in Ghosh et al. [J. Chem. Phys. 151, 054304 (2019)]. The mentioned carbon chains possess a linear cumulenic structure at the equilibrium minimum of their electronic ground state, and an electronic excited state of the ?u+1 term appears to be extremely bright optically and absorbs in the visible region of the electromagnetic spectrum. Vertical excitation energy of this state decreases and transition dipole moment increases, and as a result, the oscillator strength of this state linearly increases with an increase of the chain length. There are states belonging to 1?g, 1?u, ?g+1, 1?g, and 1?u terms, in the immediate vicinity of the ?u+1 state, which are optically dark but can gain intensity through vibronic coupling with the optically bright ?u+1 state. Construction of a coupling scheme considering the Renner-Teller coupling within the degenerate ? states and pseudo-Renner-Teller coupling between the Renner-Teller split component states as well as with the nondegenerate ? states is another motivation of this work. The coupled-state Hamiltonian is constructed in a diabatic electronic basis in terms of the dimensionless normal coordinates of the vibrational modes of the carbon chains. Both Renner-Teller and pseudo-Renner-Teller types of couplings are included in the Hamiltonian. The theoretical results are discussed in relation to the experimental findings. � 2019 Author(s).Item Electronic spectroscopy of carbon chains (C2 n +1, n = 7-10) of astrophysical importance. II. Quantum dynamics(American Institute of Physics Inc., 2019) Ghosh A.; Reddy S.R.; Mahapatra S.In continuation with Paper I [S. R. Reddy et al., J. Chem. Phys. 151, 054303 (2019)], the vibronic structure and dynamics of the 1?u+ electronic state of C15, C17, C19, and C21 chains in the coupled manifold of 1?u+-1?g-1?u- 1?g+ electronic states have been investigated in this paper. The model vibronic Hamiltonian developed through extensive ab initio quantum chemistry calculations in Paper I is employed, and first principles nuclear dynamics calculations are carried out to obtain the photoabsorption band of the 1?u+ electronic state. Both time-independent and time-dependent quantum mechanical calculations are carried out to precisely locate the vibrational levels, assign them with the progression of vibrational modes, and elucidate the impact of both Renner-Teller and pseudo-Renner-Teller couplings on them. The nonradiative decay of the 1?u+ electronic state is studied, and it is found that the decay rate is comparable with the prediction made for them to be qualified as a carrier of diffuse interstellar bands in the literature. The theoretical results are found to be in good accord with the available experimental results.Item Phylogenetic analysis of viral protein 2 of blue tongue virus(New Delhi Publisher, 2016) Prajapati, Leena; Yogalakshmi, K.N.; Kulharia, MaheshPhylogenetic analysis of viral protein 2 of blue tongue virusItem Development and validation of a robust QSAR model for benzothiazole hydrazone derivatives as Bcl-XL inhibitors(Bentham Science Publishers B.V., 2018) Gupta P.; Gutcaits A.Background: B-cell Lymphoma Extra Large (Bcl-XL) belongs to B-cell Lymphoma two (Bcl-2) family. Due to its over-expression and anti-apoptotic role in many cancers, it has been proven to be a more biologically relevant therapeutic target in anti-cancer therapy. In this study, a Quantitative Structure Activity Relationship (QSAR) modeling was performed to establish the link between structural properties and inhibitory potency of benzothiazole hydrazone derivatives against Bcl-XL. Methods: The 53 benzothiazole hydrazone derivatives have been used for model development using genetic algorithm and multiple linear regression methods. The data set is divided into training and test set using Kennard-Stone based algorithm. The best QSAR model has been selected with statistically significant r2 = 0.931, F-test =55.488 RMSE = 0.441 and Q2 0.900. Results: The model has been tested successfully for external validation (r2 pred = 0.752), as well as different criteria for acceptable model predictability. Furthermore, analysis of the applicability domain has been carried out to evaluate the prediction reliability of external set molecules. The developed QSAR model has revealed that nThiazoles, nROH, EEig13d, WA, BEHv6, HATS6m, RDF035u and IC4 descriptors are important physico-chemical properties for determining the inhibitory activity of these molecules. Conclusion: The developed QSAR model is stable for this chemical series, indicating that test set molecules represent the training dataset. The model is statistically reliable with good predictability. The obtained descriptors reflect important structural features required for activity against Bcl-XL. These properties are designated by topology, shape, size, geometry, substitution information of the molecules (nThiazoles and nROH) and electronic properties. In a nutshell, these characteristics can be successfully utilized for designing and screening of novel inhibitors.Item 1-Hydroxypyrene-based micelle-forming sensors for the visual detection of RDX/TNG/PETN-based bomb plots in water(Royal Society of Chemistry, 2018) Kovalev I.S.; Taniya O.S.; Kopchuk D.S.; Giri K.; Mukherjee A.; Santra S.; Majee A.; Rahman M.; Zyryanov G.V.; Bakulev V.A.; Chupakhin O.N.The high-lying LUMO energy levels of common aliphatic nitro-explosives require special approaches for the proper synthetic design of fluorescence chemosensors that are capable to detect ultra-trace amounts of these explosives via photo-induced electron transfer (PET) fluorescence quenching. Herein, 1-hydroxypyrene has been used as a synthetic platform to prepare a number of water soluble micelle-forming fluorescent chemosensors possessing high-lying LUMO levels. Based on these sensors a cheap and highly efficient method has been described for the detection of low-volatile aliphatic nitro explosives, such as 1,3,5-trinitroperhydro-1,3,5-triazine (RDX), pentaerythritoltetranitrate (PETN), and high volatile taggants/propellants, such as 2,3-dimethyldinitrobutane (DMDNB) or trinitroglycerin (TNG) in aqueous solutions and in vapor phase. The applicability of the sensors for the detection of nitro-explosives was fully confirmed based on the fluorescence quenching titration experiments, with the corresponding Stern–Volmer constants as high as 6.0 × 105 M−1 and the limit of detection (LOD) as low as 12 ppb. The “sphere of action” quenching mechanism has been proposed. To support this, the DFT calculations of the possible molecular complexes between the sensors and nitro-analytes were performed along with the calculations of the quenching sphere radii for the Perrin's model.Item Intramolecular Singlet Fission: Insights from Quantum Dynamical Simulations(American Chemical Society, 2018) Reddy S.R.; Coto P.B.; Thoss M.We investigate the dynamics of intramolecular singlet fission in a dimer consisting of two pentacene-based chromophores covalently bonded to a phenylene spacer using an approach that combines high-level ab initio multireference perturbation theory methods and quantum dynamical simulations. The results show that the population of the multiexcitonic state, corresponding to the first step of singlet fission, is facilitated by the existence of higher-lying doubly excited and charge transfer states that participate in a superexchange-like way. The important role played by high-frequency ring-breathing molecular vibrations in the process is also discussed.