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 CuO Nanoparticles as a Simple and Efficient Green Catalyst for the Aziridine Ring-Opening: Examination of a Broad Range of Nucleophiles(Wiley-Blackwell, 2020) Chatterjee, R; Santra, S; Chakraborty, Ghosal N; Giri, K; Zyryanov, G.V; Majee, A.It has been observed that CuO nanoparticles act as effective and reusable catalyst for the ring-opening reaction of aziridines with a wide range of nucleophiles such as alcohols, thiols, and indoles. The catalytic activity has been tested in large scale reactions. The methodology is applicable in very low catalyst loading. The reaction proceeds under solvent-free conditions. The catalyst has been used for six consecutive cycles with comparable efficiency. The present methodology could be considered as environmentally benign as indicated by the calculation of E-factors which are very low in the range of 0.37-1.31. - 2020 Wiley-VCH Verlag GmbH & Co. KGaA, WeinheimItem 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 Synthesis and photophysics of new unsymmetrically substituted 5,5′-diaryl-2,2′-bypiridine-based “push-pull” fluorophores(Elsevier, 2019) Starnovskaya, E.S; Kopchuk ,D.S; Khasanov, A.F; Tanya, O.S; Santra, S; Giri, Kousik; 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-π-A-π-D fashion, and that provides both the prospective photophysical properties and unique solvatocromic effects for the most representative compounds. © 2018 Elsevier LtdItem A study of mechanistic mapping of novel SNPs to male breast cancer(Humana Press Inc., 2019) Kaur, R.P; Kumar, V; Shafi, G; Vashistha, R; Kulharia, Mahesh; Munshi, AanjanAlterations in BRCA2, PALB2, CHEK2, and p53 genes have been identified for their association with male breast cancer in various studies. The incidence of male breast cancer in India is consistent with its global rate. The present study was carried out with an aim to evaluate the genetic alterations in male breast cancer patients from Malwa region of Punjab, India. Four male breast cancer patients belonging to different families were recruited from Guru Gobind Singh Medical College and Hospital, Faridkot, India. A total of 51 genes reported with implications in the pathogenesis of breast cancer were screened using next generation sequencing. Germline variations were found in BRCA1, BRCA2, PMS2, p53, and PALB2 genes, previously reported to be associated with MBC as well as FBC. In addition to these, 13 novel missense alterations were detected in eight genes including STK11, FZR1, PALB2, BRCA2, NF2, BAP1, BARD1, and CHEK2. Impact of these missense alterations on structure and function of protein was also analyzed through molecular dynamics simulation. Structural analysis of these single nucleotide polymorphisms (SNPs) revealed significant impact on the encoded protein functioning. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.Item Electronic spectroscopy of carbon chains (C2 n +1, n = 7-10) of astrophysical importance. I. Quantum chemistry(American Institute of Physics, 2019) Reddy, S.R; Ghosh, Arpita; Mahapatra, SusantaCarbon 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 ςu+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 1Πg, 1Πu, ςg+1, 1Δg, and 1Δu terms, in the immediate vicinity of the ςu+1 state, which are optically dark but can gain intensity through vibronic coupling with the optically bright ςu+1 state. Construction of a coupling scheme considering the Renner-Teller coupling within the degenerate Π states and pseudo-Renner-Teller coupling between the Renner-Teller split component states as well as with the nondegenerate ς 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 Evaluation of in silico designed inhibitors targeting MelF (Rv1936) against Mycobacterium marinum within macrophages(Nature Publishing Group, 2019) Dharra, R; Radhakrishnan,V.S; Prasad, T; Thakur, Z; Cirillo, J.D; Sheoran, A; Pandey, A.K; Kulharia, Mahesh; Mehta P.K.We recently identified inhibitors targeting Mycobacterium marinum MelF (Rv1936) by in silico analysis, which exhibited bacteriostatic/bactericidal activity against M. marinum and M. tuberculosis in vitro. Herein, we evaluated the effect of best four inhibitors (# 5175552, # 6513745, # 5255829, # 9125618) obtained from the ChemBridge compound libraries, on intracellular replication and persistence of bacteria within IFN-γ activated murine RAW264.7 and human THP-1 macrophages infected with M. marinum. Inhibitors # 5175552 and # 6513745 significantly reduced (p < 0.05) the intracellular replication of bacilli during day 7 post-infection (p.i.) within RAW264.7 and THP-1 macrophages infected at multiplicity of infection (MOI) of ~1.0. These observations were substantiated by electron microscopy, which revealed the protective effect of # 5175552 in clearing the bacilli inside murine macrophages. Strikingly, # 6513745 displayed synergism with isoniazid against M. marinum in murine macrophages, whereas # 5175552 significantly suppressed (p < 0.05) the persistent bacilli during day 10–14 p.i. in infected RAW264.7 and THP-1 macrophages (MOI of ~ 0.1). Moreover, # 5175552 and # 6513745 were non-cytotoxic to host macrophages at both 1X and 5X MIC. Further validation of these inhibitors against M. tuberculosis-infected macrophages and animal models has potential for development as novel anti-tubercular agents. © 2019, The Author(s).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 virus