An in silico method for designing thermostable variant of a dimeric mesophilic protein based on its 3D structure

Published in: Journal, Article, Volume : 42, Pages : 92-103

DOI : 10.1016/j.jmgm.2013.02.011

Author : Basu, Sohini; Sen, Srikanta

Abstract : Designing proteins with enhanced thermostability has been a major interest of protein engineering because of its potential industrial applications. Here, we have presented a computational method for designing dimeric thermostable protein based on rational mutations on a mesophilic protein. Exptl. and structural data indicate that the surface stability of a protein is a major factor controlling denaturation of a protein and ion-pairs are most efficient in enhancing the stability of the surfaces of the monomers and the interface between them. Our mutation based strategy is to first identify several polar or charged residues on the protein surface, interacting weakly with the rest of the protein and then replacing the side-chains of suitable neighboring residues to increase the interaction between these two residues. In stabilizing the interface, mutation is done in the interface for forming an ion pairs between the monomers. Application of this design strategy to a homo-dimeric protein and a hetero-dimeric protein as examples has produced excellent results. In both the cases the designed mutated proteins including the individual monomers and the interfaces were found to be considerably more stable than the resp. mesophilic proteins as judged by self-energies and residue-wise interaction patterns. This method is easily applicable to any multi-meric proteins.

Inculcating total selectivity for fluoride in pyrene based chromogenic receptors: An experimental and theoretical study

Published in: Journal, Volume : 1035, Pages : 174-182

DOI : 10.1016/j.molstruc.2012.09.017

Author : Kumar, Ajit; Kumar, Virendra; Neeraj; Upadhyay, K. K.; Roychowdhury, P. K.

Abstract : Three simple Schiff base receptors I-III containing pyrene skeletons were designed and synthesized. The intramol. hydrogen bonding between aldimine N-atom and phenolic OH of these Schiff bases play a crucial role towards their sensing behavior against fluoride. The receptor III exhibited total selectivity towards fluoride in acetonitrile. The basis of the above designing at the MO level was studied through d. functional theory (DFT) and time dependent d. functional theory (TD-DFT). The observed structure dependence of the binding selectivity may provide guidelines for the development of new colorimetric/fluorescent sensors for F- of further high selectivity.

Divergent asymmetric synthesis of hexahydrobenzophenanthridine dopamine D1 agonists, A-86929, and dihydrexidine

Published in: Journal, Volume : 24, Issue : 5-6, Pages : 278-284

DOI : 10.1016/j.tetasy.2013.02.003

Author : Malhotra, Rajesh; Chakrabarti, Sagar; Ghosh, Amit; Ghosh, Rajib; Dey, Tushar K.; Dutta, Swarup; Dutta, Shantanu; Roy, Subho; Basu, Sourav; Hajra, Saumen

Abstract : A divergent and scalable asym. synthesis of the dopamine D1 agonists, A-86929, and dihydrexidine with high diastereo- and enantioselectivity was accomplished from Weinreb amide 8 derived from inexpensive and easily available L-serine. The synthesis of A-86929 involves only one chromatog. purification

Do homologous thermophilic-mesophilic proteins exhibit similar structures and dynamics at optimal growth temperatures? A molecular dynamics simulation study

Published in: Journal, Article, Volume : 53, Issue : 2, Pages : 423-434

DOI : 10.1021/ci300474h

Author : Basu, Sohini; Sen, Srikanta

Abstract : Structure and dynamics both are known to be important for the activity of a protein. A fundamental question is whether a thermophilic protein and its mesophilic homolog exhibit similar dynamics at their resp. optimal growth temperatures Here, the authors addressed this question by performing mol. dynamics (MD) simulations of a natural mesophilic-thermophilic homolog pair at their resp. optimal growth temperatures to compare their structural, dynamical, and solvent properties. The proteins chosen were the mesophilic cold-shock protein of Bacillus subtilis and the thermophilic cold-shock protein of B. caldolyticus with resp. optimal growth temperatures at 35.0 and 72.0°. The MD simulations were done in explicit aqueous solvent under periodic boundary and constant pressure and temperature (CPT) conditions and continued for 10.0 ns using the same protocol for the 2 proteins, excepting the temperatures The trajectories were analyzed to compare the properties of the 2 proteins. The results indicated that the dynamical behaviors of the 2 proteins at the resp. optimal growth temperatures were remarkably similar. For the common residues in the thermophilic protein, the rms fluctuations had a general trend to be slightly higher compared to that in the mesophilic counterpart. Lindemann parameter values indicated that only a few residues exhibited solid-like dynamics while the protein as a whole appeared as a molten globule in each case. Interestingly, the water-water interaction was found to be strikingly similar in spite of the difference in temperatures while, the protein-water interaction was significantly different in the 2 simulations.

Conjugate addition of indoles and pyrroles to dihydronitronaphthalenes in water: synthesis of 3,4-fused tetrahydro-β-carbolines

Published in: Journal, Volume : 2013, Issue : 4, Pages : 772-780

DOI : 10.1002/ejoc.201201288

Author : Malhotra, Rajesh; Ghosh, Rajib; Dey, Tushar K.; Chakrabarti, Sagar; Ghosh, Amit; Dutta, Swarup; Asijaa, Sonika; Roy, Subho; Dutta, Shantanu; Basu, Sourav; Hajra, Saumen

Abstract : A catalyst-free conjugate addition of indoles and pyrroles to 1,2-dihydro-3-nitronaphthalenes in water has been developed. A variety of indoles containing electron-rich and -deficient functional groups including aza-indoles and pyrroles reacted smoothly with a number of dihydro-3-nitronaphthalenes, especially bromo derivatives For structural elaboration, the bromo functionality (dihydronitronaphthalene unit as well as indolyl unit) of the addition products was utilized for Suzuki coupling reactions and provided moderate to good yields of the desired coupling compounds The utility of the method was further demonstrated by the synthesis of 3,4-fused tetrahydro-β-carbolines, a new class of compounds, from the addition products through reduction of the nitro group to the amine and subsequent Pictet-Spengler cyclization.

Designing of a fluoride selective receptor through molecular orbital engineering

Published in: Journal, Volume : 1027, Pages : 167-174

DOI : 10.1016/j.molstruc.2012.06.020

Author : Mishra, Rakesh K.; Kumar, Virendra; Diwan, Uzra; Upadhyay, K. K.; Roy Chowdhury, P. K.

Abstract : The stepwise substitution of appropriate groups over the 3-[(2,4-dinitro-phenyl)-hydrazono]-butyric acid Et ester (R3) lead receptor R1 which showed selectivity towards fluoride in DMSO. The UV-vis and 1H NMR titration studies revealed the details of the binding between receptor R1 and fluoride. The receptor R1 also recognized fluoride in a toothpaste solution to as low as 50 ppm. The theor. simulations of recognition event at D. Functional Theory (DFT) level using B3LYP/6-31G**t basis set and polarizable continuum model (PCM) approach lead a semi-quant. match with the exptl. results.

Rhodium-catalyzed enantioselective conjugate addition of arylboronic acids to dihydronitronaphthalenes

Published in: Journal, Volume : 354, Issue : 13, Pages : 2433-2437, S2433/1-S2433/39

DOI : 10.1002/adsc.201200241

Author : Hajra, Saumen; Ghosh, Rajib; Chakrabarti, Sagar; Ghosh, Amit; Dutta, Swarup; Dey, Tushar K.; Malhotra, Rajesh; Asijaa, Sonika; Roy, Subho; Dutta, Shantanu; Basu, Sourav

Abstract : A highly enantioselective (up to 91% ee) rhodium-catalyzed asym. addition of arylboronic acids has been achieved leading to the challenging dihydro-3-nitronaphthalenes using one equivalent of phosphoramidite ligand to rhodium catalyst. A concise formal asym. synthesis of the dopamine D1 agonist, dihydrexidine was accomplished using the method.

Benzimidazolium-based simple host for fluorometric sensing of H2PO4-, F-, PO43- and AMP under different conditions

Published in: Journal, Volume : 52, Issue : 39, Pages : 5098-5103

DOI : 10.1016/j.tetlet.2011.07.110

Author : Ghosh, Kumaresh; Kar, Debasis; Chowdhury, Purnendu Roy

Abstract : Pyrene appended benzimidazolium-based simple cleft (I) has been synthesized. The open cleft of I distinguishes H2PO4- and F- selectively by showing binding induced different emission characteristics in CH3CN. The chemosensor I also functions in aqueous CH3CN and shows marked change in emission in the presence of sodium phosphate at pH 6.5 and AMP at pH 7.3. Binding studies have been carried out using fluorescence, UV-vis and 1H NMR spectroscopic techniques.

Asymmetric synthesis of a dopamine D1 agonist, dihydrexidine from D-serine

Published in: Journal, Volume : 22, Issue : 14-15, Pages : 1522-1529

DOI : 10.1016/j.tetasy.2011.08.014

Author : Malhotra, Rajesh; Ghosh, Amit; Ghosh, Rajib; Chakrabarti, Sagar; Dutta, Swarup; Dey, Tushar K.; Roy, Subho; Basu, Sourav; Hajra, Saumen

Abstract : A scalable asym. synthesis of trans-2-amino-6,7-dimethoxy-1-phenyltetralin and its N-nosyl derivative have been achieved from Garner aldehyde derived from easily available D-serine using a stereoselective PhMgBr addition, Wittig reaction and TFA-mediated Friedel-Crafts cyclization as the key steps. The synthesis of dihydrexidine is accomplished from the N-nosyl-2-amino-1-phenyltetralin.

Predicting hERG activities of compounds from their 3D structures: Development and evaluation of a global descriptors based QSAR model

Published in: Journal, Article, Volume : 46, Issue : 2, Pages : 618-630

DOI : 10.1016/j.ejmech.2010.11.042

Author : Sinha, Nandita; Sen, Srikanta

Abstract : A QSAR based predictive model of hERG activity in terms of global descriptors’ has been developed and evaluated. The QSAR was developed by training 77 compounds covering a wide range of activities and was validated based on an external test set of 80 compounds using neural network method. Statistical parameters and examination of enrichment factor indicated the effectiveness of the present model. Randomization test demonstrated the robustness of the model and cross-validation test further validated the QSAR. Domain of applicability test indicated to the high degree of reliability of the predicted results. Satisfactory performance in classifying compounds into active’ and inactive’ groups was also obtained. The cases where the QSAR failed, the possible sources of errors have been discussed.