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Computational Structural Biology & Biomolecular Recognition
Computational Structural Biology & Biomolecular Recognition
Biological systems are mainly governed by the interactions among the several macromolecules in a regulated manner. Among the several macromolecular interactions, protein-DNA, protein-protein and protein-ligand interactions are very important which control the most of the complex biological processes within a living cell. Molecular Modelling and Simulation are the powerful approach for understanding the complexity of biological systems. Several modelling and simulation techniques have been developed to explore the complexity in the biological systems depending upon its length and time scale. Using Molecular modelling and simulation techniques, my goal is to understand the important macromolecular interactions and its implications, which are not well studied. I would like to explore the thermodynamics of the macromolecules in biomolecular interactions and recognition mechanism. For study the short range interactions and electron transfer mechanism in macromolecular interactions use of ab-initio quantum chemical approaches is also my further interest. In a broad sense I am interested in understanding the macromolecular basis in biological system by studying their structure, dynamics and interactions and the correlation among them with biochemical function. My area of research are the following:
Nucleic Acids structure and function
Protein-DNA interaction & mode of biomolecular recognition
Protein-protein, protein-ligand interaction & conformational thermodynamics
Quantum chemistry of biomolecular interaction
Enzymatic activity & function
Enhanced Sampling for studying the biomolecular interaction
Ongoing Research:
Ongoing Research:
Biomolecular interactions and phase separation
Higher order DNA structure and gene regulation
Protein-DNA interaction and enzymatic activity of DNA binding protein in DNA damageand repair machinery
Solvation properties of biomolecules
Research Contribution
Research Contribution
Interaction between outer membrane and yfdX protein in Salmonella Typhi: Implication on pathogenic activities
Emergences of drug resistant virulent bacterial strains make the clinical treatment of bacterial infection often difficult. For instance, typhoid causing bacteria S. Typhi has got strains, showing resistance to antibiotics which are commonly used for the treatment of typhoid fever. Several studies indicate that gram-negative pathogenic bacteria, like S. Typhi, interacts with the host cell through their outer membrane proteins. I have studied the interaction between outer-membrane protein STY3179 and yfdX protein STY3178 proteins of Salmonella Typhi. We have proposed using homology modeling, docking followed by molecular dynamics simulation that they can form a stable complex. To understand the molecular basis of interaction between STY3178 and STY3179 I compute the conformational thermodynamics which indicates that these two proteins interact via polar and acidic residues belonging to their interfacial region. Conformational thermodynamics results further reveal instability of certain residues in extra-cellular loops of STY3179 upon complexation with STY3178 which is an indication for subsequent binding with host cell laminin. We predict that the co-occurrence of this protein pair in such gram negative bacteria may have roles in host-pathogen interaction.
Mondal M, Chakrabarti J, Ghosh M. Molecular dynamics simulations on interaction between bacterial proteins: Implication on pathogenic activities. Proteins. 86(3):370-378, 2018.
Multi-partite DNA sequence recognition by a Transcription Factor involves protein dynamics mediated DNA-sequence specific allosteric effects
Transcription factors recognize specific DNA sequences to regulate gene expression. A phage transcription factor, λ-CI forms repressive multi-protein complexes by binding to multiple target sites in the phage genome, such as OR1 and OR2, followed by interaction between two DNA bound λ-CI molecules. I have studied the role of protein dynamics and allosteric mechanism in λ-CI binding to the specific DNA sequence using molecular dynamics simulation. Upon binding to the target site OR1, λ-CI shows enhanced dynamics at the distant protein-protein interaction domain. In contrast, OR2 bound λ-CI shows quenched dynamics at this distant domain. No significant conformation change was observable at or near the protein-protein interaction site in either case. We have shown the pathway of allosteric modulation of protein dynamics and its implication on transcription factor binding. We proposed that DNA induced allostery, mediated by changes in protein dynamics, differentially stabilizes the site-specific gene regulatory complexes.
Mazumder A, Batabyal S, Mondal M, Mondol T, Choudhury S, Ghosh R, Chatterjee T, Bhattacharyya D, Pal SK and Roy S. Specific DNA sequences allosterically enhance protein-protein interaction in a transcription factor through modulation of protein dynamics: implications for specificity of gene regulation. Phys Chem Chem Phys, 19(22):14781-92, 2017.
Naiya G, Raha P, Mondal M, Pal U, Saha R, Chaudhuri S, Batabyal S, Pal S, Bhattacharyya D, Maiti N and Roy S. Conformational selection underpins recognition of multiple DNA sequences by proteins and consequent functional actions. Phys Chem Chem Phys, 18(31):21618-28, 2016.
Stacking geometry of the dinucleotide sequences of DNA and RNA in multidimensional base pair parameters hyperspace: Coarse grained Monte Carlo simulation strategy
Along with fully atomistic model, different coarse grained models are proposed to understand the structural properties of nucleic acids depending on the sequence. According to rigid base model there are six degrees of freedom between the two stacked base pairs and six each between two bases of each base pair. There were quite a few attempts to theoretically characterize stacking interaction in DNA and RNA for various values of few of these parameters, namely twist, roll, slide and rise, and mixed results were obtained. I have developed a Monte Carlo Metropolis simulation strategy based on rigid base model to understand the stacking geometry and stacking interaction of different dinucleotide sequence in DNA and RNA in 18 dimensional base pair parameters hyperspace. The ensembles of structures with canonical Watson-Crick base pairs are used to establish the accuracy of the method. We found quite good agreement between predicted twist, roll, etc. values and such values observed in different crystal structures of DNA or RNA. The developed method is used to understand stacking interaction involving A:U and G:C base pairs with non-canonical G:U base pairs. These results also show their preferences similar to observed crystal structures. This approach will be useful to study the preferred stacking geometry of other non-canonical base pairs and understand the stability of different secondary structural motifs in RNA structure.
Mondal M, Halder S, Chakrabarti J and Bhattacharyya D. Hybrid simulation approach incorporating microscopic interaction along with rigid body degrees of freedom for stacking between base pairs. Biopolymers, 105(4):212-26, 2016
Quantum chemical study of stacking interaction for non-canonical G:U wobble base pair containing dinucleotide sequences in RNA
Along with the canonical Watson-Crick base pairs, different orientations of the bases to form hydrogen-bonded non-canonical base pairs have been observed in the available RNA structures. Frequencies of occurrences of different non-canonical base pairs in RNA indicate their important role to maintain overall structure and functions. There are several reports on geometry and energetic stabilities of these non-canonical base pairs. However their stacking geometry and stacking stability with the neighboring base pairs are not well studied. Among the different non-canonical base pairs, G:U WWC is most frequently observed in the RNA double helices. Quantum chemical studies using dispersion corrected density functional theory (DFTD) and high resolution experimental data set we have studied the stacking geometry of G:U WWC base pair containing dinucleotide sequences in roll-slide parameters hyperspace for different values of twist. This study indicates that G:U WWC base pair can stack well with the canonical base pair giving rise to large interaction energy. The overall preferred stacking geometry in terms of roll, twist and slide for the eleven possible dinucleotide sequences is seen to be quite dependent on their sequences.
Mondal M, Mukherjee S, Halder S and Bhattacharyya D. Stacking geometry for non-Canonical G:U wobble base pair containing dinucleotide sequences in RNA: Dispersion Corrected DFT-D study. Biopolymers, 103(6):328-38, 2015.
Study the role of indirect readout mechanism for protein-DNA recognition: TBP-DNA interaction
In order to characterize the role of indirect readout mechanism i.e. sequence dependent conformational variability of B-DNA such as bending or flexibility, I have performed all atom molecular dynamics simulation of the human TBP-DNA complex along with regular and deformed DNA structure in absence of the binding protein. Study revealed that the TATA box containing sequence has an inherent tendency to take up a deformed conformation even without protein binding and it is more flexible. We proposed a mode of molecular recognition mechanism that the DNA structure alters between a straight form and a bent form with wide minor groove width and the bent form gets arrested by the protein through hydrogen bonds and electrostatic interactions when bending and minor groove opening enhances substantially. I have also studied the role of intercalated phenylalanine residues in TBP-DNA complex using quantum chemical method. We proposed that aromatic stacking interaction between the bases and phenyl rings gives the stability of the kinks in the two terminal of the binding region of DNA. This interaction indirectly helps to protein-DNA recognition mechanism and stable transcription initiation complex formation.
Mondal M, Mukherjee S and Bhattacharyya D. Contribution of phenylalanine side chain intercalation in TATA-box binding protein-DNA interaction: molecular dynamics and dispersion corrected density functional theory studies. J Mol Modeling, 20(11):2499, 2014.
Mondal M, Choudhury D, Chakrabarti J and Bhattacharyya D. Role of indirect readout mechanism in TATA box binding protein-DNA interaction. J Comput Aided Mol Des, 29(3):283-95, 2015
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