Research topics and problems of future interests
(brief descriptions)
Interaction of phase separated IDPs with cell membranes
Intrinsically disordered proteins (IDPs) can undergo liquid-liquid phase separation (LLPS) that plays a crucial role in intracellular compartmentalization. We are interested in understanding how does the phase separated charged IDPs behave in the presence of membranes and alter the membrane morphology. As the conformational space is vast for biologically relevant timescales (~ms to s) and lengthscales (~micron), we need to employ coarse-grained (CG) molecular dynamics. We find that the phase separated polypeptide droplet induces a negative curvature and local demixing in lipid bilayers. However, explicit solvent CG models (such as Martini) also becomes substantially expensive in the biologically relevant time- and length-scales. We thus employed a solvent-free CG model (Cooke-Kremer-Deserno model) with a reasonable description of the lipid-IDP interaction. There we could observe processes like endocytosis, exocytosis, and multilayered stacked membrane formations induced by LLPS. Recently we delved into the sequence sensitivity in membrane remodeling by polyampholytes. There we found that the blocky charge sequences can remodel a membrane more strongly than a coacervate formed by polyampholytes with scrambled charge sequences.
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References
- S. Mondal and Q. Cui. J. Phys. Chem. Lett. 14, 4532-4540 (2023)
- S. Mondal and Q. Cui. Chem. Sci. 13, 7933 - 7946 (2022)
Water under nanoconfinement
Water in crowded environments are omnipresent. Here, we studied the effect of confinements, of different size and shapes, on the structural and dynamical properties of water. We first focused on dielectric permittivity tensor and its anisotropic behaviour under nanoconfinement. We find that, in the case of non-spherical enclosures, the dielectric constant exhibits substantial anisotropy due to different dielectric boundary conditions. We derived the linear response realtions, starting from first principles, to calculate the differnet components of static dielectric constant from simulation trajectories in carbon nanotubes and graphene slit pores. We find that there is a slight enhancement along the 'open' directions and huge attenuation along the 'closed' directions. The same holds true for the diffusion tensor as well. We explained these observations from a microscopic/molecular perspective. We carried out a simple capacitor model-based analysis that quite beautifully explains the 'anomalously low out-of-plane dielectric constants' experimentally observed by Geim and co-workers.
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References:
- S. Mondal and B. Bagchi. J. Chem. Phys. 154, 044501 (2021).
- S. Mondal and B. Bagchi. Nano. Lett. 20 (12) 8959–8964 (2020).
- S. Mondal and B. Bagchi. J. Chem. Phys. 152 (22), 224707 (2020).
- S. Mondal and B. Bagchi. J. Phys. Chem. Lett. 10 (20), 6287 (2019).
- S. Mondal, S. Acharya, and B. Bagchi. Phys. Rev. Research 1 (3), 033145 (2019).
Microdroplet Chemistry
Mass spectrometry stuidies reveal that, several organic reactions (if not all) exhibit a marked increase in the reaction rate when performed in small-sized aqueous droplets generated by electrospray technique. However, a theoretical understanding of the same was missing. We teamed up with Prof. Richard Zare (Stanford Univesity) and Prof. Rajib Biswas (IIT Tirupati) to come up with an analytically solvable model to describe the unusual rate enhancement in microdroplets. From the solutions, we observed that the mean-reaction-time scales quadratically with the droplet radius. By employing quantum chemical calculations we show that the presence of nearby charges and electric field can also fecilitate bond breaking by lowering the activation energy. Therefore, the competition between the timescales of diffusion and intrinsic timescale of bond breaking determines the enhancement factor. In future, we plan to incorporate the effect of electrical double layer and pH in our model to make it more realistic.
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References:
- S. Mondal, S. Acharya, R. Biswas, B. Bagchi, and R. N. Zare. J. Chem. Phys. 148 (24), 244704 (2018)
Bio-molecular hydration dynamics
A layer of water molecules, few angstrom thick, surrounds biomolecules. Such water molecules are known to play an important role in the structure and dynamics of biomolecules. However, there exist different views, based on both experimental and theoretical results, on the dynamical timescales of the protein and DNA hydration layers. We attempted to solve this long-standing controversy by showing that there exist a wode log-normal distribution of the translational and rotational relaxation timescales across the hydration layer. Different experiments seemingly probe different part of this distribution and sometimes an averaged observation. Later we explained the origin of a multitute of timescales in the solvation dynamics of a natural probe (Tryptophan) bound to a protein. We also developed a continous time random walk based theoretical model to understand the power law behaviour in DNA solvation dynamics. More recently, we have explored the role of water molecules in controlling the protein motions from an energetics as well as from the viewpoint of internal and external frictions. In future, we aim to understand the importance of quantum effects and polarizability on such systems.
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References:
- S. Mondal, S. Mukherjee, and B. Bagchi. J. Phys. Chem. Lett. 8 (19), 4878-4882 (2017).
- S. Mondal, S. Mukherjee, and B. Bagchi. J. Chem. Phys. 147, 154901 (2017).
- S. Mondal, S. Mukherjee, and B. Bagchi. Chem. Phys. Lett. 683, 29-37 (2017).
- S. Mondal, S. Mukherjee, and B. Bagchi. J. Chem. Phys. 147 (2), 024901-1 (2017).
- S. Mukherjee, S. Mondal, S. Acharya, and B. Bagchi. Phys. Rev. Lett. 128(10), 108101, (2022).
- S. Mukherjee, S. Mondal, and B. Bagchi. Phys. Rev. Lett. 122 (5), 058101 (2019).
Insulin hexamer
Hexameric insulin acts as a storage of insulin in our body. The hexamer produces biologically active monomers (through dimeric intermediates) which controls the blood sugar level. The insulin hexamer is quite a robust structure with a fairly spherical cavity that houses approximately ten water molecules. This, however, was a lesser known fact. Starting with the X-ray crystallographic data from Prof. B. Gopal's group (MBU, IISc), we carried out atomistic MD simulation to study the role of these internal water molecules in the stability of the hexameric assembly. Later, with the same team, we explored the role of ethanol in the stability of the insulin hexamer. In future, we have plans to explore the entire dissociation pathway (hexamer >> dimers >> monomers) by employing advanced sampling algorithms.
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References:
- S.Mukherjee, S.Mondal, A.A.Deshmukh, B.Gopal, and B.Bagchi. J. Phys. Chem. B 122 (5), 1631-1637 (2018).
- S.Mukherjee, S.Mondal, A.A.Deshmukh, B.Gopal, and B.Bagchi. J. Phys. Chem. B 123 (49), 10365-10375 (2019).
Insulin dimer
Dissociation of insulin dimer is an important step in the production of biologically active insulin monomers. We studied the dissociation pathway and role of water with the help of atomistic molecular dynamics simulations and metadynamics based advanced sampling techniques. We also explored the effect of ethanol on the dissociation energetics. We find that amphiphilic solvents like ethanol substantialy alters the pathway and results in an attenuated activation barrier. More recently, we focused into the early stages of dimer dissociation and the effect of dimensionality and memory effects. Our results are in good agreement with contemporary experimental (2D-IR) and theoretical (metadynamics and MSM) results.
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References:
- S.Mondal, S.Mukherjee, S.Acharya, and B.Bagchi. J. Phys. Chem. B, 125(29), 7958-7966, (2021).
- S.Acharya, S.Mondal, S.Mukherjee, and B.Bagchi. J. Phys. Chem. B, 125(34), 9678-9691, (2021).
- P.Banerjee, S.Mondal, and B.Bagchi. J. Chem, Phys. 149 (11), 114902 (2018).
- P.Banerjee, S.Mondal, and B.Bagchi. J. Chem. Phys. 150 (8), 084902 (2019).
Small molecule modeling
Medicinally important small molecule Metformin (N,N-dimethylbiguadinine) is a globally used anti-diabetic drug which is also used as a combination drug in chemitherapy for certain cancers. Nonetheless, the molecular property of Metformin was poorly understood, especially from a theoretical/computational viewpoint. We, as a first, developed a sustainable model forcefield for Metformin and applied it to study its interaction with B-DNAs of different composition. In this project, we collaborated with Prof. A. J. Bhattacharyya's group (SSCU, IISc) who provided important experimental validations of our model. Since then, our force field has been used by several other groups who obtained a decent match with experiments. Interestingly, there is evidence of the formation of a chiral assembly of Metformin induced by DNA. In future, we have plans to study the interaction of Metformin with AMP-activated Kinase that is reportedly responsible for its anti-tumour activity.
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References:
- S. Mondal, R. N. Samajdar, S. Mukherjee, A. J. Bhattacharyya, and B. Bagchi. J. Phys. Chem. B 122 (8), 2227-2242 (2018).
Modeling of infectious disease dynamics
Predictive model simulations are often useful in understanding the course of an infectious disease such as COVID and important for public health policies. In this project, almost out of mere curiosity and influenced by its similarity to chemical kinetics, we attempted to understand the dynamics of disease spread and attainment of herd immunity. We employed a modified version of SIR (Susceptible-Infected-Removed) and later SAIR (Susceptible-Asymptomatic-Infected-Removed) models in a series of studies that revealed that a slow attainment of herd immunity is less fatal to the humanity. We also explored the effects of quarantining, social distancing, and lockdown through our models to comprehend the effectiveness of these measures. However, we find that the predictive power of such models are quite poor and should be used carefully.
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References:
- S.Mondal, S.Mukherjee, and B.Bagchi. J. Chem. Phys. 153 (11), 114119 (2020).
- S.Mukherjee, S.Mondal, and B. Bagchi. J. Chem. Sci., 133(4), 1-18, (2021).
Active matter
Active systems are far-from-equilibrium systems where energy flows in and out. Flocking of birds, formation of animal herds and fish schools can be explained by active matter simulations. Non-living objects can also show active behaviour in the presence of some motor force. We tried to understand the behaviour of Ising spin systems with a spin rotation at a constant angular velocity (ω0). We could develop a phase diagram in terms of the coupling strength (J) and the magnitude of the angular spin. We find that for cetrain combinations of J and ω0, the system shows active matter like behaviour. Our preliminary simulations were with one-dimensional system. We have future plans to expand our study in higher dimensions and to describe the rate of entropy production in such systems (à la Prigogine). Also we have plans to modify Vicsek model for realistic systems.
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References:
- S.Mondal, S.S.Iyer, and B.Bagchi. arXiv preprint arXiv:2107.04215, (2021).