Arnab Mukherjee

Indian Institute of Science Education and Research, Pune | IISER · Department of Chemistry

Viruses are known for their extremely high mutation rates, allowing them to evade both the human immune system and many forms of standard medicine. Despite this, the RNA dependent RNA polymerase (RdRp) of the RNA viruses has been largely conserved, and any significant mutation of this protein is unlikely. The recent COVID-19 pandemic presents a nee...

We present SPOTLIGHT - a proof-of-concept for a method capable of designing a diverse set of novel drug molecules through a rule-based approach. The model constructs molecules atom-by-atom directly at the active site of a given target protein. SPOTLIGHT has the potential to be faster and more efficient than many existing methods that rely on genera...

Viruses are known for their extremely high mutation rates, allowing them to evade both the human immune system and many forms of standard medicine. Despite this, the RNA Dependent RNA Polymerase (RdRp) of the RNA viruses has been largely conserved, and any significant mutation to this protein is unlikely. The recent COVID-19 pandemic presents the n...

Two self-assembled barrel-rosette ion channels have been developed using bis(1,3-propanediol)-linked m-dipropynylbenzene-based molecules. The system with an additional amide arm acted as a better channel compared to that having an ester arm. The amide-linked channel displayed substantial channel activity and excellent chloride selectivity in the li...

The structure of a protein plays a pivotal role in determining its function. Often, the protein surface's shape and curvature dictate its nature of interaction with other proteins and biomolecules. However, marked by corrugations and roughness, a protein's surface representation poses significant challenges for its curvature‐based characterization....

We report the development of supramolecular bis(cholyl) ion channels by using oxalamide and hydrazide as selectivity filters. The hydrazide system displayed superior chloride transport activity than oxalamide via the formation...

DNA carries the genetic code of life, with different conformations associated with different biological functions. Predicting the conformation of DNA from its primary sequence, although desirable, is a challenging problem owing to the polymorphic nature of DNA. We have deployed a host of machine learning algorithms, including the popular state-of-t...

Computational drug design is increasingly becoming important with the new and unforeseen diseases like COVID‐19. In this study, we present a new computational de novo drug design and repurposing method and applied it to find plausible drug candidates for the receptor binding domain (RBD) of SARS‐CoV‐2 (COVID‐19). Our study comprises three steps: at...

DNA-protein interactions regulate several biophysical functions, yet the mechanism of only a few is investigated in molecular detail. An important example is the intercalation of transcription factor proteins into DNA that produce bent and kinked DNA. Here, we have studied the molecular mechanism of the intercalation of a transcription factor SOX4...

div> DNA carries the genetic code of life. Different conformations of DNA are associated with various biological functions. Predicting the conformation of DNA from its primary sequence, although desirable, is a challenging problem owing to the polymorphic nature of DNA. Although a few efforts were made in this regard, currently there exists no me...

Finding a cure for Covid-19 is of immediate and paramount importance. In this study, we propose new and repurpose drugs to prevent SARS-Cov-2 (Covid-19) viral attack on human cells. Our study comprises three steps: generation of new molecules, structural similarity mapping to existing approved and investigational drugs, and validation of their bind...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Synthetic transmembrane ion transport systems are emerging as new tools for anticancer therapy. Here, a series of 2-hydroxy-N¹,N³-diarylisophthalamide-based fluorescent ion channel-forming compounds are reported. Ion transport studies across large unilamellar vesicles confirmed that the compound with two 3,5-bis(trifluoromethyl)phenyl arms is the m...

Intercalation into DNA is the interaction mode of some anthracycline antibiotics. Recently, this process’s molecular mechanism was explored using the static free energy landscape. Here we explore the dynamical effects in the intercalation of proflavine into DNA by calculating the transmission coefficient κ -- providing a measure of the departure fr...

An impressive array of antigene approaches has been developed for recognition of double helical DNA over the past three decades; however, few have exploited the ‘Watson–Crick’ base-pairing rules for establishing sequence-specific recognition. One approach employs peptide nucleic acid as a molecular reagent and strand invasion as a binding mode. How...

Deviation from the Kramers’s inverse viscosity dependence of rate, k∝1⁄η, is often attributed to the presence of internal friction in proteins after Ansari et al. in 1992 showed that the folding rate could fit the equation, k∝1⁄((η+σ)), where σ is considered as internal friction. Several experimental and computational studies thereafter used fits t...

We report the development of a new class of nucleic acid ligands that is comprised of Janus bases and MPPNA backbone and is capable of binding rCAG-repeats in a sequence-specific and selective manner via, inference, bivalent H-bonding interactions. Individually, the interactions between ligands and RNA are weak and transient. However, upon the ins...

Controlling of ligand mediated G-quadruplex (GQ) DNA formation and stabilization is an important and challenging aspect due to its active involvement in many biologically important processes like, DNA replication, transcription etc. Here, we have demonstrated that topotecan (TPT), a potential anticancer drug, can instigate the formation and stabili...

The remarkable progress in the field of ionic liquids (ILs) in the last two decades has involved investigations on different aspects of ILs in various conditions. The nontoxic and biocompatible nature of ILs makes them a suitable substance for the storage and application of biomolecules. In this regard, the aqueous IL solutions have attracted a lar...

This study reports the self-assembled transmembrane anion channel formation by small-molecule fumaramides. Such artificial ion channel formation was confirmed by ion transport across liposomes and planar bilayer conductance measurements. The...

The relation between the dynamic (e.g., diffusion) and thermodynamic (e.g., entropy) properties of water and water-like liquids has been an active area of research for a long time. Although several studies have investigated the diffusivity and entropy for different systems, these studies have probed either the configurational entropy or the excess...

The right-handed DNA helix exhibits two major conformations, A-DNA and B-DNA, depending on the environmental conditions. The B-DNA to A-DNA (B→A) transition is sequence specific, cooperative, and reversible. The reduced water activity due to the addition of solvents like ethanol or the presence of protein or drug molecules causes B→A transition. In...

We have studied the complex dielectric properties of a series of alcohols in 0.5-10 THz frequency range using THz time-domain spectroscopy. The dielectric response observed has contribution from a Debye relaxation process and three damped harmonic oscillators. Combination of experimental observations, all-atom molecular dynamics simulations and ab...

Misfolding and aggregation of prion proteins are associated with several neurodegenerative diseases. Therefore, understanding the mechanism of the misfolding process is of enormous interest in the scientific community. It has been speculated and widely discussed that the native PrPC form needs to undergo substantial unfolding to a more stable PrPC*...

Despite the great interest in the artificial ion channel design, only a small number of channel forming molecules are currently available for addressing challenging problems, particularly in the biological systems. Recent advances on chloride-mediated cell-death, aided by synthetic ion carriers, endorsed us the development of chloride selective sup...

Ionic liquids are known to stabilize DNA for much longer than water can. While the source of this stability has commonly been attributed to thermodynamic aspects, we probe the dynamical aspects of the ionic liquids near DNA to further our understanding of this stability. Using molecular dynamics simulation, we calculated the mean residence time (MR...

One-pot synthesis of a C3-symmetric benzoxazine-based tris-urea compound is discussed. (1)H NMR titrations indicate a stronger Cl(-) binding compared that of Br(-) and I(-) by the receptor. Effective Cl(-) transport across liposomal membranes via a Cl(-)/X(-) antiport mechanism is confirmed. Theoretical calculation suggests that a few water molecul...

Solutes determine the properties of a solution. In this study, we probe ionic solutions through the entropy of individual water molecules in the solvation shells around different cations and anions. Using a method recently developed by our group, we show the solvation shell entropy stemming from the individual contributions correlate extremely well...

Derived from a strategically chosen hexafluorinated dicarboxylate linker aimed at the designed synthesis of a superhydrophobic metal-organic framework (MOF), the fluorine-rich nanospace of a water-stable MOF (UHMOF-100) exhibits excellent water-repellent features. It registered the highest water contact angle (≈176°) in the MOF domain, marking the...

The Lab-on-a-chip technology based on electrophoresis via nanopores is advancing at a fast pace to achieve low cost, fast, and reliable genomic sequencing. However, such a promising technique for genome sequencing is challenged by the uncontrolled faster DNA translocation speed and low signal to noise ratio. In this study, we have performed all-ato...

Proflavine is a small molecule that intercalates into DNA and, thereby, acts as an anticancer agent. Intercalation of proflavine is shown to be a two-step process in which the first step is believed to be the formation of a pre-intercalative outside bound state. Experimental studies so far are unable to capture the nature of the outside bound state...

The protein-DNA interactions induce conformational changes in DNA such as B-form to A-form transition at a local level. Such transitions are associated with a junction free energy cost at the boundary of two different conformations in a DNA molecule. In this study, we have performed umbrella sampling simulations to find free energy values of B-A tr...

Binding of transcription factor (TF) proteins with DNA may cause severe kinks in the latter. Here, we investigate the molecular origin of the DNA kinks observed in the TF-DNA complexes using small molecule intercalation pathway, crystallographic analysis, and free energy calculations involving four different transcription factor (TF) protein-DNA co...

Water dynamics in the solvation shell around biomolecules play a vital role in their stability, function, and recognition processes. Although extensively studied through various experimental and computational methods, dynamical timescales of water near DNA is highly debated. The residence time of water is one such dynamical quantity that has been p...

The study of DNA under high hydrostatic pressure provides fundamental insights into the nature of interactions responsible for its structure and its remarkable stability in extreme conditions. We have investigated the structural changes in DNA under 2000 bar external pressure using electronic structure calculations and molecular dynamics simulation...

Artificial anion selective ion channels with single-file multiple anion-recognition sites are rare. Here, we have designed, by hypothesis, a small molecule that self-organizes to form a barrel rosette ion channel in the lipid membrane environment. Being amphiphilic in nature, this molecule forms nanotubes through intermolecular hydrogen bond format...

Entropy of water plays an important role in both chemical and biological processes e.g. hydrophobic effect, molecular recognition etc. Here we use a new approach to calculate translational and rotational entropy of the individual water molecules around different hydrophobic and charged solutes. We show that for small hydrophobic solutes, the transl...

Here, we investigate the effect of urea in the unfolding dynamics of flavin adenine dinucleotide (FAD), an important enzymatic cofactor, through steady state, time-resolved fluorescence spectroscopic and molecular dynamics (MD) simulation studies. Steady state results indicate the possibility of urea induced unfolding of FAD, inferred from increasi...

DNA carries an inherent polymorphism, which surfaces under various external conditions. While B-form remains predominant under normal physiological conditions for most of the DNA sequences, low humidity and increased ion concentration cause B- to A-form transition. Certain proteins and molecules also sometimes cause local deformation of the DNA to...

The ability of small molecules to perturb the natural structure and dynamics of nucleic acids is intriguing and has potential applications in cancer therapeutics. Intercalation is a special binding mode where the planar aromatic moiety of a small molecule is inserted between a pair of base pairs, causing structural changes in the DNA and leading to...

DNA intercalation is a clinically relevant biophysical process due to its potential to inhibit the growth and survival of tumor cells and microbes through the arrest of the transcription and replication processes. Extensive kinetic and thermodynamic studies have followed since the discovery of the intercalative binding mode. However, the molecular...

This article reports the alteration of the excited state photophysics of a molecular rotor, namely 9-(dicyano-vinyl)julolidine (DCVJ), which has been extensively used to report protein aggregation and protein conformational changes, by the various cavity sizes of cyclodextrin (CD) macrocyclic hosts, with the help of steady state, time-resolved fluo...

DNA intercalation, a biophysical process of enormous clinical significance, has surprisingly eluded molecular understanding for several decades. With appropriate configurational restraint (to prevent dissociation) in all-atom metadynamics simulations, we capture the free energy surface of direct intercalation from minor groove-bound state for the f...

Flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) are derivatives of riboflavin (RF), a water-soluble vitamin, more commonly known as vitamin B(2). Flavins have attracted special attention in the last few years because of the recent discovery of a large number of flavoproteins. In this work, these flavins are used as extrinsic fluor...

Atomic-scale molecular dynamics and free energy calculations in explicit aqueous solvent are used to study the complex mechanism by which a molecule can intercalate between successive base pairs of the DNA double helix. We have analyzed the intercalation pathway for the anticancer drug daunomycin using two different methods: metadynamics and umbrel...

The interplay of entropy components in a molecular recognition process is complex but intriguing. In this study, we probed into the origin of this interplay among the drug, DNA, and water entropy in the intercalation process (free → minor groove-bound → intercalation) of an anticancer drug daunomycin, resulting in small entropy difference (+1.1 kca...

Intercalation of anti-cancer drugs into DNA is the insertion of the planar aromatic portion of the drug molecules between a pair of DNA basepairs, inducing certain local structural changes in the DNA and subsequently stopping its replication. Despite its importance, a detailed mechanistic understanding of this process at the molecular level is lack...

Intercalation into DNA (insertion between a pair of base pairs) is a critical step in the function of many anticancer drugs. Despite its importance, a detailed mechanistic understanding of this process at the molecular level is lacking. We have constructed, using extensive atomistic computer simulations and umbrella sampling techniques, a free ener...

Rotational diffusion of a protein is determined largely by its interaction with the surrounding solvent, water. This interaction derives contributions from both the size (short-range interaction) and the charge distribution (long-range interaction) of the protein. Here we show that if the size and shape of the proteins are properly included in the...

Hydropathy scale is widely used to obtain a measure of the effective interaction between any two amino acid residues in proteins and is based on the assumption that attraction between two hydrophobic groups and repulsion between hydrophilic groups (in water) can be translated straightforwardly to protein environment. Here we employ a recently devel...

Fluorescence resonance energy transfer (FRET) is routinely used to study equilibrium and dynamical properties of polymers and biopolymers in the condensed phases. It is now being widely used in conjunc- tion with single molecule spectroscopy where one usually employs the Förster expression which predicts (1/R6) distance dependence of the energy tra...

We present a solvent-implicit minimalistic model potential among the amino acid residues of proteins, obtained by using the known native structures [deposited in the Protein Data Bank (PDB)]. In this model, the amino acid side chains are represented by a single ellipsoidal site, defined by the group of atoms about the center of mass of the side cha...

Rotational friction on proteins and macromolecules is known to derive contributions from at least two distinct sources – hydrodynamic (due to viscosity) and dielectric friction (due to polar interactions). In the existing theoretical approaches, the effect of the latter is taken into account by increasing the size of the protein with the addition o...

Rotational friction on proteins and macromolecules is known to derive contributions from at least two distinct sources -- hydrodynamic (due to viscosity) and dielectric friction (due to polar interactions). In the existing theoretical approaches, the effect of the latter is taken into account in an {\it ad hoc} manner, by increasing the size of the...

The folding of an extended protein to its unique native state requires establishment of specific, predetermined, often distant, contacts between amino acid residue pairs. The dynamics of contact pair formation between various hydrophobic residues during folding of two different small proteins, the chicken villin head piece (HP-36) and the Alzheimer...

Folding dynamics and energy landscape picture of protein conformations of HP-36 andβ-amyloid (Aβ) are investigated by extensive Brownian dynamics simulations, where the inter amino acid interactions are given by a minimalistic model (MM) we recently introduced [J. Chem. Phys. 118 4733 (2003)]. In this model, a protein is constructed by taking two a...

Folding dynamics and energy landscape picture of protein conformations of HP-36 and beta-amyloid (Abeta) are investigated by extensive Brownian dynamics simulations, where the inter amino acid interactions are given by a minimalistic model (MM) we recently introduced [J. Chem. Phys. 118 4733 (2003)]. In this model, a protein is constructed by takin...

Fluorescence resonance energy transfer (FRET) dur- ing folding of a model protein, HP-36, is inve stigated by Brownian dynamics simulation. Computer simu- lations of this protein show that folding kinetics is non-exponential and multistage, after a fast initial hydrophobic collapse. This multistage dynamics can be ca ptured in FRET with a suitably...

Diffusion of a tagged particle near a constraining biological surface is examined numerically by modeling the surface-water interaction by an effective potential. The effective potential is assumed to be given by an asymmetric double well constrained by a repulsive surface towards $r=0$ and unbound at large distances. The time and space dependent p...

We explore the correlation between the energy landscape and topology in the folding of a model protein (chicken villin headpiece HP-36) by using a force-field which incorporates the effects of water through a hydropathy scale and the role of helical propensity of amino acids through a nonlocal harmonic potential. Each amino acid is represented by o...

The dynamics of contact pair formation between various hydrophobic residues during folding of a model protein Hp-36 is investigated by Brownian dynamics simulation. Hydropathy scale and non-local helix propensity of amino acids are used to model the complex interaction potential. The resulting structure of the model protein mimics the native state...

We have carried out NPT molecular dynamics simulations of isolated ellipsoids in a glass forming binary mixture to gain insight into the nature of orientational relaxation (OR) in a viscous liquid. At high pressures when the liquid is highly viscous, the OR is found to occur mainly via correlated hopping, sometimes involving participation of severa...

A self-consistent microscopic theory is developed to understand the anomalously weak concentration dependence of ionic self-diffusion coefficient D(ion) in electrolyte solutions. The self-consistent equations are solved by using the mean spherical approximation expressions of the static pair correlation functions for unequal sizes. The results are...

Extensive isothermal-isobaric (NPT) molecular dynamics simulations at many different temperatures and pressures have been carried out in the well-known Kob–Andersen binary mixture model to monitor the effect of pressure (P) and temperature (T) on the dynamic properties such as the viscosity (η) and the self-diffusion (Di) coefficients of the binary...

Orientational relaxation (OR) in a viscous, glassy liquid is investigated by carrying out extensive NPT molecular dynamics simulations of isolated ellipsoids in a glass forming binary mixture. Near the glass transition, the OR occurs mainly via hopping involving either a ring- or a tunnel like motion, with the participation of several neighboring a...

Binary mixtures show many kinds of fascinating dynamical behaviour which has eluded microscopic description till very recently. In this work we show that much of the anomalous behaviour can be explained by building suitable models and carrying out theoretical and simulation studies. Specifically, three well-known problems have been addressed here....

Although many experimental studies over the years have shown strong (inverse) correlation between excess viscosity and excess volume of a binary mixture, there does not seem to exist any microscopic theoretical study of such behavior. In this work, we introduce and study two new models of binary mixture with the aim of removing this lacuna. Our mod...

In order to understand the long known anomalies in the composition dependence of diffusion and viscosity of binary mixtures, we introduce here two new models and carry out extensive molecular dynamics simulations. In these models, the two molecular species (A and B) have the same diameter and mass. In model I the interspecies interaction is more at...

In this work we introduce two models to understand the anomalous composition dependence of viscosity of binary mixtures. Both models consist of a mixture of two molecular species (A and B) with the same diameter and mass but varying solute–solvent Lennard-Jones interaction. In model I, the two different species are strongly attractive while in mode...