arXiv subjects

Sayantan Mondal

Publications and source records attributed to Sayantan Mondal.

25 records · Page 2Linked to original sources

arXiv2018

Adverse effect of ethanol on insulin dimer stability

Alcohol is widely believed to have an effect on diabetes, often considered beneficial in small amounts but detrimental in excess. The reasons are not fully known but questions have been asked about the stability of insulin oligomers in the presence of ethanol. We compute the free energy surface (FES) and the pathway of insulin dimer dissociation in water and in 5% and 10% water-ethanol mixture. We find that in the presence of ethanol the barrier energy of dissociation reaction decreases by about 40% even in 5% water-ethanol solution. In addition, ethanol induces a significant change in the reaction pathway. We obtain estimates of the rate of reaction and binding energy for all the three systems and those agree well with the previous experimental results for the insulin dimer dissociation in water. The computed FES in water exhibits ruggedness due to the existence of a number of intermediate states surrounded by high and broad transition state region. However, the presence of ethanol smoothens out the ruggedness. We extracted the conformations of the intermediate states along the minimum energy pathway in all the three systems and analyzed the change in microscopic structures in the presence of ethanol. Interestingly, we discover a stable intermediate state in water-ethanol mixtures where the monomers are separated (center-to-center) by about 3 nm and the contact order parameter is close to zero. This intermediate is stabilized by the distribution of ethanol and water molecules at the interface and which, significantly, serves to reduce the dissociation rate constant .The solvation of the two monomers during the dissociation and proteins' departure from native state configuration are analyzed to obtain insight into the dimer dissociation processes.

q-bio.BM↗

arXiv2018

In search of the origin of long-time power-law decay in DNA solvation dynamics

Experiments reveal that DNA solvation dynamics (SD) is characterized by multiple time scales ranging from a few ps to hundreds of ns and in some cases even up to microseconds. The last part of decay is slow and is characterized by a power law (PL). The microscopic origin of this PL is not yet clearly understood. Here we present a theoretical study based on time dependent statistical mechanics and computer simulations. Our investigations show that the primary candidates responsible for this exotic nature of SD are the counterions and ions from the buffer solution. We employ the model developed by Oosawa for polyelectrolyte solution that includes effects of counterion fluctuations to construct a frequency dependent dielectric function. We use it in the continuum model of Bagchi, Fleming and Oxtoby only to find that it fails to explain the slow PL decay of DNA solvation dynamics. We then extend the model by employing the continuous time random walk technique developed by Scher-Montroll-Lax. This approach can explain the long time PL decay, in terms of the collective response of the counter ions. From MD simulations we find frequent occurrence of random walk of tagged counter ions along the phosphate backbone. We propose a generalized random walk model for counterion hopping and carry out kinetic Monte Carlo simulations to show that the nonexponential contribution to solvation dynamics can indeed arise from dynamics of such ions. We also employ a Mode Coupling Theory analysis to understand the slow relaxation that originates from ions in solution. Explicit evaluation suggests that buffer ion contribution could explain logarithmic time dependence in the ns time scale, but not a power law. From MD simulations we find log-normal distributions of relaxation times of water dynamics inside the grooves. This is responsible for the initial faster multiexponential decay of SD.

cond-mat.stat-mech↗

arXiv2018

Towards Understanding the Structure, Dynamics and Bio-activity of Diabetic Drug Metformin

Small molecules are often found to exhibit extraordinarily diverse biological activities. Metformin is one of them. It is widely used as anti-diabetic drug for type-two diabetes. In addition to that, metformin hydrochloride shows anti-tumour activities and increases the survival rate of patients suffering from certain types of cancer namely colorectal, breast, pancreas and prostate cancer. However, theoretical studies of structure and dynamics of metformin have not yet been fully explored. In this work, we investigate the characteristic structural and dynamical features of three mono-protonated forms of metformin hydrochloride with the help of experiments, quantum chemical calculations and atomistic molecular dynamics simulations. We validate our force field by comparing simulation results to that of the experimental findings. Nevertheless, we discover that the non-planar tautomeric form is the most stable. Metformin forms strong hydrogen bonds with surrounding water molecules and its solvation dynamics show unique features. Because of an extended positive charge distribution, metformin possesses features of being a permanent cationic partner toward several targets. We study its interaction and binding ability with DNA using UV spectroscopy, circular dichroism, fluorimetry and metadynamics simulation. We find a non-intercalating mode of interaction. Metformin feasibly forms a minor/major groove-bound state within a few tens of nanoseconds, preferably with AT rich domains. A significant decrease in the free-energy of binding is observed when it binds to a minor groove of DNA.

q-bio.BM↗

arXiv2017

Cavity Waters Govern Insulin Association and Release: Inferences from Experimental Data and Molecular Dynamics Simulations

While a monomer of the ubiquitous hormone insulin is the biologically active form in the human body, its hexameric assembly acts as an efficient storage unit. However, the role of water molecules in the structure, stability and dynamics of the insulin hexamer is poorly understood. Here we combine experimental data with molecular dynamics simulations to investigate the shape, structure and stability of an insulin hexamer focusing on the role of water molecules. Both X-Ray analysis and computer simulations show that the core of the hexamer cavity is barrel-shaped, holding, on an average, sixteen water molecules. These encapsulated and constrained molecules impart structural stability to the hexamer. Apart from the electrostatic interactions with Zn2+ ions, an intricate hydrogen bond network amongst cavity water and neighboring protein residues stabilizes the hexameric association. These water molecules solvate six glutamate residues inside the cavity decreasing electrostatic repulsions amongst the negatively charged carboxylate groups. They also prevent association between glutamate residues and Zn2+ ions and maintain the integrity of the cavity. Simulations reveal that removal of these waters results in a collapse of the cavity. Subsequent analyses also show that the hydrogen bond network among these water molecules and protein residues that face the inner side of the cavity is more rigid with a slower relaxation as compared to that of the bulk solvent. Dynamics of cavity water reveal certain slow water molecules which form the back bone of the stable hydrogen bond network. The analysis presented here suggests a dominant role of structurally conserved water molecules in maintaining the integrity of the hexameric assembly and potentially modulating the dissociation of this assembly into the functional monomeric form.

q-bio.BM↗

arXiv2017

On the origin of diverse time scales in the protein hydration layer solvation dynamics: A molecular dynamics simulation study

In order to inquire the microscopic origin of observed multiple time scales in solvation dynamics we carry out several computer experiments. We perform atomistic molecular dynamics simulations on three protein-water systems namely, Lysozyme, Myoglobin and sweet protein Monellin. In these experiments we mutate the charges of the neighbouring amino acid side chains of certain natural probes (Tryptophan) and also freeze the side chain motions. In order to distinguish between different contributions, we decompose the total solvation energy response in terms of various components present in the system. This allows us to capture the interplay among different self and cross-energy correlation terms. Freezing the protein motions removes the slowest component that results from side chain fluctuations, but a part of slowness remains. This leads to the conclusion that the slow component in the ~20-80 ps range arises from slow water molecules present in the hydration layer. While the more than 100 ps component may arise from various sources namely, adjacent charges in amino acid side chains, the water molecules that are hydrogen bonded to them and a dynamically coupled motion between side chain and water. The charges, in addition, enforce a structural ordering of nearby water molecules and helps to form local long-lived hydrogen bonded network. Further separation of the spatial and temporal responses in solvation dynamics reveals different roles of hydration and bulk water. We find that the hydration layer water molecules are largely responsible for the slow component whereas the initial ultrafast decay arise predominantly (~80%) due to the bulk. This agrees with earlier theoretical observations. We also attempt to rationalise our results with the help of a molecular hydrodynamic theory that was developed using classical time dependent density functional theory in a semi quantitative manner.

cond-mat.soft↗

arXiv2017

Distinguishing dynamical features of water inside protein hydration layer: Distribution reveals what is hidden behind the average

Since the pioneering works of Pethig, Grant and Wuthrich on protein hydration layer, many studies have been devoted to find out if there are any general and universal characteristic features that can distinguish water molecules inside the protein hydration layer from bulk. Given that the surface itself varies from protein to protein, and that each surface facing the water is heterogeneous, search for universal features has been elusive. Here, we perform atomistic molecular dynamics simulation in order to propose and demonstrate that such defining characteristics can emerge if we look not at average properties but the distribution of relaxation times. We present results of calculations of distributions of residence times and rotational relaxation times for four different protein-water systems, and compare them with the same quantities in the bulk. The distributions in the hydration layer is unusually broad and log-normal in nature, due to the simultaneous presence of peptide backbones that form weak hydrogen bonds, hydrophobic amino acid side chains that form no hydrogen bond and charged polar groups that form strong hydrogen bond with the surrounding water molecules. The broad distribution is responsible for the non-exponential dielectric response and also agrees with large specific heat of the hydration water. Our calculations reveal that while the average time constant is just about 2-3 times larger than that of bulk water, it provides a poor representation of the real behaviour. In particular, the average leads to the erroneous conclusion that water in the hydration layer is bulk-like. However, the observed and calculated lower value of static dielectric constant of hydration layer remained difficult to reconcile with the broad distribution observed in dynamical properties. We offer a plausible explanation of these unique properties.

cond-mat.soft↗

arXiv2017

Dynamical coupling between protein conformational fluctuation and hydration water: Heterogeneous dynamics of biological water

We investigate dynamical coupling between water and amino acid side-chain residues in solvation dynamics by selecting residues often used as natural probes, namely tryptophan, tyrosine and histidine, located at different positions on protein surface and having various degrees of solvent exposure. Such differently placed residues are found to exhibit different timescales of relaxation. The total solvation response, as measured by the probe is decomposed in terms of its interactions with (i) protein core, (ii) side-chain atoms and (iii) water molecules. Significant anti cross-correlations among these contributions are observed as a result of side-chain assisted energy flow between protein core and hydration layer, which is important for the proper functionality of a protein. It is also observed that there are rotationally faster as well as slower water molecules than that of bulk solvent, which are considered to be responsible for the multitude of timescales that are observed in solvation dynamics. We also establish that slow solvation derives a significant contribution from protein side-chain fluctuations. When the motion of the protein side-chains is forcefully quenched, solvation either becomes faster or slower depending on the location of the probe.

q-bio.BM↗