Spectroscopic and Ab-initio Studies of OH---S and CH---Y(Y=O,S) H-bonded Systems
Modeling the Metabolic Pathways
Stability, metastability and aggregation in Prion proteins: Importance of capturing the rare events
In contrast to the molecular machinery where nature performs fascinatingly well, there are many examples where things may go terribly wrong leading to life-threatening diseases! In this talk we shall try to understand the elusive problem of “prion propagation” and their aggregation into insoluble fibrils that cause a multitude of neurodegenerative disorders. I shall talk about our recent efforts in identifying the mysterious misfolded scrapie (PrPSc) form of a prion protein that is considered to infect the healthy cellular prions (PrPC) by inducing misfolding in them. Using extensive Replica Exchange Molecular Dynamics (REMD) simulations we have been able to identify many low-lying transient misfolded states that might catalyze the aggregation pathway through hydrophobic interactions. We also speculate that the secondary structural elements in a cellular Prion are in fact stabilized by weak tertiary contacts leading to very low barrier towards misfolding.
We shall also discuss our futuristic ideas about understanding the hydrophobic effects around a complex molecular surface (e.g. proteins), which seem to play a very important role in various self-assembly, aggregation and binding processes. Our long term goal would be to build a computationally efficient, yet quantitative implicit solvation model that would give us solvation thermodynamics of any arbitrary molecular surface.
The curious case of Cytochrome c Oxidase: Role of protein electrostatics in biomolecular structure-function correlation
Nature has created a wide array of fascinating molecular machinery, and their efficiency is unparalleled when compared to their man-made counterparts. Be it photosynthesis (conversion of light into chemical energy), or enzyme catalysis (speeding up difficult chemical reactions), or ion channels (filtration device with high degree of specificity), or self-assembly of small molecules into organized structures, we have a lot to learn from biology! The need for a molecular level understanding of nature has been dramatically asserted by Richard Feynman: Everything that living things do can be understood in terms of the jiggling and wiggling of atoms. Following this ambitious approach, my goal is to understand the complex biomolecular functions and properties from a molecular point of view. Using statistical mechanics based computational techniques, we are able to connect the molecular interactions (energetics) to their structural, thermodynamic and kinetic properties. The ultimate challenge is to obtain the underlying free energy surfaces for any (bio)chemical processes with quantitative accuracy and computational efficiency.
In this talk, I shall take up the example of the fascinating molecular machinery involved in the proton transport processes in a trans-membrane enzyme Cytochrome c Oxidase (CcO), which reduces oxygen (O2) to water in our respiratory cycle and uses the released energy to pump protons across the membrane. I shall discuss the importance of electrostatic interactions, the role of dielectric heterogeneity of the protein interior in affecting the pKa and protonation state of the key ionizable residues, and the role of internal water molecules therein. We shall demonstrate how molecular thermodynamics can provide physical insights into the function of complex biomolecules.
Fluorescent Sensors for Signaling Phospholipids
Elucidating the Structural Basis of Substrate Recognition by the Proteasomes: A Global Approach
PSMD9, a non-ATPase subunit of the 19S regulatory complex of the 26S proteasome harbours an uncharacterized PDZ-like domain which is well known for protein-protein interaction. PDZ domains interact with C-terminal residues of the interacting partner. In quest for partners of PSMD9, we performed C-terminal tetrapeptide screen representing the C-termini of proteins of human proteome to test the ability of these peptides to bind to PSMD9 and consequently demonstrate that proteins harbouring those C-terminal residues interact with PSMD9. Here, we report that PSMD9 interacts with the C-terminal residues of hnRNPA1, S14, a ligand growth hormone and IL6 receptor via its PDZ-like domain. Studies in our lab have also shown that PSMD9-hnRNPA1 interaction is important for NF-κB signaling. Through homology modeling, docking studies, site directed mutagenesis and simulation, we provide an insight into the probable structure of PDZ domain of PSMD9 and the residues important for the interaction and functions of PSMD9.
New Solids having Novel Interfaces with Tunable Properties
Ultra-thin atomic layers open a possibility for interacting with individual atoms in a material. At the same time, control over their synthesis, bulk production, large area single crystal synthesis, amenabilities in transfer processesetc. open avenues for engineering them for suitable applications. Recently, development of new solids from interfacing distinct atomic layers received tremendous scientific attention. A new solid from in-plane bond saturated and electronically dissimilaratomic sheets, such as graphene and hexagonal boron nitride (hBN), called van der Waals solids is one such solid where new and unprecedented phenomena are found to be emanating from the interface. This is a paradigm shift in the materials science since these interface induced phenomena are found to be tunable to large extends. Moreover, some of these tunable phenomena at the interfaces are useful in energy harvesting and storage applications. The solids generated by other means of interfacing atomic layers are also found to be excelling in various fields. My talk will be focusing on some of the engineering aspects of 2D materials for various fields.
1. Artificially stacked atomic layers: towards new van der Waals solids, Gao et al. Nano Letters, 12, 3518-3525 (2012).Two dimensional materials: Mix and Match”Nature Nanotechnology, doi:10.1038/nnano.2012.139.
2. Engineering photophenomena in large three-dimensional van der Waals heterostructures, Krishna et al. NaturePhysics(Under Review).
3. Cross-linked 3D Graphene Nanoribbon Monolith Electrodes, Vineesh et al. Nanoscale (Under Review).
5. Wu et al. A three-dimensionally bonded spongy graphene material with both super compressive elasticity and near-zero Poisson's ratio,Nature Communications (Accepted).
Metabolic Paradigm of Sleep
Reduced sleep duration is a hallmark of modern-day society and is increasingly associated with medical conditions, such as diabetes, obesity, metabolic syndrome, and cardiovascular disease. Therefore, altered metabolism is a key to understand the processes related to sleep debt and clinical conditions associated to sleep. A metabolomic investigation by our lab has shown significant metabolic alteration in sleep deprived mice compared to baseline metabolic status. Major circulatory lipid component was found to be altered. In addition, we also showed presence of cross-species metabolic markers of sleep debt across rodents and humans. In addition, we also made progress investigating metabolic correlates of brain function during sleep. These results will be discussed in light of the clinical phenotypes of reduced sleep and sleep disorders.
Understanding Amyloid Beta Aggregation in terms of its Distal Folding Contacts
Title : To be announced
Photocatalytic Application of Atomic Layer Deposited (ALD) TiO2 on Fibrous Nano-Silica (KCC-1)
Single Molecular Spectroscopy of Single Live Cell
The 2014 Nobel Prize in Chemistry has been awarded for the development of Single Molecule Spectroscopy. We will discuss some recent application of this technique to the study of a single live cell. In a confocal microscope, the size of the focused spot (~200 nm = 0.2 m) is one-hundredth of the dimension of a cell. Thus one can probe different regions/organelles in a cell. Utilizing this, we will describe several new phenomena inside a live cell [1-5]. Specifically, we have discovered found substantial differences between a cancer cell and a normal cell [1-4]. The gold nano-clusters preferentially enter or stain a cancer cell compared to a non-malignant cell . The red-ox processes (thiol-disulfide interconversion) lead to intermittent structural oscillations leading to fluctuations in fluorescence intensity in a single live cell [2-3]. Such oscillations are absent for a cancer cell . The number of lipid droplets are much higher in a cancer cell. We detected stochastic resonance during gene silencing in a cancer cell .
1. S. Chattoraj, et al. "Fluorescent Gold Nano-Cluster inside a Live [UTF-8?]Cell,â€ J. Phys. Chem. C 118
(2014, in press).
2. S. Chattoraj, et al. "Role of Red-Ox Cycle in Structural Oscillations and Solvation Dynamics in Mitochondria,"
J. Phys. Chem. B 118 (2014, in press).
3. S. Ghosh, et al. "Solvation Dynamics and Intermittent Oscillation of a Cell Membrane: " J. Phys. Chem. B 118
4. R. Chowdhury, et al. "Confocal Microscopy of Cytoplasmic Lipid Droplets in a Live Cancer Cell”
Med. Chem. Comm. 5 (2014) 536-539.
5. S. Chattoraj, et al. "Dynamics of Gene Silencing in a Live Cell," J. Phys. Chem. Lett. 5 (2014) 1012-16.
Examining Protein Ligand Interactions Using Single Molecule Force Spectroscopy
Investigations Of Thermal Properties Of Carbon Nanotubes And Metal Oxide Nanomaterials Using Raman Spectroscopy And Molecular Dynamics Simulations
Single-walled carbon nanotubes (SWCNTs) are cylindrical tubes formed from covalently bonded carbon atoms and are described mathematically by performing a rolling operation on the honeycomb planar lattice of a single graphite layer. In the current study, we have examined closely the thermal expansion properties of these quasi one-dimensional objects using experimental Raman spectroscopy and Molecular Dynamics simulations. The Raman measurements have been performed employing a Thermo Scientific DXR spectrometer and a heated cell over a range of temperatures (27-200 deg C), while the Molecular Dynamics simulations utilize the powerful and versatile software package - Large-scale Atomic Molecular Massively Parallel Simulator (LAMMPS). The Raman spectra of the SWCNTs were investigated under thermal loading via two methods, namely laser heating and the externally heated cell, in an effort to demonstrate the bond softening and resultant red-shift of the various Raman features of SWCNTs. In addition, metal oxide nanomaterials can provide insight into the changes in structure and properties that result from the chemisorption of oxygen in the lattice and the way energy is stored in nanomaterials. We have examined the characteristics of graphitic and metal oxide nanomaterials using Resonant Raman Spectroscopy at 514, 532 and 780 nm laser excitations using the DXR Smart Raman spectrometer and a Renishaw inVia Raman Microscope. Computational atomistic analysis of the associated phonon thermodynamics has been performed with the goal of determining the effect that temperature has on the vibrational frequencies of the nanomaterials. In many future applications of graphitic nanomaterials, the electronic devices will have to endure high temperatures during manufacturing and/or operation, whereby the induced strain and thermal expansion characteristics may serve as significant quality/reliability control factors.Intriguing results from both experimental measurements and simulation studies help to shed light on the thermal properties of SWCNTs and metal oxide nanomaterials that have important ramifications for their use in electronic devices.
Strategies to Reduce Rate of Charge Recombination
Modulating excitons generated as a result of photoinduced electron transfer in crowded environments is vital for the development of photo-functional materials.1 The hetero-junctions (HJs) in organic photovoltaics are termed as “transport highways” for the charge carriers to the respective electrodes.2Careful design and organization of molecular architectures at the HJs in organic solar cells dictates the fate of excitons generated. Molecular organization relies on interplay between various inter/intra molecular interactions such as multi-pole electrostatic interactions, dispersion and inductive effects, p-p interactions, hydrogen bonding etc. which determines electronic and optical properties associated with these materials. Myriads of models have been proposed in enhancing the survival times of the excitons generated at the HJs. Mullen and co-workers3 substantiated that compromise and dominance of various inter and intra molecular interactions operating in donor (D) - acceptor (A) self-assembled systems could generate segregated D-D/A-A stacks, D-A interdigitating alternate stacks etc. Aida and co-workers4 demonstrated the photochemical generation of spatially separated charge carriers through co-axial nanotubular arrangement of D and A. Wasielewski et al.5extended the survival time of charge separated states through self-assembled D-A tetramers, trefoils, dimers and hydrogen bonded foldamers.Recent report from our group6 demonstrated the importance of supramolecular vesicular scaffold in reducing the rate of charge recombination of the charge separated states.7Recently we are successful in synthesizing near-orthogonal D-A helical and columnar stacks wherein the latter undergo self-assembly in CHCl3 to form spherical aggregates which couldhelp in sustaining the charge transfer intermediates for longer timescales through D-A stacks. The following scheme represents the different models of D-A self-assembled systems reported and under investigation.
3. (a) Dössel, L. F.; Kamm, V.; Howard, I. A.; Laquai, F.; Pisula, W.; Feng, X.; Li, C.; Takase, M.; Kudernac, T.; De Feyter, S.; Müllen, K., J. Am. Chem. Soc. 2012,134 (13), 5876-5886;(b) Samorì, P.; Fechtenkötter, A.; Reuther, E.; Watson, M. D.; Severin, N.; Müllen, K.; Rabe, J. P., Adv. Mater. 2006,18 (10), 1317-1321;(c) Mativetsky, J. M.; Kastler, M.; Savage, R. C.; Gentilini, D.; Palma, M.; Pisula, W.; Müllen, K.; Samorì, P., Adv. Funct. Mater. 2009,19 (15), 2486-2494.
4. (a) Yamamoto, Y.; Fukushima, T.; Suna, Y.; Ishii, N.; Saeki, A.; Seki, S.; Tagawa, S.; Taniguchi, M.; Kawai, T.; Aida, T., Science 2006,314 (5806), 1761-1764;(b) Li, W.-S.; Saeki, A.; Yamamoto, Y.; Fukushima, T.; Seki, S.; Ishii, N.; Kato, K.; Takata, M.; Aida, T., Chem.-Asian J. 2010,5 (7), 1566-1572.
5. (a) Gunderson, V. L.; Smeigh, A. L.; Kim, C. H.; Co, D. T.; Wasielewski, M. R., J. Am. Chem. Soc. 2012,134 (9), 4363-4372;(b) Lefler, K. M.; Kim, C. H.; Wu, Y.-L.; Wasielewski, M. R., J. Phys. Chem. Lett. 2014,5 (9), 1608-1615;(c) Lefler, K. M.; Co, D. T.; Wasielewski, M. R., J. Phys. Chem. Lett. 2012,3 (24), 3798-3805;(d) Wu, Y.-L.; Brown, K. E.; Wasielewski, M. R., J. Am. Chem. Soc. 2013,135 (36), 13322-13325.
6. (a) Cheriya, R. T.; Joy, J.; Alex, A. P.; Shaji, A.; Hariharan, M., J. Phys. Chem. C. 2012,116 (23), 12489-12498;(b) Cheriya, R. T.; Nagarajan, K.; Hariharan, M., J. Phys. Chem. C. 2013,117 (7), 3240-3248.