Debnath, Ananya

Understanding the regulatory factors of self-assembly processes is a necessity in order to modulate the nano-structures and their properties. Here, the self-assembly mechanism of a peptide-perylenediimide (P-1) conjugate in mixed solvent systems of THF/water is studied and the semiconducting properties are correlated with the morphology. In THF, right handed helical fibers are formed while in 10% THF-water, the morphology changes to nano-rings along with a switch in the helicity to left-handed orientation. Experimental results combined with DFT calculations reveal the critical role of thermodynamic and kinetic factors to control these differential self-assembly processes. In THF, P-1 forms right handed helical fibers in a kinetically controlled fashion. In case of 10% THF-water, the initial nucleation of the aggregate is controlled kinetically. Due to differential solubility of the molecule in these two solvents, elongation of the nuclei into fibers is restricted after a critical length leading to the formation of nano-rings which is governed by the thermodynamics. The helical fibers show superior semi-conducting property to the nano-rings as confirmed by conducting-AFM and conventional I-V characteristics.

Capturing structure and dynamics of both lipids and water near membranes using simulations as in experiments is a challenging task till date. Dimyristoylphophatidylcholine (DMPC) lipid bilayers with Berger and CHARMM36 force-fields have been investigated at fluid phase with TIP3P and TIP4P/2005 water models. Interfacial water molecules (IW) near lipid bilayers exhibit local distorted tetrahedrality within the first hydration shell of interface water for both water models. Anomalous diffusion exponents of IW hydrogens show oscillations without decaging at an intermediate length scale slightly larger than the intermolecular separation. The non-Gaussian parameters of bulk water decay to zero for both water models at a time-scale consistent with previously reported neutron scattering experiments, whereas IW exhibit β to α relaxations which are universal signatures of glassy dynamics. These results provide insights on the choice of force-fields to apprehend underlying physical laws of water relaxations near membranes and will be useful to study membrane phase transitions in future.

Micelles with different symmetries have immense applications on cosmetic formulations, oil recovery, drug delivery and so on. To understand the controlling factors responsible for shape transformations of micelles and to achieve the relevant time and length scale, a multi-scale approach is used where an all atomistic simulation is employed to derive a coarse-grained (CG) model for the micelles. Cationic surfactants, behenyltrimethyl ammonium chloride (BTMAC) in water self-assemble into a cylindrical micellar phase which transforms into a spherical micellar phase upon addition of a co-surfactant, stearyl alcohol, SA. The bonded distributions of the CG model are derived by the canonical sampling of their respective AA simulations. Martini non-bonded potentials are found to be suitable to obtain the cylindrical micellar phase as in the AA model for BTMAC/water system, but not for the mixed system. Parameterization of martini force field enables to obtain the size distributions of the spherical micelle consistent with the AA ones. Our simulations reveal that a correct interplay between the head-group size and hydrophilicity is crucial for obtaining the micellar size distributions. Thus, the current study provides insights on the controlling factors of the cylindrical to spherical shape transformations of the micelles and shows the suitability of multi-scale ansatz to achieve the relevant length and time scale, inaccessible to the experiments, otherwise.

Dynamics of hydration layers of a dimyristoylphosphatidylcholine (DMPC) bilayer are investigated using an all atom molecular dynamics simulation. Based upon the geometric criteria, continuously residing interface water molecules which form hydrogen bonds solely among themselves and then concertedly hydrogen bonded to carbonyl, phosphate, and glycerol head groups of DMPC are identified. The interface water hydrogen bonded to lipids shows slower relaxation rates for translational and rotational dynamics compared to that of the bulk water and is found to follow sub-diffusive and non-diffusive behaviors, respectively. The mean square displacements and the reorientational auto-correlation functions are slowest for the interfacial waters hydrogen bonded to the carbonyl oxygen since these are buried deep in the hydrophobic core among all interfacial water studied. The intermittent hydrogen bond auto-correlation functions are calculated, which allows breaking and reformations of the hydrogen bonds. The auto-correlation functions for interfacial hydrogen bonded networks develop humps during a transition from cage-like motion to eventual power law behavior of t-3/2. The asymptotic t-3/2 behavior indicates translational diffusion dictated dynamics during hydrogen bond breaking and formation irrespective of the nature of the chemical confinement. Employing reactive flux correlation analysis, the forward rate constant of hydrogen bond breaking and formation is calculated which is used to obtain Gibbs energy of activation of the hydrogen bond breaking. The relaxation rates of the networks buried in the hydrophobic core are slower than the networks near the lipid-water interface which is again slower than bulk due to the higher Gibbs energy of activation. Since hydrogen bond breakage follows a translational diffusion dictated mechanism, chemically confined hydrogen bond networks need an activation energy to diffuse through water depleted hydrophobic environments. Our calculations reveal that the slow relaxation rates of interfacial waters in the vicinity of lipids are originated from the chemical confinement of concerted hydrogen bond networks. The analysis suggests that the networks in the hydration layer of membranes dynamically facilitate the water mediated lipid-lipid associations which can provide insights on the thermodynamic stability of soft interfaces relevant to biological systems in the future.

We investigated structural and dynamical properties of nanodiscs comprising dimyristoylphosphatidylcholine (DMPC) lipids and major scaffold protein MSP1Δ(1-22) from human apolipoprotein A-1 using combined all-atom and coarse-grained (CG) molecular dynamics (MD) simulations. The computational efficiency of the Martini-CG force field enables the spontaneous self-assembly of lipids and scaffold proteins into stable nanodisc structures on time scales up to tens of microseconds. Subsequent all-atom and CG-MD simulations reveal that the lipids in the nanodisc have lower configurational entropy and higher acyl tail order than in a lamellar bilayer phase. These altered average properties arise from rather differential behavior of lipids, depending on their location in the nanodisc. Since the scaffold proteins exert constrictive forces from the outer rim of the disc toward its center, lipids at the center of the nanodisc are highly ordered, whereas annular lipids that are in contact with the MSP proteins are remarkably disordered due to perturbed packing. Although specific differences between all-atom and CG simulations are also evident, the results obtained at both levels of resolution are in overall good agreement with each other and provide atomic level interpretations of recent experiments. Thus, the present study highlights the applicability of multiscale simulation approaches for nanodisc systems and opens the way for future applications, including the study of nanodisc-embedded membrane proteins. (Graph Presented).

Trigonella foenum-graecum (fenugreek) is an important medicinal plant, well known for its antiinflammatory properties. However, the underlying cellular and molecular mechanisms of its action remain largely unknown. The apoptosis associated speck like protein containing a caspase recruitment domain (CARD) (ASC) is central to inflammatory and cell death pathways in innate and adaptive immunity. Here, we show that fenugreek seed extract provides cytoprotection to bacterial lipopolysaccharide (LPS) inflammed and nanosilica-treated fibroblasts via a reactive oxygen species independent pathway. All atom molecular dynamics simulations of ASC-ligand complex reveal that individual phytochemicals in fenugreek can bind to ASC via specific non-covalent interactions. These data show that a synergistic effect of fenugreek phytochemicals with the ASC protein alters its molecular properties resulting in altered cellular function. Such information is crucial to the development of targeted therapeutic interventions for inflammatory diseases.

The influence of water concentrations on phase transformations of a surfactant/co-surfactant/water system is investigated by using all atom molecular dynamics simulations. At higher water concentrations, where surfactant (behenyl trimethyl ammonium chloride, BTMAC) to co-surfactant (stearyl alcohol, SA) ratio is fixed, BTMAC and SA self-assemble into spherical micelles, which transform into strongly interdigitated one dimensional rippled lamellar phases upon decreasing water concentrations. Fragmentation or fusions of spherical micelles of different sizes are evident from the radial distribution functions at different temperatures. However, at lower water concentrations rippled lamellar phase transforms into an LβI phase upon heating. Our simulations reveal that the concentrations of water can influence available space around the head groups which couple with critical thickness to accommodate the packing fraction required for respective phases. This directs towards obtaining a controlling factor to design desired phases important for industrial and medical applications in the future.

Nuclear pore complexes (NPCs) are very selective filters that sit on the membrane of the nucleus and monitor the transport between the cytoplasm and the nucleoplasm. For the central plug of NPC two models have been suggested in the literature. The first suggests that the plug is a reversible hydrogel while the other suggests that it is a polymer brush. Here we propose a model for the transport of a protein through the plug, which is general enough to cover both the models. The protein stretches the plug and creates a local deformation, which together with the protein, we refer to as the bubble. We start with the free energy for creation of the bubble and consider its motion within the plug. The relevant coordinate is the center of the bubble which executes random walk. We find that for faster relaxation of the gel, the diffusion of the bubble is greater. © 2014 Elsevier B.V. All rights reserved.

The correct interplay of interactions between protein, pigment and lipid molecules is highly relevant for our understanding of the association behavior of the light harvesting complex (LHCII) of green plants. To cover the relevant time and length scales in this multicomponent system, a multi-scale simulation ansatz is employed that subsequently uses a classical all atomistic (AA) model to derive a suitable coarse grained (CG) model which can be backmapped into the AA resolution, aiming for a seamless conversion between two scales. Such an approach requires a faithful description of not only the protein and lipid components, but also the interaction functions for the indispensable pigment molecules, chlorophyll b and chlorophyll a (referred to as chl b/chl a). In this paper we develop a CG model for chl b and chl a in a dipalmitoylphosphatidyl choline (DPPC) bilayer system. The structural properties and the distribution behavior of chl within the lipid bilayer in the CG simulations are consistent with those of AA reference simulations. The non-bonded potentials are parameterized such that they fit to the thermodynamics based MARTINI force-field for the lipid bilayer and the protein. The CG simulation shows chl aggregation in the lipid bilayer which is supported by fluorescence quenching experiments. It is shown that the derived chl model is well suited for CG simulations of stable, structurally consistent, trimeric LHCII and can in the future be used to study their large scale aggregation behavior.

The effect of dimethyl sulfoxide (DMSO) on a model 1,2-dimyristoyl-sn-glycero-3-phosphocholine lipid membrane is investigated during a rapid supercooling from 350 to 250 K using a total of 165.0198μs all-atom molecular dynamics simulations. Our findings reveal that the addition of DMSO above a critical concentration induces significant alterations in the gel phase of the membrane at supercooled temperatures, shifting the gel phase to a fluid phase evident from area per lipid, order parameter, and d-spacing. Notably, an anomalous contraction is observed in bilayers in the presence of DMSO with the same critical concentrations as the temperature is cooled from 300 K. As the concentration of DMSO rises at supercooled temperatures, the interface becomes increasingly populated with DMSO molecules, approaching a two-dimensional percolation threshold. This process leads to an expansion in the area occupied by each lipid molecule, creating free space around the lipid tails. Subsequently, the population of DMSO and water at the hydrophobic core becomes energetically favorable at a supercooled temperature compared to the higher temperature above the critical concentration of DMSO. The higher population of DMSO and water at the interface and at the hydrophobic core increases the disorder and fluidity of the lipids and gradually changes the gel phase toward the fluid phase. Thus, our results provide the molecular mechanism of DMSO-induced fluidity of the membrane at supercooled temperature relevant for cell banking in the future.