Bulletin of the American Physical Society
APS March Meeting 2010
Volume 55, Number 2
Monday–Friday, March 15–19, 2010; Portland, Oregon
Session J10: Protein-Protein Interaction and Protein Aggregation |
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Sponsoring Units: DBP Chair: Ka Yee Lee, University of Chicago Room: A106 |
Tuesday, March 16, 2010 11:15AM - 11:27AM |
J10.00001: Protein-Protein Interactions from Linear-Scaling First Principles Quantum Mechanical Calculations Daniel Cole, Chris-Kriton Skylaris, Eeson Rajendra, Ashok Venkitaraman, Mike Payne A modification of the MM-PBSA technique for calculating binding affinities of biomolecular complexes is presented. Classical molecular dynamics is used to explore the motion of the extended interface between two peptides derived from the BRC4 repeat of BRCA2 and the eukaryotic recombinase RAD51. The resulting trajectory is sampled using the linear-scaling density functional theory code, \textsc{onetep}, to determine from first principles, and with high computational efficiency, the relative free energies of binding of the $\sim$2800 atom receptor-ligand complexes. This new method provides the basis for computational interrogation of protein-protein and protein-ligand interactions, within fields ranging from chemical biological studies to small molecule binding behaviour, with both unprecedented chemical accuracy and affordable computational expense. [Preview Abstract] |
Tuesday, March 16, 2010 11:27AM - 11:39AM |
J10.00002: Direct Force Measurements on Neurofilaments: Gel Expanded to Gel Condensed Transition R. Beck, J. Deek, J.B. Jones, C.R. Safinya Neurofilaments (NFs)--the major cytoskeletal constituent of axons in vertebrates, consist of three subunit proteins assembled to form filaments with protruding unstructured C-terminus sidearms. Liquid crystal gel networks of sidearm-mediated NF assemblies play a key role in the mechanical while disruptions of this network, due to over-accumulation or incorrect sidearm interactions, are a hallmark of motor neuron diseases. Using synchrotron SAXS [1,2] and microscopy techniques [1,3] we report a direct force measurement of reconstituted NF-gels under osmotic pressure (P), which revealed the role of subunit sidearms on structure and interaction of NFs. With increasing P, near physiological condition, the gels undergo an abrupt nonreversible gel expanded to gel condensed transition that indicates sidearm-mediated attractions between NFs. This attraction is consistent with an electrostatic model of interpenetrating chains.\\[4pt] [1] J.B. Jones, C.R. Safinya, Biophys. J. \textbf{95}, 823 (2008);\\[0pt] [2] R. Beck \textit{et al.}, Nature Mat. (2009) in press;\\[0pt] [3] H. Hess \textit{et al.} Langmuir \textbf{24,} 8397 (2008) [Preview Abstract] |
Tuesday, March 16, 2010 11:39AM - 11:51AM |
J10.00003: Kinetics of Lipofuscin Formation in Aging Retinal Pigment Epithelium Cells Fereydoon Family, K.I. Mazzitello, C.M. Arizmendi, Hans E. Grossniklaus Lipofuscin is a deposit that is formed over time by aggregation and clustering of incompletely degraded membrane material in various types of cells. Lipofuscin is made of free-radical-damaged protein and fat and is known to be present in age- related macular dgeneration (AMD), Alzheimer disease, and Parkinson disease. AMD is the leading cause of blindness in adults. The degradation of retinal pigment epithelium cells (RPE) through accumulation of lipsofuscin is considered a significant pathogenic factor in the development of AMD. We will present the results of a study of the kinetics of lipofuscin growth in RPE cells using Kinetic Monte Carlo simulations and scaling theory on a cluster aggregation model. The model captures the essential physics of lipofuscin growth in the cells. A remarkable feature is that small particles may be removed from the cells while the larger ones become fixed and grow by aggregation. We compare our results with the number of lipofuscin granules in eyes with early age-related degeneration. [Preview Abstract] |
Tuesday, March 16, 2010 11:51AM - 12:03PM |
J10.00004: Thymic Selection of T-Cell Receptors as an Extreme Value Problem Andrej Kosmrlj, Arup K. Chakraborty, Mehran Kardar, Eugene I. Shakhnovich T lymphocytes (T cells) orchestrate adaptive immune responses that clear pathogens from infected hosts. T cells recognize short peptides (p) derived from foreign proteins, which are bound to major histocompatibility complex (MHC) gene products (displayed on antigen- presenting cells). Recognition occurs when T cell receptor (TCR) proteins expressed on T cells bind sufficiently strongly to antigen- derived pMHC complexes on the surface of antigen-presenting cells. A diverse repertoire of self-tolerant TCR sequences is shaped during development of T cells in the thymus by processes called positive and negative selection. We map thymic selection processes to an extreme value problem and provide analytic expression for the amino acid composition of selected TCR sequences (which enable its recognition functions). [Preview Abstract] |
Tuesday, March 16, 2010 12:03PM - 12:15PM |
J10.00005: The effect of human microtubule-associated-protein tau on the assembly structure of microtubules and its ionic strength dependence M.C. Choi, U. Raviv, H.P. Miller, M.R. Gaylord, E. Kiris, D. Ventimiglia, D.J. Needleman, P.J. Chung, J. Deek, N. LaPointe, M.W. Kim, L. Wilson, S.C. Feinstein, C.R. Safinya Microtubules (MTs), 25 nm protein nanotubes, are among the major filamentous elements of the eukaryotic cytoskeleton involved in intracellular trafficking, cell division and the establishment and maintenance of cell shape. Microtubule-associated-protein tau regulates tubulin assembly, MT dynamics and stability. Aberrant tau action has long been correlated with numerous neurodegenerative diseases, including Alzheimer's, and fronto-temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) Using synchrotron small angle x-ray scattering (SAXS) and binding assay, we examine the effects of tau on the assembly structure of taxol-stabilized MTs. We find that tau regulates the distribution of protofilament numbers in MTs as reflected in the observed increase in the average radius of MTs with increasing the tau/tubulin molar ratio. Additionally, tau-MT interactions are mediated to a large extent via electrostatic interactions: the binding affinity of tau to MTs is ionic strength dependent. Supported by DOE-BES DE-FG02-06ER46314, NSF DMR-0803103, NIH NS35010, NIH NS13560. (Ref) M.C. Choi, S.C. Feinstein, and C.R. Safinya et al. \textit{Biophys. J.} 97; 519 (2009). [Preview Abstract] |
Tuesday, March 16, 2010 12:15PM - 12:27PM |
J10.00006: Brownian dynamics simulation of sickle hemoglobin bundle formation Ya Liu, James Gunton, Amit Chakrabarti The physical properties of biopolymer fibers, such as their stability and degree of aggregation, are implicated in many diseases, including sickle cell anemia. The natural chirality of protofilaments plays a crucial role in the formation of sickle hemoglobin fiber which leads to the permanent blockage of microvessels. We use Brownian dynamics to investigate the kinetics of fiber aggregation. The geometrical helical structure and chirality of the filaments are modeled by anisotropic patch-like interactions. We present the kinetics of fiber formation and study the possibility of a finite critical fiber bundle size. We compare our results with various experimental and theoretical results. This work is supported by grants from the NSF and the G. Harold and Leila Y. Mathers Foundation. [Preview Abstract] |
Tuesday, March 16, 2010 12:27PM - 12:39PM |
J10.00007: Dynamics in Alzheimer's disease: the role of peptide flexibility on amyloid beta aggregation Maria Antonieta Sanchez Farran, Janna Maranas Aggregates of the amyloid beta peptide (A$\beta )$ are thought to trigger brain cell death in Alzheimer's patients. Two different types of A$\beta $ aggregates have been identified: soluble, and insoluble. Soluble aggregates are formed in early stages of peptide association, whereas insoluble aggregates are the final state of aggregation. Interestingly, it is the soluble aggregates, not the insoluble ones, which correlate with disease progression. Despite the relevance of soluble aggregates as a target for Alzheimer's disease, their mechanism of formation is unknown. The role of local flexibility in protein function has recently received attention: in this study we ask if local flexibility plays a similar role in how soluble aggregates form. To answer this question, we perform all-atom molecular dynamics simulations of the wild-type A$\beta $ monomer, and two mutated forms that vary in their ability to form soluble aggregates. We find that enhanced flexibility facilitates the formation and availability of nucleation sites by allowing the peptide to more easily access the conformations most favorable to association. Peptides with high flexibility show larger conformational changes than less flexible peptides, the extent of these changes could determine the ability of A$\beta $ to self associate. [Preview Abstract] |
Tuesday, March 16, 2010 12:39PM - 12:51PM |
J10.00008: Structure and stability of proteins upon adsorption to hydrophobic surfaces Sumit Sharma, Gaurav Anand, Georges Belfort, Sanat Kumar Experimental evidence suggests that protein molecules adsorbed to hydrophobic surfaces are thermally more stable than in the bulk. To understand this observation, adsorption of a model lattice protein on hydrophobic surfaces was studied using Monte Carlo simulations. It was observed that surfaces with intermediate hydrophobicities can stabilize the secondary structure in adsorbed protein molecules. This happens because an unfolded protein molecule loses conformational freedom upon adsorption, thereby driving the melting point to higher values. However, highly hydrophobic surfaces perturb the secondary structure of the adsorbed proteins. Overall, depending on the magnitude of the surface hydrophobicity, different equilibrium regimes of proteins, namely, aggregated-desorbed; folded-adsorbed; highly aggregated-adsorbed; and weakly aggregated-strongly adsorbed are observed. [Preview Abstract] |
Tuesday, March 16, 2010 12:51PM - 1:03PM |
J10.00009: Dynamic Similarities in Pathological Forms of $\alpha $-Synuclein Ryan Bradley, Janna Maranas The natively unstructured, membrane-bound protein $\alpha $-synuclein is thought to play a role in vesicle trafficking. Its native function is subverted in the pathogenesis of Parkinson's disease, during which it forms fibrillar cytoplasmic aggregates in specific regions in the brain. It is believed that oligomers of $\alpha $-synuclein are the toxic species, whereas sequestration into fibrils is neuroprotective. Evidence that $\alpha $-synuclein changes shape as it interacts with membranes suggests that altered dynamics may drive the initial aggregation steps. To test this hypothesis, we conducted separate molecular dynamics simulations of native, mutated, and chemically-damaged forms of $\alpha $-synuclein, representing the distinct genetic and sporadic causes of the disease. We measured the fractal dimension of individual amino-acid trajectories in order to identify differences in mobility between each simulated protein. Trajectories with higher fractal dimensions are space-filling, and thus correspond to more random, constrained motion; conversely, lower fractal dimensions indicate more directed motions. Although the disease-causing variants of $\alpha $-synuclein are distinct, they show highly similar dynamical differences from the native form. This suggests that altered dynamics may facilitate oligomerization. [Preview Abstract] |
Tuesday, March 16, 2010 1:03PM - 1:15PM |
J10.00010: On the electrostatic properties of the phase-separating protein, Gamma-B crystallin K. Michael Martini, Dawn Hollenbeck, Andreas Langner, David Ross, Anthony Harkin, Edward Nelson, George Thurston Solutions of the eye lens protein Gamma-B crystallin exhibit liquid-liquid phase separation that we find to have interesting pH and ionic strength dependences. To work towards a model for the data, we construct a grand-canonical partition function that incorporates the free energies of proton occupancy patterns on a protein and its neighboring proteins. We evaluate the work of charging numerically in a coarse-grained Debye-Huckel type model. We validate the computations by comparison to analytically tractable configurations. With use of relevant data on proton affinities, we use Monte-Carlo simulation to study the charging statistics of interacting charge networks of Gamma-B crystallin. Application of this model to a single Gamma-B crystallin molecule is in reasonable agreement with currently available potentiometric titration data for dilute solutions. This model can now be applied to study the mutual charging pattern statistics and consequent interactions of closely neighboring Gamma-B crystallin molecules. [Preview Abstract] |
Tuesday, March 16, 2010 1:15PM - 1:27PM |
J10.00011: Model for evaluating patterned charge regulation contribution to electrostatic interactions between proteins Dawn Hollenbeck, K. Michael Martini, Andreas Langner, David Ross, Anthony Harkin, Edward Nelson, George Thurston We study the pattern-specific work of charging for two spherical model proteins in close proximity in ionic solution, using a grand-canonical partition function together with a coarse-grained, linear Debye-Huckel model to calculate the needed work of charging for each possible proton occupancy configuration. We seek to delineate a parameter-space phase diagram to characterize the circumstances under which patterned charge regulation, attractions due to heterogeneous protein charging patterns, and screened net protein charge could individually dominate the electrostatic portion of the interaction between model particles. Within the model, we place titratable residues in accordance with the tertiary protein structure, as is done in the case of a single protein within the Tanford-Kirkwood protein electrostatics model. We use Monte-Carlo simulation and analytical work to evaluate how the local statistics of the charging patterns on each protein respond to close proximity and relative orientation of neighboring proteins. [Preview Abstract] |
Tuesday, March 16, 2010 1:27PM - 1:39PM |
J10.00012: In situ measurements of protein structural changes during adsorption James Forrest, Kanwarjeet Kaur, Katarina Ilic, Brad Hall, Lyndon Jones Adsorption of protein onto a solid surface often leads to structural changes in the protein. The extent of denaturation upon adsorption is a fundamental problem in biomaterials. We describe the use of protein conjugated gold nanoparticle to probe changes in the protein tertiary structure upon adsorption. The changes in protein structure that can accompany adsorption give rise to detectable changes in the Localized Surface Plasmon Resonance (LSPR) of the gold nanoparticle. While not a direct probe of biological activity, the results allow one to determine in-situ the impact of adsorption on the protein tertiary structure. The technique can also distinguish the protein very near the substrate, from that much further away. This feature allows us to obtain a depth profile of protein tertiary structure. [Preview Abstract] |
Tuesday, March 16, 2010 1:39PM - 1:51PM |
J10.00013: Neutron scattering and phase separation of Gamma-B crystallin vs. pH, ionic strength and protein concentration George Thurston, K. Michael Martini, Kenneth Desmond, Elias Putzig, Zachary Dell, Dawn Carter, Dawn Hollenbeck, Nicholas Dexter, Andreas Langner, David Ross, Anthony Harkin, Edward Nelson, Malin Zackrisson-Oskolkova, Anna Stradner, Nicolas Dorsaz, Giuseppe Foffi, Peter Schurtenberger We study the pH, ionic strength and concentration dependence of liquid-liquid phase separation and neutron scattering of the eye lens protein Gamma-B crystallin. At pH 7, lowering ionic strength raises the cloud points. Neutron scattering indicates anisotropic protein interactions, in agreement with prior information. At lower pH phase separation disappears, and protein repulsions increase at low ionic strength. We seek to evaluate the roles of (i) patterned charge regulation, (ii) biasing of relative protein orientation due to local charge patches, and (iii) screened net protein charge for these phenomena. We apply a grand-canonical partition function model for charge regulation and other interactions, as input to Monte Carlo and neutron scattering computations. [Preview Abstract] |
Tuesday, March 16, 2010 1:51PM - 2:03PM |
J10.00014: Exploring the Effect of Preferential Hydration on the Dynamics of Lysozyme in Glycerol-Water Solutions Krista G. Freeman, Alexander Agapov, Kiril A. Streletzky, Alexei P. Sokolov The relaxation processes of the protein lysozyme in glycerol-water solutions were studied with Dielectric Spectroscopy and Dynamic Light Scattering (DLS) in a wide temperature range. Analysis of the dielectric spectra revealed three relaxation processes: protein rotation, large scale protein motions (slow $\delta $-relaxation), and solvent $\alpha $-relaxation. Analysis reveals a decoupling of protein dynamics from the solvent relaxation. These effects were also studied by comparing the protein diffusion as measured by DLS and the viscosity of solutions. Both spectroscopic techniques suggest preferential hydration of the protein in solution. [Preview Abstract] |
Tuesday, March 16, 2010 2:03PM - 2:15PM |
J10.00015: Influence of gold nanoparticle size on the orientation and activity of adsorbed proteins Kanwarjeet Kaur, James Forrest We used UV-visible extinction spectroscopy to study the orientation and activity of rabbit immunoglobulin G and Protein A from Staphylococcus aureus adsorbed onto gold nanoparticles of various sizes (10-60nm). There is a shift in the localised surface plasmon resonance peak due to the interaction of proteins with the nanoparticles. The proteins adopt different orientations on smaller spheres as compared to larger spheres. IgG adopts end-on orientation on bigger spheres with the Fc domain directed towards the spheres. It displays no activity towards Protein A. This study shows that the curvature of nanoparticles strongly influences the orientation of adsorbed proteins. This could be useful in the designing of colloidal drug carriers. [Preview Abstract] |
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