Bulletin of the American Physical Society
APS March Meeting 2016
Volume 61, Number 2
Monday–Friday, March 14–18, 2016; Baltimore, Maryland
Session K41: Physics of Proteins: Protein-Protein InteractionsFocus
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Sponsoring Units: DBIO DPOLY DCOMP Chair: Wei Wang, Nanjing University Room: 344 |
Wednesday, March 16, 2016 8:00AM - 8:36AM |
K41.00001: Random close packing in protein cores Invited Speaker: Corey OHern Shortly after the determination of the first protein x-ray crystal structures, researchers analyzed their cores and reported packing fractions $\phi \approx 0.75$, a value that is similar to close packing equal-sized spheres. A limitation of these analyses was the use of `extended atom' models, rather than the more physically accurate `explicit hydrogen' model. The validity of using the explicit hydrogen model is proved by its ability to predict the side chain dihedral angle distributions observed in proteins. We employ the explicit hydrogen model to calculate the packing fraction of the cores of over $200$ high resolution protein structures. We find that these protein cores have $\phi \approx 0.55$, which is comparable to random close-packing of non-spherical particles. This result provides a deeper understanding of the physical basis of protein structure that will enable predictions of the effects of amino acid mutations and design of new functional proteins. [Preview Abstract] |
Wednesday, March 16, 2016 8:36AM - 8:48AM |
K41.00002: Predicting protein-peptide interactions from scratch Chengfei Yan, Xianjin Xu, Xiaoqin Zou Protein-peptide interactions play an important role in many cellular processes. The ability to predict protein-peptide complex structures is valuable for mechanistic investigation and therapeutic development. Due to the high flexibility of peptides and lack of templates for homologous modeling, predicting protein-peptide complex structures is extremely challenging. Recently, we have developed a novel docking framework for protein-peptide structure prediction. Specifically, given the sequence of a peptide and a 3D structure of the protein, initial conformations of the peptide are built through protein threading. Then, the peptide is globally and flexibly docked onto the protein using a novel iterative approach. Finally, the sampled modes are scored and ranked by a statistical potential-based energy scoring function that was derived for protein-peptide interactions from statistical mechanics principles. Our docking methodology has been tested on the Peptidb database and compared with other protein-peptide docking methods. Systematic analysis shows significantly improved results compared to the performances of the existing methods. Our method is computationally efficient and suitable for large-scale applications. [Preview Abstract] |
Wednesday, March 16, 2016 8:48AM - 9:00AM |
K41.00003: Computational Studies of Protein-Protein Interface Designs Jennifer Gaines, Corey O'Hern, Lynne Regan We implement a hard-sphere model for amino acid structure to study natural and designed protein-protein interfaces. Current computational methods have found limited success in designing novel interfaces and resorted to implementing several rounds of experimental mutation and selection to achieve successful designs. Here, we show that the hard-sphere model can recapitulate the side chain dihedral angle distributions for amino acids at natural protein-protein interfaces. In addition, we calculate the packing fraction in naturally occurring interfaces and find that it is comparable to dense random packing in protein cores. We then evaluate a number of successful and unsuccessful prior computational designs in terms of the number of allowed side chain dihedral angle conformations and the packing fraction of residues at the interface. [Preview Abstract] |
Wednesday, March 16, 2016 9:00AM - 9:12AM |
K41.00004: Characterizing the statistical properties of protein surfaces Ji Hyun Bak, Anne-Florence Bitbol, William Bialek Proteins and their interactions form the body of the signaling transduction pathway in many living systems. In order to ensure the accuracy as well as the specificity of signaling, it is crucial that proteins recognize their correct interaction partners. How difficult, then, is it for a protein to discriminate its correct interaction partner(s) from the possibly large set of other proteins it may encounter in the cell? An important ingredient of recognition is shape complementarity. The ensemble of protein shapes should be constrained by the need for maintaining functional interactions while avoiding spurious ones. To address this aspect of protein recognition, we consider the ensemble of proteins in terms of the shapes of their surfaces. We take into account the high-resolution structures of E.coli non-DNA-binding cytoplasmic proteins, retrieved from the Protein Data Bank. We aim to characterize the statistical properties of the protein surfaces at two levels: First, we study the intrinsic dimensionality at the level of the ensemble of the surface objects. Second, at the level of the individual surfaces, we determine the scale of shape variation. We further discuss how the dimensionality of the shape space is linked to the statistical properties of individual protein surfaces. [Preview Abstract] |
Wednesday, March 16, 2016 9:12AM - 9:24AM |
K41.00005: Difference in aggregation between functional and toxic amyloids studied by atomistic simulations Martin Carballo Pacheco, Ahmed E. Ismail, Birgit Strodel Amyloids are highly structured protein aggregates, normally associated with neurodegenerative diseases such as Alzheimer's disease. In recent years, a number of nontoxic amyloids with physiologically normal functions, called functional amyloids, have been found. It is known that soluble small oligomers are more toxic than large fibrils. Thus, we study with atomistic explicit-solvent molecular dynamics simulations the oligomer formation of the amyloid-$\beta$ peptide A$\beta_{25-35}$, associated with Alzheimer's disease, and two functional amyloid-forming tachykinin peptides: kassinin and neuromedin K. Our simulations show that monomeric peptides in extended conformations aggregate faster than those in collapsed hairpin-like conformations. In addition, we observe faster aggregation by functional amyloids than toxic amyloids, which could explain their lack of toxicity. [Preview Abstract] |
Wednesday, March 16, 2016 9:24AM - 9:36AM |
K41.00006: Oligomer stability of Amyloid-$\beta$ (A$\beta$) 25-35 : A Dissipative Particle Dynamics study Igor Pivkin, Emanuel Peter Alzheimer's disease is strongly associated with an accumulation of Amyloid-$\beta$ (A$\beta$) peptide plaques in the human brain. A$\beta$ is a 43 residues long intrinsically disordered peptide and has a strong tendency to form aggregates. Evidence accumulates that A$\beta$ acts toxic to the neurons in the brain through the formation of small soluble oligomers. A$\beta$ 25-35 is the smallest fragment of A$\beta$ which still retains its toxicity and its ability to form extended fibrils. In this talk we will present the results from simulations of aggregation of up to 100 A$\beta$ 25-35 peptides using a novel polarizable coarse-grained protein model in combination with Dissipative Particle Dynamics. [Preview Abstract] |
Wednesday, March 16, 2016 9:36AM - 9:48AM |
K41.00007: A thermodynamic study of Abeta(16-21) dissociation from a fibril using computer simulations. CRISTIANO DIAS, Farbod Mahmoudinobar, Zhaoqian Su Here, I will discuss recent all-atom molecular dynamics simulations with explicit water in which we studied the thermodynamic properties of Abeta(16-21) dissociation from an amyloid fibril. Changes in thermodynamics quantities, e.g., entropy, enthalpy, and volume, are computed from the temperature dependence of the free-energy computed using the umbrella sampling method. We find similarities and differences between the thermodynamics of peptide dissociation and protein unfolding. Similarly to protein unfolding, Abeta(16-21) dissociation is characterized by an unfavorable change in enthalpy, a favorable change in the entropic energy, and an increase in the heat capacity. A main difference is that peptide dissociation is characterized by a weak enthalpy-entropy compensation. We characterize dock and lock states of the peptide based on the solvent accessible surface area. The Lennard-Jones energy of the system is observed to increase continuously in lock and dock states as the peptide dissociates. The electrostatic energy increases in the lock state and it decreases in the dock state as the peptide dissociates. These results will be discussed as well as their implication for fibril growth. [Preview Abstract] |
Wednesday, March 16, 2016 9:48AM - 10:00AM |
K41.00008: Role of mutation on fibril formation in small peptides by REMD Farbod Mahmoudinobar, Cristiano Dias Amyloid fibrils are now recognized as a common form of protein structure. They have wide implications for neurological diseases and entities involved in the survival of living organisms, e.g., silkmoth eggshells. Biological functions of these entities are often related to the superior mechanical strength of fibrils that persists over a broad range of chemical and thermal conditions desirable for various biotechnological applications, e.g., to encapsulate drugs. Mechanical properties of fibrils was shown to depend strongly on the amino acid sequence of its constituent peptides whereby bending rigidities can vary by two orders of magnitude. Therefore, the rational design of new fibril-prone peptides with tailored properties depends on our understanding of the relation between amino acid sequence and its propensity to fibrillize. In this presentation I will show results from extensive Replica Exchange Molecular Dynamics (REMD) simulations of a 12-residue peptide containing the fibril-prone motif KFFE and its mutants. Simulations are performed on monomers, dimers, and tetramers. I will discuss effects of side chain packing, hydrophobicity, charges and beta-sheet propensity on fibril formation. [Preview Abstract] |
Wednesday, March 16, 2016 10:00AM - 10:12AM |
K41.00009: Oligomerization of the protein tau in the Alzheimer's disease Luca Larini The Alzheimer's disease is characterized by the formation of protein aggregates both within and outside of the brain's cells, the neurons. Within the neurons, the aggregation of the microtubule associated protein tau leads to the destruction of the microtubules in the axon of the neuron. Tau is extremely flexible and is classified as an intrinsically disordered protein due to its low propensity to form secondary structure. Tau promotes tubulin assembly into microtubules, which are an essential component of the cytoskeleton of the axon. The microtubule binding region of tau consists of 4 pseudo-repeats that are critical for aggregation as well. In this study, we focus on the aggregation propensity of different segments of the microtubule binding region as well as post-translational modifications that can alter tau dynamics and structure. We have performed replica exchange molecular dynamics simulations to characterize the ensemble of conformations of the monomer and small oligomers as well as how these structures are stabilized or destabilized by mutations and post-translational modifications. [Preview Abstract] |
Wednesday, March 16, 2016 10:12AM - 10:24AM |
K41.00010: ABSTRACT WITHDRAWN |
Wednesday, March 16, 2016 10:24AM - 10:36AM |
K41.00011: Nuclear magnetic resonance studies of bovine $\gamma$B-crystallin George Thurston, Jeffrey Mills, Lea Michel, Kaylee Mathews, John Zanet, Angel Payan, Keith Van Nostrand, Michael Kotlarchyk, David Ross, Christopher Wahle, John Hamilton Anisotropy of shape and/or interactions play an important role in determining the properties of concentrated solutions of the eye lens protein, $\gamma$B-crystallin, including its liquid-liquid phase transition. We are studying $\gamma$B anisotropic interactions with use of nuclear magnetic resonance (NMR) concentration- and temperature-dependent chemical shift perturbations (CSPs). We analyze two-dimensional heteronuclear spin quantum coherence (HSQC) spectra on backbone nitrogen and attached hydrogen nuclei for CSPs, up to 3 percent volume fraction. Cumulative distribution functions of the CSPs show a concentration and temperature-dependent spread. Many peaks that are highly shifted with either concentration or temperature are close (i) crystal intermolecular contacts (ii) locations of cataractogenic point mutations of a homologous human protein, human $\gamma$D-crystallin, and (iii) charged amino-acid residues. We also discuss the concentration- and temperature-dependence of NMR and quasielastic light scattering measurements of rotational and translational diffusion of $\gamma$B crystallin in solution, affected by interprotein attractions. [Preview Abstract] |
Wednesday, March 16, 2016 10:36AM - 10:48AM |
K41.00012: Membrane Pore Formation by Amyloid beta (25-35) Peptide Nabin Kandel, Suren Tatulian Amyloid (A$\beta$) peptide contributes to Alzheimer's disease by a yet unidentified mechanism. One of the possible mechanisms of A$\beta$ toxicity is formation of pores in cellular membranes. We have characterized the formation of pores in phospholipid membranes by the A$\beta_{25-35}$ peptide (GSNKGAIIGLM) using fluorescence, Fourier transform infrared spectroscopy (FTIR) and circular dichroism (CD) techniques. CD and FTIR identified formation of $\beta$-sheet structure upon incubation of the peptide in aqueous buffer for 2 hours. Unilamellar vesicles composed of a zwitterionic lipid, 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC), and 70$\%$ POPC plus 30$\%$ of an acidic lipid, 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), are made in 30 mM CaCl$_{2}$. Quin-2, a fluorophore that displays increased fluorescence upon Ca$^{2+}$ binding, is added to the vesicles externally. Peptide addition results in increased Quin-2 fluorescence, which is interpreted by binding of the peptide to the vesicles, pore formation, and Ca$^{2+}$ leakage. The positive and negative control measurements involve addition of a detergent, Triton X-100, which causes vesicle rupture and release of total calcium, and blank buffer, respectively. [Preview Abstract] |
Wednesday, March 16, 2016 10:48AM - 11:00AM |
K41.00013: Holographic characterization of protein aggregates Chen Wang, Xiao Zhong, David Ruffner, Alexandra Stutt, Laura Philips, Michael Ward, David Grier Holographic characterization directly measures the size distribution of subvisible protein aggregates in suspension and offers insights into their morphology. Based on holographic video microscopy, this analytical technique records and interprets holograms of individual aggregates in protein solutions as they flow down a microfluidic channel, without requiring labeling or other exceptional sample preparation. The hologram of an individual protein aggregate is analyzed in real time with the Lorenz-Mie theory of light scattering to measure that aggregate’s size and optical properties. Detecting, counting and characterizing subvisible aggregates proceeds fast enough for time-resolved studies, and lends itself to tracking trends in protein aggregation arising from changing environmental factors. No other analytical technique provides such a wealth of particle-resolved characterization data in situ. Holographic characterization promises accelerated development of therapeutic protein formulations, improved process control during manufacturing, and streamlined quality assurance during storage and at the point of use. [Preview Abstract] |
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