Bulletin of the American Physical Society
APS March Meeting 2016
Volume 61, Number 2
Monday–Friday, March 14–18, 2016; Baltimore, Maryland
Session X41: Physics of Proteins: Structure and Dynamics IIFocus
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Sponsoring Units: DBIO DPOLY DCOMP Chair: Yi Cao, Nanjing University Room: 344 |
Friday, March 18, 2016 8:00AM - 8:12AM |
X41.00001: Dual-resolution modeling demonstrates greater conformational heterogeneity of CENP-A/H4 dimer than that of H3/H4 Haiqing Zhao Centromere protein A (CENP-A) is a centromere-specific H3 histone variant and shares only about 50\% amino acid sequence identity with the canonical H3 protein. CENP-A is required for packaging the centromere and for the proper separation of chromosomes during mitosis. Despite their discrete functions, previously reported crystal structures of the CENP-A/H4 and H3/H4 dimers reveal surprising similarity. In this work, we characterize the structure and dynamics of CENP-A/H4 and H3/H4 dimers with a dual-resolution approach, using both all-atom and coarse-grained (CG) molecular dynamics (MD) simulations. Interestingly, the histone dimer containing CENP-A is more structurally variable than the canonical H3 dimer. Furthermore, our calculations revealed significant conformational distinctions between the interface profiles of CENP-A/H4 and H3/H4. In addition, the presence of the CENP-A-specific chaperone HJURP dramatically reduced the conformational heterogeneity of CENP-A/H4. Overall, these results are in general agreement with the available experimental data and provide new dynamic insights into the mechanisms underpinning the chaperone-mediated assembly of CENP-A nucleosomes \textit{in vivo}. [Preview Abstract] |
Friday, March 18, 2016 8:12AM - 8:24AM |
X41.00002: Aggregation of alpha-synuclein by a coarse-grained Monte Carlo simulation Barry Farmer, Ras Pandey Alpha-synuclein, an intrinsic protein abundant in neurons, is believed to be a major cause of neurodegenerative diseases (e.g. Alzheimer, Parkinson's disease). Abnormal aggregation of ASN leads to Lewy bodies with specific morphologies. We investigate the self-organizing structures in a crowded environment of ASN proteins by a coarse-grained Monte Carlo simulation. ASN is a chain of 140 residues. Structure detail of residues is neglected but its specificity is captured via unique knowledge-based residue-residue interactions. Large-scale simulations are performed to analyze a number local and global physical quantities (e.g. mobility profile, contact map, radius of gyration, structure factor) as a function of temperature and protein concentration. Trend in multi-scale structural variations of the protein in a crowded environment is compared with that of a free protein chain. [Preview Abstract] |
Friday, March 18, 2016 8:24AM - 8:36AM |
X41.00003: Network Analysis Reveals the Recognition Mechanism for Mannose-binding Lectins Yunjie Zhao, Yiren Jian, Chen Zeng The specific carbohydrate binding of mannose-binding lectin (MBL) protein in plants makes it a very useful molecular tool for cancer cell detection and other applications. The biological states of most MBL proteins are dimeric. Using dynamics network analysis on molecular dynamics (MD) simulations on the model protein of MBL, we elucidate the short- and long-range driving forces behind the dimer formation. The results are further supported by sequence coevolution analysis. We propose a general framework for deciphering the recognition mechanism underlying protein-protein interactions that may have potential applications in signaling pathways. [Preview Abstract] |
Friday, March 18, 2016 8:36AM - 8:48AM |
X41.00004: \textbf{Unliganded EphA3 dimerization promoted by the SAM domain} Kalina Hristova, Deo Singh, Christopher King, Fozia Ahmed, Elena Pasquale The EphA3 receptor tyrosine kinase regulates morphogenesis during development, and is overexpressed and mutated in a variety of cancers. EphA3 activation is believed to follow a ``seeding mechanism'' model, in which ligand binding to the monomeric receptor acts as a trigger for signal-productive receptor clustering. We use a novel approach to study EphA3 lateral interactions on the surface of live cells, and we demonstrate that EphA3 forms dimers in the absence of ligand binding. We further show that these dimers are stabilized by interactions involving the EphA3 SAM domain. The discovery of unliganded EphA3 dimers challenges the current understanding of the chain of EphA3 activation events, and suggests that EphA3 may follow the ``pre-formed dimer'' model of activation known to be relevant for other receptor tyrosine kinases. This work also establishes a new role for the SAM domain in promoting Eph receptor lateral interactions and signaling on the cell surface. [Preview Abstract] |
Friday, March 18, 2016 8:48AM - 9:00AM |
X41.00005: Dissecting the active site of a photoreceptor protein Wouter Hoff, Miwa Hara, Jie Ren, Farzaneh Moghadam, Aihua Xie, Masato Kumauchi While enzymes are quite large molecules, functionally important chemical events are often limited to a small region of the protein: the active site. The physical and chemical properties of residues at such active sites are often strongly altered compared to the same groups dissolved in water. Understanding such effects is important for unraveling the mechanisms underlying protein function and for protein engineering, but has proven challenging. Here we report on our ongoing efforts on using photoactive yellow protein (PYP), a bacterial photoreceptor, as a model system for such effects. We will report on the following questions: How many residues affect active site properties? Are these residues in direct physical contact with the active site? Can functionally important residues be recognized in the crystal structure of a protein? What structural resolution is needed to understand active sites? What spectroscopic techniques are most informative? Which weak interactions dominate active site properties? [Preview Abstract] |
Friday, March 18, 2016 9:00AM - 9:12AM |
X41.00006: Statistical mechanics of hydrophobic amino acids in aqueous solution: A joint experimental scattering and computational study Lingshuang Song, Lin Yang, Wei Huang, Jie Meng, Sichun Yang How hydrophobic amino acids interact with each other is still a fundamental question in understanding protein dynamics and folding. Here, we describe an integrative experimental-computational approach of combining x-ray solution scattering and atomistic molecular simulations to determine the molecular properties of a hydrophobic leucine amino acid in an aqueous solution. First, scattering data were acquired at a series of amino acid and salt concentrations and these scattering profiles were further used to calibrate atomistic molecular simulations via a single parameter for solute-solvent interaction. Second, these accurate data of atomistic leucine simulations were used to quantify the effective interacting potentials via a structural simplification of one-bead-per-residue and two-bead-per-residue representations. Third, comparative energetic analyses between the one-bead and two-bead representations were performed to reach a simple picture of residue-residue interactions with an accurate energy function. Taken together, this joint experimental-computational study provides critical insights into microscopic interactions of hydrophobic amino acids in solution with a profound application for studying molecular dynamics of, e.g., intrinsically disordered proteins and their folding. [Preview Abstract] |
Friday, March 18, 2016 9:12AM - 9:24AM |
X41.00007: Mapping the temperature-dependent conformational landscapes of the dynamic enzymes cyclophilin A and urease Robert Thorne, Daniel Keedy, Matthew Warkentin, James Fraser, David Moreau, Hakan Atakisi, Peter Rau Proteins populate complex, temperature-dependent ensembles of conformations that enable their function. Yet in X-ray crystallographic studies, roughly 98\% of structures have been determined at 100 K, and most refined to only a single conformation. A combination of experimental methods enabled by studies of ice formation and computational methods for mining low-density features in electron density maps have been applied to determine the evolution of the conformational landscapes of the enzymes cyclophilin A and urease between 300 K and 100 K. Minority conformations of most side chains depopulate on cooling from 300 to $\sim$200 K, below which subsequent conformational evolution is quenched. The characteristic temperatures for this depopulation are highly heterogeneous throughout each enzyme. The temperature-dependent ensemble of the active site flap in urease has also been mapped. These all-atom, site-resolved measurements and analyses rule out one interpretation of the protein-solvent glass transition, and give an alternative interpretation of a dynamical transition identified in site-averaged experiments. They demonstrate a powerful approach to structural characterization of the dynamic underpinnings of protein function. [Preview Abstract] |
Friday, March 18, 2016 9:24AM - 9:36AM |
X41.00008: Computational modeling of the side chain dihedral angle distributions of methionine using hard-sphere repulsive and short-range attractive interactions Alejandro Virrueta, Corey O'Hern, Lynne Regan Methionine (Met) is a versatile amino acid found frequently both in protein cores and at protein-protein interfaces. Thus, a complete description of the structure of Met is tantamount to a fundamental understanding of protein structure and design. In previous work, we showed that our hard-sphere dipeptide model is able to recapitulate the side chain dihedral angle distributions observed in high-resolution protein crystal structures for the 8 amino acids we have studied to date: Val, Thr, Ser, Leu, Ile, Cys, Tyr, and Phe. Using the same approach, we can predict the observed Met side chain dihedral angle distributions $P(\chi_1)$ and $P(\chi_2)$, but not $P(\chi_3)$. In this manuscript, we investigate the possible origins of the discrepancy and identify the minimal additions to the hard-sphere dipeptide model necessary to quantitatively predict $P(\chi_3)$ of Met. We find that applying a Lennard-Jones potential with weak attraction between hydrogen atoms is sufficient to achieve predictions that match the observed $\chi_3$ side chain dihedral angle probability distributions for Met, Nle, and Mse without negatively affecting our results for the 8 previously studied amino acids. [Preview Abstract] |
Friday, March 18, 2016 9:36AM - 9:48AM |
X41.00009: Model comparison in X-ray crystallography David Sivak, Nathan Babcock, Daniel Keedy, James Fraser X-ray crystallographers conventionally infer a single best-fit structure from experimental data. Recently, attention has turned to inference of multiple structures and more generally to more complex model types that improve quality of fit---yet potentially increase overfitting to experimental noise. Significant research effort has been focused on inferring the best-fit parameters within a given model type, yet comparatively little attention has been given to selection between model types. Using metrics from the statistics community, we develop a model comparison framework for statistically-rigorous inference of protein conformational heterogeneity. We compare these information criteria to conventional model comparison criteria, and we assess their utility for judging different model types on their balance between quality of fit and model parsimony. [Preview Abstract] |
Friday, March 18, 2016 9:48AM - 10:00AM |
X41.00010: Small-Angle Neutron Scattering study of the NIST mAb reference material Maria Monica Castellanos, Yun Liu, Susan Krueger, Joseph Curtis Monoclonal antibodies (mAbs) are of great interest to the biopharmaceutical industry because they can be engineered to target specific antigens. Due to their importance, the biomanufacturing initiative at NIST is developing an IgG1 mAb reference material `NIST mAb', which can be used by industry, academia, and regulatory authorities. As part of this collaborative effort, we aim at characterizing the reference material using neutron scattering techniques. We have studied the small-angle scattering profile of the NIST mAb in a histidine buffer at 0 and 150 mM NaCl. Using Monte Carlo simulations, we generate an ensemble of structures and calculate their theoretical scattering profile, which can be directly compared with experimental data. Moreover, we analyze the structure factor to understand the effect of solution conditions on the protein-protein interactions. Finally, we have measured the solution scattering of the NIST mAb, while simultaneously performing freeze/thaw cycles, in order to investigate if the solution structure was affected upon freezing. The results from neutron scattering not only support the development of the reference material, but also provide insights on its stability and guide efforts for its development under different formulations. [Preview Abstract] |
Friday, March 18, 2016 10:00AM - 10:12AM |
X41.00011: Replica-exchange Wang-Landau simulations of the H0P lattice protein model Guangjie Shi, Thomas W\"{u}st, Ying Wai Li, David P. Landau The hydrophobic-polar (HP) lattice protein model has been the subject of intensive investigation in an effort to aid our understanding of protein folding. However, the high ground state degeneracies caused by its simplification stands in contrast to the generally unique native states of natural proteins. Here we proposed a simple modification, by introducing a new type of ``neutral'' monomer, 0, i.e. neither hydrophobic nor polar, thus rendering the model more realistic without increasing the difficulties of sampling significantly\footnote{G. Shi, T. W\"{u}st, Y. W. Li and D. P. Landau J. Phys.: Conf. Ser. 640, 012017 (2015)}. With the replica exchange Wang--Landau (REWL) scheme \footnote{T. Vogel, Y. W. Li, T. W\"{u}st, and D. P. Landau, Phys. Rev. Lett., 110, 210603 (2013)} we investigated several widely studied HP proteins and their H0P counterparts. Dramatic differences in both ground state and thermodynamic properties have been found. For example, the H0P version of Crambin shows more clear two-step folding and 3 order of magnitudes less ground state degeneracy than its HP counterpart. [Preview Abstract] |
Friday, March 18, 2016 10:12AM - 10:24AM |
X41.00012: Experimental and Computational Study of Beta-Galactosidase Inhibition Anthony Cooper, Luca Larini In this study, we combine experiments and simulations to design novel inhibitors of enzymes. We aim to characterize the inhibition mechanism which we show to be dependent on the aggregation of inhibitor peptides. As a model system we chose to use $\beta $-galactosidase. We selected four peptides out of 10,000 initially screened using microarrays and that show the greatest Michaelis-Menten constant and highest solubility. Molecular dynamics simulations were performed to identify the exact mechanism of action of these peptides. We show that the positive residues, like arginine and lysine, are crucial for inhibiting enzyme activity. According to simulations, these residues are also responsible for the conformations adopted by the peptide in solution. Dynamic light scattering study revealed that the aggregation of peptides with the enzyme takes place and is responsible for inhibiting enzyme activity. [Preview Abstract] |
Friday, March 18, 2016 10:24AM - 10:36AM |
X41.00013: ABSTRACT MOVED TO M1.392 |
Friday, March 18, 2016 10:36AM - 10:48AM |
X41.00014: Dynamic switching mechanisms of a CC chemokine, CCL5 (RANTES). A simulation study. Emanuel Peter, Igor Pivkin CCL5 (RANTES) belongs to the class of pro-inflammatory chemokines which are part of the human immune-response. It is known to activate leukocytes through its associated chemokine receptor 5 (CCR5) and plays a key role in several malignancies, including HIV-1 infections and cancer. In this talk, we present our results from enhanced sampling simulations of the CCL5 (RANTES) monomer. We find that this protein can adopt 2 different conformations : a globular form, with an orthogonal alignment of the N-terminal part, and a 'cis' form, in which the N-terminus is aligned parallel to the $\beta$-strand interface. A detailed analysis of the structure reveals that each of these states is stabilized by salt-bridges along the sequence, and corresponds to a defined dihedral-geometry of the 2 disulfide bridges Cys10-34 and Cys11-50. We derive a uniform distribution of transitions from the globular form of CCL5 (RANTES), and find that each of the main conformers adopts different electrostatic patterns. [Preview Abstract] |
Friday, March 18, 2016 10:48AM - 11:00AM |
X41.00015: Using Excel To Study The Relation Between Protein Dihedral Angle Omega And Backbone Length Christopher Shew, Samari Evans, Xiuping Tao How to involve the uninitiated undergraduate students in computational biophysics research? We made use of Microsoft Excel to carry out calculations of bond lengths, bond angles and dihedral angles of proteins. Specifically, we studied protein backbone dihedral angle omega by examining how its distribution varies with the length of the backbone length. It turns out Excel is a respectable tool for this task. An ordinary current-day desktop or laptop can handle the calculations for midsized proteins in just seconds. Care has to be taken to enter the formulas for the spreadsheet column after column to minimize the computing load. [Preview Abstract] |
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