Bulletin of the American Physical Society
APS March Meeting 2014
Volume 59, Number 1
Monday–Friday, March 3–7, 2014; Denver, Colorado
Session L11: Focus Session: Physics of Proteins II |
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Sponsoring Units: DBIO DPOLY Chair: Corey O'Hern, Yale University Room: 203 |
Wednesday, March 5, 2014 8:00AM - 8:12AM |
L11.00001: Thermal stability and folding kinetics analysis of intrinsically disordered protein, securin Chia-Ching Chang, Hsueh-Liang Chu, Li-Ping Ho Lacking a stable tertiary structure, intrinsically disordered proteins (IDPs) possess particular functions in cell regulation, signaling, and controlling pathways. The study of their unique structure features, thermal stabilities, and folding kinetics is intriguing. In this study, an identified IDP, securin, was used as a model protein. By using a quasi-static five-step (on-path) folding process, the function of securin was restored and analyzed by isothermal titration calorimetry. Fluorescence spectroscopy and particle size analysis indicated that securin possessed a compact hydrophobic core and particle size. The glass transition of securin was characterized using differential scanning microcalorimetry. Furthermore, the folding/unfolding rates (k$_{\mathrm{obs}}$) of securin were undetectable, implying that the folding/unfolding rate is very fast and that the conformation of securin is sensitive to solvent environment change. Therefore, securin may fold properly under specific physiological conditions. In summary, the thermal glass transition behavior and undetectable k$_{\mathrm{obs}}$ of folding/unfolding reactions may be two of the indices of IDP. [Preview Abstract] |
Wednesday, March 5, 2014 8:12AM - 8:24AM |
L11.00002: Predicting the conformational preferences of proteins using a physics-based free energy method Arijit Roy, Alberto Perez, Justin Maccallum, Ken A. Dill Protein molecules often undergo conformational changes. In order to get insights about the forces that drive such changes, it would be useful to have a method that computes the per-residue contributions to the conversion free energy. Here, we will describe the ``Confine-Convert-Release'' (CCR) method which is applicable to large conformational changes of proteins. CCR correctly predicts the stable states of several ``chameleon'' sequences that have previously been challenging for molecular simulations. CCR can often discriminate better from worse predictions of native protein models in CASP. We will show how the total conversion free energies can be parsed into per-residue free-energy components. Such parsing gives insights into which amino acids are most responsible for given transformations. For example, we are able to ``reverse-engineer'' the known design principles of the chameleon proteins. This opens up the possibility for systematic improvements in structure-prediction scoring functions, in the design of protein conformational switches, and in interpreting protein mechanisms at the amino-acid level. [Preview Abstract] |
Wednesday, March 5, 2014 8:24AM - 8:36AM |
L11.00003: Investigating the mechanisms leading to protein aggregation Ruth McNamara, Jennifer J. McManus The formation of protein aggregates is a feature of several diseases and is a problem during the manufacture of biopharmaceutical and protein based food products. During processing, stability may become compromised leading to the condensation of proteins to form non-native aggregates. The aim of this work is to induce aggregation on model proteins by the imposition of a particular stress to evaluate the extent of aggregation and to assess the degree of structural change to the protein. Aggregation of two proteins, lysozyme and bovine serum albumin has been induced by several mechanisms. Using various techniques (electrophoresis, HPLC, spectroscopic analysis, and microscopic techniques) both the level of aggregation extent of protein unfolding has been investigated for a range of solution conditions. Our results show that the amount of aggregation depends strongly on the mechanism by which non-native aggregation proceeds, and within each mechanism, solution conditions are an important factor. With the exception of aggregation by self-association (which is concentration dependent), the appearance of aggregation is driven by structural changes induced by the applied stress (heat, chemical denaturant, oxidation or contact with a surface). [Preview Abstract] |
Wednesday, March 5, 2014 8:36AM - 9:12AM |
L11.00004: Novel insights into protein signaling by high-resolution structural biology Invited Speaker: Ilme Schlichting |
Wednesday, March 5, 2014 9:12AM - 9:24AM |
L11.00005: Bioinformatic prediction and in vivo validation of residue-residue interactions in human proteins Daniel Jordan, Erica Davis, Nicholas Katsanis, Shamil Sunyaev Identifying residue-residue interactions in protein molecules is important for understanding both protein structure and function in the context of evolutionary dynamics and medical genetics. Such interactions can be difficult to predict using existing empirical or physical potentials, especially when residues are far from each other in sequence space. Using a multiple sequence alignment of 46 diverse vertebrate species we explore the space of allowed sequences for orthologous protein families. Amino acid changes that are known to damage protein function allow us to identify specific changes that are likely to have interacting partners. We fit the parameters of the continuous-time Markov process used in the alignment to conclude that these interactions are primarily pairwise, rather than higher order. Candidates for sites under pairwise epistasis are predicted, which can then be tested by experiment. We report the results of an initial round of \emph{in vivo} experiments in a zebrafish model that verify the presence of multiple pairwise interactions predicted by our model. These experimentally validated interactions are novel, distant in sequence, and are not readily explained by known biochemical or biophysical features. [Preview Abstract] |
Wednesday, March 5, 2014 9:24AM - 9:36AM |
L11.00006: Study on the Dynamics of Influenza Hemagglutinin Based on Energy Landscape Theory Xingcheng Lin, Nathanial Eddy, Jeffrey Noel, Paul Whitford, Jianpeng Ma, Jose Onuchic Hemagglutinin (HA2), a homotrimeric influenza surface protein crucial for membrane fusion, undergoes an drastic structural rearrangement during viral invasion of the host. X-ray crystallography shows that the pre- and post-fusion configurations have largely disparate secondary, tertiary and quaternary structures. Simulations allow us to explore the time-dependent high resolution structural information and function of HA2 dynamics. Here we use an approach based on energy landscape theory that combines the native information from both the starting and end points. Our simulation shows two key events in the conformational transition of HA2: The extension of its fusion peptides away from the viral membrane and the melting of its globular C-terminal portion. The similar timescale and a kinetic competition between these two events lead to two main pathways and generic kinetic intermediates during this transition. Through considering the biological context of HA, we test perturbations of the baseline model that are useful in understanding the robustness of our predictions and how they translate into the function of HA. The all-atom explicit solvent simulation is performed and convince the cracking phenomenon at the start of this protein dynamics. [Preview Abstract] |
Wednesday, March 5, 2014 9:36AM - 9:48AM |
L11.00007: Investigation of protein fluctuations via Anisotropic Network Model and Molecular Dynamics Osman B. Okan, Deniz Turgut, Aravind Rammohan, Angel E. Garcia, Rahmi Ozisik We use Anisotropic Network Model (ANM) and compare its protein fluctuation predictions against molecular dynamics (MD) simulations and experimental findings for 210 globular proteins. The ANM results are analyzed using bond orientational order (BOO) parameters. We show that BOO parameters could be reformulated as a sum of contact density and geometrical (distribution of contacts in space) components. This reformulation of BOO makes it possible to investigate the role of each individual component separately, and identify cut--off ranges where each component dominates protein fluctuations. Our results indicate that the widely accepted correlation between mean squared displacements (MSDs) and inverse contact density is valid for ANM within the cut-off range of 10--15 {\AA}. We show that the two components of the BOO dominate protein fluctuations at different length scales: contact density at small length scales and geometric distribution of residues at length scales comparable to the protein size. It is also shown that the relationship between MSD and contact density is firmly rooted in BOO, and is rendered possible with a unique distribution of residues that nullifies the average geometric component's contribution to the BOO within the 10$-$15 {\AA} cut-off.\textunderscore \textunderscore [Preview Abstract] |
Wednesday, March 5, 2014 9:48AM - 10:00AM |
L11.00008: Ensemble Activation of G-Protein$-$Coupled Receptors Revealed by Small-Angle Neutron Scattering Xiang-qiang Chu, Suchithranga Perera, Utsab Shrestha, Udeep Chawla, Andrey Struts, Shuo Qian, Michael Brown Rhodopsin is a G-protein$-$coupled receptor (GPCR) involved in visual light perception and occurs naturally in a membrane lipid environment. Rhodopsin photoactivation yields \textit{cis-trans} isomerization of retinal giving equilibrium between inactive Meta-I and active Meta-II states. Does photoactivation lead to a single Meta-II conformation, or do substates exist as described by an ensemble-activation mechanism (EAM)? We use small-angle neutron scattering (SANS) to investigate conformational changes in rhodopsin-detergent and rhodopsin-lipid complexes upon photoactivation. Meta-I state is stabilized in CHAPS-solubilized rhodopsin, while Meta-II is trapped in DDM-solubilized rhodopsin. SANS data are acquired from 80{\%} D$_{2}$O solutions and at contrast-matching points for both DDM and CHAPS samples. Our experiments demonstrate that for detergent-solubilized rhodopsin, SANS with contrast variation can detect structural differences between the rhodopsin dark-state, Meta-I, Meta-II, and ligand-free opsin states. Dark-state rhodopsin has more conformational flexibility in DDM micelles compared to CHAPS, which is consistent with an ensemble of activated Meta-II states. Furthermore, time-resolved SANS enables study of the time-dependent structural transitions between Meta-I and Meta-II, which is crucial to understanding the ensemble-based activation. [Preview Abstract] |
Wednesday, March 5, 2014 10:00AM - 10:12AM |
L11.00009: Conformational entropic maps of functional coupling domains in GPCR activation: A case study with beta2 adrenergic receptor Fan Liu, Ravinder Abrol, William Goddard III, Dennis Dougherty Entropic effect in GPCR activation is poorly understood. Based on the recent solved structures, researchers in the GPCR structural biology field have proposed several ``local activating switches'' that consisted of a few number of conserved residues, but have long ignored the collective dynamical effect (conformational entropy) of a domain comprised of an ensemble of residues. A new paradigm has been proposed recently that a GPCR can be viewed as a composition of several functional coupling domains, each of which undergoes order-to-disorder or disorder-to-order transitions upon activation. Here we identified and studied these functional coupling domains by comparing the local entropy changes of each residue between the inactive and active states of the $\beta $2 adrenergic receptor from computational simulation. We found that agonist and G-protein binding increases the heterogeneity of the entropy distribution in the receptor. This new activation paradigm and computational entropy analysis scheme provides novel ways to design functionally modified mutant and identify new allosteric sites for GPCRs. [Preview Abstract] |
Wednesday, March 5, 2014 10:12AM - 10:24AM |
L11.00010: A theory for protein dynamics: Global anisotropy and a normal mode approach to local complexity Jeremy Copperman, Pablo Romano, Marina Guenza We propose a novel Langevin equation description for the dynamics of biological macromolecules by projecting the solvent and all atomic degrees of freedom onto a set of coarse-grained sites at the single residue level. We utilize a multi-scale approach where molecular dynamic simulations are performed to obtain equilibrium structural correlations input to a modified Rouse-Zimm description which can be solved analytically. The normal mode solution provides a minimal basis set to account for important properties of biological polymers such as the anisotropic global structure, and internal motion on a complex free-energy surface. This multi-scale modeling method predicts the dynamics of both global rotational diffusion and constrained internal motion from the picosecond to the nanosecond regime, and is quantitative when compared to both simulation trajectory and NMR relaxation times. Utilizing non-equilibrium sampling techniques and an explicit treatment of the free-energy barriers in the mode coordinates, the model is extended to include biologically important fluctuations in the microsecond regime, such as bubble and fork formation in nucleic acids, and protein domain motion. [Preview Abstract] |
Wednesday, March 5, 2014 10:24AM - 11:00AM |
L11.00011: TBD Invited Speaker: Dongping Zhong |
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