Bulletin of the American Physical Society
APS March Meeting 2013
Volume 58, Number 1
Monday–Friday, March 18–22, 2013; Baltimore, Maryland
Session J45: Focus Session: Physics of Proteins II |
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Sponsoring Units: DBIO Chair: Wouter Hoff, Oklahoma State University Room: Hilton Baltimore Holiday Ballroom 4 |
Tuesday, March 19, 2013 2:30PM - 2:42PM |
J45.00001: Probing Single-Molecule Protein Conformational Folding-Unfolding Dynamics: The multiple-State and Multiple-Channel Energy Landscape H. Peter Lu, Zhijiang Wang, Yufan He The folding-unfolding dynamics of protein provides an important understanding of the protein conformational dynamics and functions. We have used single-molecule fluorescence resonance energy transfer combined with statistical data analysis to characterize enzyme and signaling protein fundamental conformational dynamics of Calmodulin (CaM) and kinase (6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase, HPPK). The concentration dependence of FRET efficiency of GdmCl indicates the unfolding conformational transition of the proteins. At 2M of denaturant solvent, the majority of the HPPK and CaM protein molecules are under fluctuating folding-unfolding conformational changes, spending about half time in their native state and half time in their unfolded state. We obtained the fluctuation rates from the autocorrelation function analyses of the protein conformational fluctuation trajectories, and we have identified multiple intermediate states involving in bunched time dynamics and the related energy landscape. We had also analyzed the protein folding-unfolding pathways using detailed balance theoretical model analysis in order to understand the complex multiple-state and multiple-channel protein dynamics. [Preview Abstract] |
Tuesday, March 19, 2013 2:42PM - 2:54PM |
J45.00002: Thermodynamics and kinetics of apoazurin folding under macromolecular crowding effect and chemical interference Fabio Zegarra, Margaret Cheung Proteins fold in a cellular milieu crowded by different kinds of macromolecules. They exert volume exclusion impacting protein folding processes in vivo. Folding processes, however, has been studied by chemical denaturation under in vitro conditions. The impact of the two factors as an attempt to advance the understanding of folding mechanism in vivo is not understood. Here, we investigate the folding mechanisms of apoazurin affected by the macromolecular crowding and chemical interference by using coarse-grained molecular simulations. Crowding agents are modeled as hard-spheres and the chemical denaturation effects are implemented into an energy function of the side chain and backbone interactions. Protein folding stability, mechanism, and kinetics rates of apoazurin under chemical interference and macromolecular crowding conditions are being investigated. [Preview Abstract] |
Tuesday, March 19, 2013 2:54PM - 3:06PM |
J45.00003: Using Electronic Properties of Adamantane Derivatives to Analyze their Ion Channel Interactions: Implications for Alzheimer's Disease Jason Bonacum The derivatives of adamantane, which is a cage-like diamondoid structure, can be used as pharmaceuticals for the treatment of various diseases and disorders such as Alzheimer's disease. These drugs interact with ion channels, and they act by electronically and physically hindering the ion transport. The electronic properties of each compound influence the location and level of ion channel hindrance, and the specific use of each compound depends on the functional groups that are attached to the adamantane base chain. Computational analysis and molecular simulations of these different derivatives and the ion channels can provide useful insight into the effect that the functional groups have on the properties of the compounds. Using this information, conclusions can be made about the pharmaceutical mechanisms, as well as how to improve them or create new beneficial compounds. Focusing on the electronic properties, such as the dipole moments of the derivatives and amino acids in the ion channels, can provide more efficient predictions of how these drugs work and how they can be enhanced. [Preview Abstract] |
Tuesday, March 19, 2013 3:06PM - 3:42PM |
J45.00004: A scoring framework for predicting protein structures Invited Speaker: Xiaoqin Zou We have developed a statistical mechanics-based iterative method to extract statistical atomic interaction potentials from known, non-redundant protein structures. Our method circumvents the long-standing reference state problem in deriving traditional knowledge-based scoring functions, by using rapid iterations through a physical, global convergence function. The rapid convergence of this physics-based method, unlike other parameter optimization methods, warrants the feasibility of deriving distance-dependent, all-atom statistical potentials to keep the scoring accuracy. The derived potentials, referred to as ITScore/Pro, have been validated using three diverse benchmarks: the high-resolution decoy set, the AMBER benchmark decoy set, and the CASP8 decoy set. Significant improvement in performance has been achieved. Finally, comparisons between the potentials of our model and potentials of a knowledge-based scoring function with a randomized reference state have revealed the reason for the better performance of our scoring function, which could provide useful insight into the development of other physical scoring functions. The potentials developed in the present study are generally applicable for structural selection in protein structure prediction. [Preview Abstract] |
Tuesday, March 19, 2013 3:42PM - 3:54PM |
J45.00005: Structure of a protein (H2AX): a comparative study with knowledge-based interactions Miriam Fritsche, Dieter Heermann, Barry Farmer, Ras Pandey The structural and conformational properties of the histone protein H2AX (with143 residues) is studied by a coarse-grained model as a function of temperature (T). Three knowledge-based phenomenological interactions (MJ [1], BT [2], and BFKV [3]) are used as input to a generalized Lennard-Jones potential for residue-residue interactions. Large-scale Monte Carlo simulations are performed to identify similarity and differences in the equilibrium structures with these potentials. Multi-scale structures of the protein are examined by a detailed analysis of their structure functions. We find that the radius of gyration ($R_{g})$ of H2AX depends non-monotonically on temperature with a maximum at a characteristic value $T_{c}$, a common feature to each interaction. The characteristic temperature and the range of non-monotonic thermal response and decay pattern are, however, sensitive to interactions. A comparison of the structural properties emerging from three potentials will be presented in this talk. \\[4pt] [1] S. Miyazawa and R.L. Jernigan, Macromolecules 18, 534 (1985).\\[0pt] [2] M.R. Betancourt and D. Thirumalai, Protein Sci. 2, 361 (1999).\\[0pt] [3] U. Bastolla et al. Proteins 44, 79 (2001). [Preview Abstract] |
Tuesday, March 19, 2013 3:54PM - 4:06PM |
J45.00006: Investigation of phonon-like excitation in hydrated protein powders by neutron scattering Xiang-qiang (Rosie) Chu, Eugene Mamontov, Hugh O'Neill, Qiu Zhang, Alexander Kolesnikov Detecting the phonon dispersion relations in proteins is essential for understanding the intra-protein dynamical behavior. Such study has been attempted by X-ray in recent years [1,2]. However, for such detections, neutrons have significant advantages in resolution and time-efficiency compare to X-rays. Traditionally the collective motions of atoms in protein molecules are hard to detect using neutrons, because of high incoherent scattering background from intrinsic hydrogen atoms in the protein molecules. The recent availability of a fully deuterated green fluorescent protein (GFP) synthesized by the Bio-deuteration Lab at ORNL opens new possibilities to probe collective excitations in proteins using inelastic neutron scattering. Using a direct time-of-flight Fermi chopper neutron spectrometer, we obtained a full map of the meV phonon-like excitations in the fully deuterated protein. The Q range of the observed excitations corresponds to the length scale close to the size of the secondary structures of proteins and reflects the collective intra-protein motions. Our results show that hydration of GFP seems to harden, not soften, the collective motions. This result is counterintuitive but in agreement with the observations by previous neutron scattering experiments [3].\\[4pt] [1] PRL 101, 135501 (2008).\\[0pt] [2] Soft Matter 7, 9848 (2011).\\[0pt] [3] J. Phys. Chem. B 113, 5001 (2009). [Preview Abstract] |
Tuesday, March 19, 2013 4:06PM - 4:18PM |
J45.00007: Biological Signaling: the Role of ``Electrostatic Epicenter'' in ``Protein Quake'' and Receptor Activation Aihua Xie, Sandip Kaledhonkar, Zhouyang Kang, Johnny Hendriks, Klaas Hellingwerf Activation of a receptor protein during biological signaling is often characterized by a two state model: a receptor state (also called ``off state'') for detection of a stimuli, and a signaling state (``on state'') for signal relay. Receptor activation is a process that a receptor protein is structurally transformed from its receptor state to its signaling state through substantial conformational changes that are recognizable by its downstream signal relay partner. What are the structural and energetic origins for receptor activation in biological signaling? We report extensive evidence that further support the role of ``electrostatic epicenter'' in driving ``protein quake'' and receptor activation. Photoactive yellow protein (PYP), a bacterial blue light photoreceptor protein for the negative phototaxis of a salt loving \textit{Halorhodospira halophia}, is employed as a model system in this study. We will discuss potential applications of this receptor activation mechanism to other receptor proteins, including B-RAF receptor protein that is associated with many cancers. [Preview Abstract] |
Tuesday, March 19, 2013 4:18PM - 4:30PM |
J45.00008: Fluctuation-allosteric regulation of protein function: Continuum elastic model and its geometrical implications Michael S. Dimitriyev, Paul M. Goldbart, T.C.B. McLeish In many proteins, function is strongly modified by the binding of some small ligand to the protein surface. We address the issue of {\it fluctuation\/} allostery, in which thermal motion of the protein medium far from the binding site is a key factor in determining the activity of the protein (i.e., the strength with which it functions). We develop a simple, coarse-grained model in which the protein is viewed as a homogeneous, isotropic, elastic continuum of specified shape, and the binding of the ligand is regarded as a small alteration of this shape. We construct a perturbative approach to the response of the thermal fluctuations to a shape-alteration as a diagnostic of the impact on protein activity that ligand binding causes. At leading order in the size of the ligand, we show how this response is determined via familiar geometrical properties of the ligand shape. Thus, we find that there are \lq\lq sweet spots\rq\rq\ for ligand binding---determined by the overall shape of the protein and location of its active site---for which the effects of ligand binding are qualitatively enhanced. To simplify the analysis whilst retaining the essential geometrical ideas, we present results for the case of a scalar field rather than the true vector displacement field of elasticity. [Preview Abstract] |
Tuesday, March 19, 2013 4:30PM - 4:42PM |
J45.00009: Predicting Allostery Wiring Diagrams within Motor Proteins Riina Tehver Motor proteins are intricate molecular machines that make use of allostery as a basis of their function. Fundamental questions in trying to understand the operational mechanism of the motors is, therefore, how allostery communicated is within the proteins, what are the pathways that transmit allosteric signals, how to model and predict them. We have proposed a normal-mode analysis based perturbation model that predicts the pathways based on the structure and chemical composition of the molecules. We use the model to investigate allosteric pathways (allostery wiring diagrams) within motor proteins myosin V and VI. [Preview Abstract] |
Tuesday, March 19, 2013 4:42PM - 4:54PM |
J45.00010: Direct evidence on the force-stabilized calcium binding of the gelsolin G6 domain Yi Cao, Chunmei Lv, Xiang Gao, Meng Qin, Wei Wang Many proteins are subjected to forces in vivo. However, how force controls the structure, ligand binding and function has only been studied recently with the invention of single molecule force spectroscopy techniques. Generally, force will destabilize the native conformation of a protein and decrease its affinity to ligands. Here we show, for the first time, that force can also increase the ligand binding affinity. We used single molecule force spectroscopy by atomic force microscopy (AFM) to study the effect of calcium binding on the unfolding of the G6 domain of gelsolin. We found that at saturated calcium concentration, the unfolding forces of G6 are $\sim$ 40 pN, which are significantly higher than those of apo G6 of $\sim$ 20 pN. At intermediate calcium concentrations, the unfolding forces show a unimodal distribution, indicating fast inter-conversion rate between apo and holo G6. More strikingly, we found that if the binding constant of G6 is independent of force, the predicted unfolding forces based on the kinetic parameters obtained from apo and holo G6 are significantly lower than the experimentally obtained ones. To reconcile such discrepancy, we proposed a new model, in which we considered that the binding affinity of calcium to G6 is also force dependent. Fitting this model to experimental data clearly indicates that G6 has much higher calcium binding affinity at higher forces. We proposed that such a special force stabilized calcium binding may be important for the function of gelsolin in vivo. [Preview Abstract] |
Tuesday, March 19, 2013 4:54PM - 5:06PM |
J45.00011: THz Microscopy of Anisotropy and Correlated Motions in Protein Crystals Katherine Niessen, Gheorghe Acbas, Edward Snell, Andrea Markelz We introduce a new technique, Crystal Anisotropy Terahertz Microscopy (CATM) which can directly measure correlated intra-molecular protein vibrations. The terahertz (THz) frequency range (5-100 cm$^{\mathrm{-1}})$ corresponds to global correlated protein motions, proposed to be essential to protein function [1, 2]. CATM accesses these motions by removal of the relaxational background of the solvent and residue side chain librational motions. We demonstrate narrowband features in the anisotropic absorbance for hen egg-white lysozyme (HEWL) single crystals as well as HEWL with triacetylglucosamine (HEWL-3NAG) inhibitor single crystals. The most prominent features for the HEWL crystals appear at 45 cm$^{\mathrm{-1}}$, 69 cm$^{\mathrm{-1}}$, and 78 cm$^{\mathrm{-1}}$ and the strength of the absorption varies with crystal orientation relative to the THz polarization. Calculations show similar anisotropic features, suggesting specific correlated mode identification is possible. 1. Hammes-Schiffer, S. and S.J. Benkovic, Relating Protein Motion to Catalysis. Annu. Rev. Biochem., 2006. 75: p. 519-41. 2. Henzler-Wildman, K.A., et al., Intrinsic motions along an enzymatic reaction trajectory. Nature, 2007. 450(7171): p. 838-U13. [Preview Abstract] |
Tuesday, March 19, 2013 5:06PM - 5:18PM |
J45.00012: Intrinsic Mean Square Displacement in Lysozyme Derya Vural, Henry R. Glyde, Liang Hong The internal dynamics of proteins is the essential interest of biophysics. The mean square displacement (MSD) of hydrogen in proteins and its associated hydration water is obtained by molecular dynamic (MD) simulation. The MSD as currently determined depends on the time of the MD simulation. A method is proposed in this paper to obtain the intrinsic MSD $\langle r^2\rangle$ of hydrogen in the proteins. The intrinsic MSD is independent of the simulation time and defined as the infinite time value of calculated MSD that appears in the Debye-Waller factor. The method consists of fitting a model to the incoherent intermediate scattering function. The model contains the intrinsic MSD and a rate constant characterizing the motions of H in the protein. The method is illustrated by obtaining the intrinsic MSD $\langle r^2\rangle$ of lysozyme in $100$ ns and $1$ $\mu$s MD simulations. [Preview Abstract] |
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