Bulletin of the American Physical Society
APS March Meeting 2014
Volume 59, Number 1
Monday–Friday, March 3–7, 2014; Denver, Colorado
Session J32: Focus Session: Physics of Proteins I |
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Chair: Donghua Zhou, Oklahoma State University Room: 708-712 |
Tuesday, March 4, 2014 2:30PM - 2:42PM |
J32.00001: Copper and Zinc Chelation as a Treatment of Alzheimer's Disease Miroslav Hodak, Jerry Bernholc Alzheimer's disease (AD) is a neurodegenerative disorder affecting millions of people in the U.S. The cause of the disease remains unknown, but amyloid-$\beta$ (A$\beta$), a short peptide, is considered causal its pathogenesis. At cellular level, AD is characterized by deposits mainly composed of A$\beta$ that also contain elevated levels of transition metals ions. Targeting metals is a promising new strategy for AD treatment, which uses moderately strong metal chelators to sequester them from A$\beta$ or the environment. PBT2 is a chelating compound that has been the most promising in clinical trials. In our work, we use computer simulations to investigate complexes of a close analog of PBT2 with Cu$^{2+}$ and Zn$^{2+}$ ions. The calculations employ KS/FD DFT method, which combines Kohn-Sham DFT with the frozen-density DFT to achieve efficient description of explicit solvent beyond the first solvation shell. Our work is based on recent experiments and examines both 1:1 and 2:1 chelator-metal stochiometries detected experimentally. The results show that copper attaches more strongly than zinc, find that 1:1 complexes involve water in the first coordination shell and determine which one of several possible 2:1 geometries is the most preferable. [Preview Abstract] |
Tuesday, March 4, 2014 2:42PM - 2:54PM |
J32.00002: Structural Transitions and Aggregation in Amyloidogenic Proteins Timothy Steckmann, Prem Chapagain, Bernard Gerstman Amyloid fibrils are a common component in many debilitating human neurological diseases such as Alzheimer's and Parkinson's. A detailed molecular-level understanding of the formation process of amyloid fibrils is crucial for developing methods to slow down or prevent these horrific diseases. Alpha-helix to beta-sheet structural transformation is commonly observed in the process of fibril formation. We performed replica-exchange molecular dynamics simulations of structural transformations in an engineered model peptide cc-beta. Several sets of simulations with different number of cc-beta monomers were considered. Conversion of alpha-helix monomers to beta strands and the aggregation of beta strand monomers into sheets were analyzed as a function of the system size. Hydrogen bond analysis was performed and the beta-aggregate structures were characterized by a nematic order parameter. [Preview Abstract] |
Tuesday, March 4, 2014 2:54PM - 3:06PM |
J32.00003: Computational stability ranking of mutated hydrophobic cores in staphylococcal nuclease and T4 lysozyme using hard-sphere and stereochemical constraints Alejandro Virrueta, Alice Zhou, Corey O'Hern, Lynne Regan Molecular dynamics methods have significantly advanced the understanding of protein folding and stability. However, current force-fields cannot accurately calculate and rank the stability of modified or \textit{de novo} proteins. One possible reason is that current force-fields use knowledge-based corrections that improve dihedral angle sampling, but do not satisfy the stereochemical constraints for amino acids. I propose the use of simple hard-sphere models for amino acids with stereochemical constraints taken from high-resolution protein crystal structures. This model can enable a correct consideration of the entropy of side-chain rotations, and may be sufficient to predict the effects of single residue mutations in the hydrophobic cores of staphylococcal nuclease and T4 lysozyme on stability changes. I will computationally count the total number of allowed side-chain conformations $\Omega $ and calculate the associated entropy, S $=$ k$_{\mathrm{B}}$ln($\Omega )$, before and after each mutation. I will then rank the stability of the mutated cores based on my computed entropy changes, and compare my results with structural and thermodynamic data published by the Stites and Matthews groups. If successful, this project will provide a novel framework for the evaluation of entropic protein stabilities, and serve as a possible tool for computational protein design. [Preview Abstract] |
Tuesday, March 4, 2014 3:06PM - 3:42PM |
J32.00004: Single-Molecule Ion Channel Conformational Dynamics in Living Cells Invited Speaker: H. Peter Lu Stochastic and inhomogeneous conformational changes regulate the function and dynamics of ion channels that are crucial for cell functions, neuronal signaling, and brain functions. Such complexity makes it difficult, if not impossible, to characterize ion channel dynamics using conventional electrical recording alone since that the measurement does not specifically interrogate the associated conformational changes but rather the consequences of the conformational changes. Recently, new technology developments on single-molecule spectroscopy, and especially, the combined approaches of using single ion channel patch-clamp electrical recording and single-molecule fluorescence imaging have provided us the capability of probing ion channel conformational changes simultaneously with the electrical single channel recording. By combining real-time single-molecule fluorescence imaging measurements with real-time single-channel electric current measurements in artificial lipid bilayers and in living cell membranes, we were able to probe single ion-channel-protein conformational changes simultaneously, and thus providing an understanding the dynamics and mechanism of ion-channel proteins at the molecular level. The function-regulating and site-specific conformational changes of ion channels are now measurable under physiological conditions in real-time, one molecule at a time. We will focus our discussion on the new development and results of real-time imaging of the dynamics of gramicidin, colicin, and NMDA receptor ion channels in lipid bilayers and living cells. Our results shed light on new perspectives of the intrinsic interplay of lipid membrane dynamics, solvation dynamics, and the ion channel functions. [Preview Abstract] |
Tuesday, March 4, 2014 3:42PM - 3:54PM |
J32.00005: Thermal response of alpha-synuclein structure with knowledge-based residue-residue interactions Peter Mirau, Barry Farmer, Ras Pandey Structure and dynamics of alpha-synuclein (140 residues) are studied via a coarse-grained Monte Carlo simulation as a function of temperature. Knowledge-based residue-residue [1] interactions are used as input to a generalized LJ potential. We analyze a number of local and global physical quantities such as residue mobility profiles, contact map, radius of gyration, structure factor, etc. We find that the radius of gyration ($R_{g})$ of the protein increases on increasing the temperature within a range. Although the thermal response of the gyration radius shifts with the type of knowledge-based interaction potential, general feature of linear response is retained. These findings are consistent with the NMR measurements [2] on the variation of the gyration radius with the temperature. Detailed analysis of structure factor reveals the thermal response of multi-scale segmental conformations.\\[4pt] [1] S. Miyazawa and R.L. Jernigan, Macromolecules 18,534 (1985); M.R. Betancourt and D. Thirumalai, Protein Sci. 2,361 (1999). \\[0pt] [2] J.R. Allison et al. JACS 131, 18314 (2009). [Preview Abstract] |
Tuesday, March 4, 2014 3:54PM - 4:06PM |
J32.00006: Simulation Model of Protein Transport and Stabilization Apichart Linhananta In a previous communication (Linhananta et al., Biophys. J., 2011, 100, 459), we reported results of a simulation model of a protein in solvents with protein-solvent contact energy parameter $\varepsilon _{ps}$, which mimics the effects of osmolytes ( $\varepsilon _{ps}>0$) and denaturants ($% \varepsilon _{ps}<0$ ). Here a model three-helix-bundle (THB) protein in solvents is confined in cylindrical cavity to mimic GroEL/ES. The interior wall is characterized by the protein-wall energy $\varepsilon _{pw}$ , and solvent-wall energy, $\varepsilon _{sw}$. Simulations found a substantial increase in the folding temperature from $T^{\ast }=4.2$, in scaled unit, for THB in vacuum, to $T^{\ast }>6.0$ for confined THB in osmolytes. The model is generalized to THB and solvents confined in two connected cylindrical segments. The bottom segment represents the interior of a GroEL/ES, with the sidewall characterized by the parameters $\varepsilon _{pw}$ and $\varepsilon _{sw}$. The upper segment represents the exterior surrounding the GroEL/ES, with periodic boundary condition on the sidewall. The protein and solvents can move through the channel connecting the two segments. Simulation data reveals new insights on the transport of unfolded proteins into GroEL/ES. [Preview Abstract] |
Tuesday, March 4, 2014 4:06PM - 4:18PM |
J32.00007: The heat released in single catalytic events locally enhances enzyme diffusion Konstantinos Tsekouras, Clement Riedel, Christian Wilson, Kambiz Hamadani, Susan Marqusee, Steve Presse, Carlos Bustamante Recent experiments have shown that some enzymes catalyzing highly exothermic reactions exhibit increased diffusion with rising substrate concentration. We present a stochastic theory linking increased enzyme diffusion to reaction rate, discuss other possible origins for diffusion coefficient increases and finally provide a mechanistic interpretation showing how the heat released by the reaction perturbs the enzyme. [Preview Abstract] |
Tuesday, March 4, 2014 4:18PM - 4:30PM |
J32.00008: Measuring Conformational Dynamics of Single Biomolecules Using Nanoscale Electronic Devices Maxim V. Akhterov, Yongki Choi, Patrick C. Sims, Tivoli J. Olsen, O. Tolga Gul, Brad L. Corso, Gregory A. Weiss, Philip G. Collins Molecular motion can be a rate-limiting step of enzyme catalysis, but motions are typically too quick to resolve with fluorescent single molecule techniques. Recently, we demonstrated a label-free technique that replaced fluorophores with nano-electronic circuits to monitor protein motions. The solid-state electronic technique used single-walled carbon nanotube (SWNT) transistors to monitor conformational motions of a single molecule of T4 lysozyme while processing its substrate, peptidoglycan. As lysozyme catalyzes the hydrolysis of glycosidic bonds, two protein domains undergo 8 {\AA} hinge bending motion that generates an electronic signal in the SWNT transistor. We describe improvements to the system that have extended our temporal resolution to 2 $\mu s$. Electronic recordings at this level of detail directly resolve not just transitions between open and closed conformations but also the durations for those transition events. Statistical analysis of many events determines transition timescales characteristic of enzyme activity and shows a high degree of variability within nominally identical chemical events. The high resolution technique can be readily applied to other complex biomolecules to gain insights into their kinetic parameters and catalytic function. [Preview Abstract] |
Tuesday, March 4, 2014 4:30PM - 4:42PM |
J32.00009: Observation of Protein Structural Vibrational Mode Sensitivity to Ligand Binding Katherine Niessen, Mengyang Xu, Edward Snell, Andrea Markelz We report the first measurements of the dependence of large-scale protein intramolecular vibrational modes on ligand binding. These collective vibrational modes in the terahertz (THz) frequency range (5-100 cm$^{-1})$ are of great interest due to their predicted relation to protein function. Our technique, Crystals Anisotropy Terahertz Microscopy (CATM), allows for room temperature, table-top measurements of the optically active intramolecular modes. CATM measurements have revealed surprisingly narrowband features [1]. CATM measurements are performed on single crystals of chicken egg-white lysozyme (CEWL) as well as CEWL bound to tri-N-acetylglucosamine (CEWL-3NAG) inhibitor. We find narrow band resonances that dramatically shift with binding. Quasiharmonic calculations are performed on CEWL and CEWL-3NAG proteins with CHARMM using normal mode analysis. The expected CATM response of the crystals is then calculated by summing over all protein orientations within the unit cell. We will compare the CATM measurements with the calculated results and discuss the changes which arise with protein-ligand binding. \\[4pt] [1] G. Acbas, K.A. Niessen, E. Snell, and A.G. Markelz, ``Optical Measurements of Long-Range Protein Structural Motions,'' Nature Communications, In Press. [Preview Abstract] |
Tuesday, March 4, 2014 4:42PM - 4:54PM |
J32.00010: Using engineered intra-molecular disulfide bonds to identify FIMs that matter Wouter Hoff, Masato Kumauchi, Eefei Chen The realization that proteins are not the static structures derived from crystallographic structure determination, but instead undergo conformational dynamics on a wide range of length- and time-scales started a novel field of research that has remained active to the present day. Protein dynamics have been shown to occur on a complex energy landscape, and can be divided into equilibrium fluctuations (EFs) and non-equilibrium functionally important motions (FIMs). Much effort has been spent on the complex task of discovering and describing such FIMs. However, if a region of a protein is found to undergo conformational changes during function, this is not sufficient to conclude that this motion is important for protein function. We use engineered intra-molecular disulfide bonds as an experimental tool to examine functionally critical conformational changes. In this approach the effect of preventing large-scale motions in a specific region of the protein by the introduction of an intramolecular covalent crosslink on protein functional dynamics is examined. We will report results of the application of this approach to photoactive yellow protein, a bacterial photosensor. [Preview Abstract] |
Tuesday, March 4, 2014 4:54PM - 5:06PM |
J32.00011: Live cell FLIP: anomalous protein diffusion and its fluctuation Minghao Guo, Martin Gruebele Macromolecular crowding in the cell modulates protein structure and stability, as well as protein diffusion and transportation in cytoplasm. This crowded environment limits the protein diffusion in a confined space and gives rise to anomalous subdiffusion at long time and distance scales. The anomalous diffusion in living cells have been sufficiently studied with fluorescence recovery after photobleaching (FRAP). However, this method focuses on local diffusion, giving too little information about the global cellular environment. Fluorescence loss in photobleaching (FLIP), though giving up details about short distance behavior, provides a better view on the larger scale of anomalous diffusion. We use this powerful tool combined with numerical simulation to study the temperature and protein conformation dependence of diffusion in living cells. We compared the different anomalous behaviors of protein diffusion between cells. The fluctuation of diffusion in cellular microenvironment is also studied. [Preview Abstract] |
Tuesday, March 4, 2014 5:06PM - 5:18PM |
J32.00012: Molecular Dynamic Study to Determine the Ammonia Conduction Mechanisms in Human RhCG and Bacterial Homoloques Ugur Akgun The transport of Ammonia is provided by Amt/MEP/Rh protein superfamily. The x-ray structures of AmtB from Escherichia coli, Rh50 from Nitrosomonas europaea, and human RhCG show only few differences on periplasmic vestibules. After more than microsecond simulation on three models, we determined the striking difference on conduction mechanism between bacterial AmtB and Human RhCG proteins. In AmtB the backbone carbonyl groups at the periplasmic vestibule direct charged ammonia to the conserved aromatic cage at the bottom of the vestibule. Furthermore, two partially stacked phenyl rings of F107 and F215, separating the periplasmic vestibule from the hydrophobic lumen, flip open and closed \textit{simultaneously }with a frequency of approximately 108 flipping events per second. During the passage from the phenyl gates charged ammonia releases its proton and becomes gas. However, the absence of an aromatic cage on Rh proteins and a strongly conserved E166 residue in the vicinity hints different conduction mechanism. Our studies confirm the conserved E166 emerges as a strong charged ammonia recruitment site for Human RhCG. The conserved phenyl gate behaves different for Rh proteins and the synchronized motion is not observed. These findings suggest a different deprotonation mechanism than bacterial AmtB. [Preview Abstract] |
Tuesday, March 4, 2014 5:18PM - 5:30PM |
J32.00013: Conformational Transition Mechanism of Adenylate Kinase: A Comparison of All-Atom Molecular Dynamics Simulation to Coarse-Grained Methods Mustafa Tekpinar, Ahmet Yildirim Adenylate kinase (ADK) performs a large conformational transition between its open and closed conformations. In this transition, order of conformational events can be investigated by molecular dynamics (MD) method. However, MD method requires large-scale computational resources and a significant amount of time to observe a full conformational transition. On the other hand, coarse-grained methods can produce transition pathways in a short amount of time with a questionable accuracy. To assess accuracy of coarse-grained methods, they need to be compared with all-atom models. Due to this reason, we produced a full conformational transition of ADK from closed state to open state by using all-atom classical molecular dynamics. This conformational transition has been compared with 7 coarse-grained methods in terms of order of conformational events. In the end, we evaluated successes and failures of each coarse-grained method. [Preview Abstract] |
Tuesday, March 4, 2014 5:30PM - 5:42PM |
J32.00014: Conformational Analysis of Single Polymer Chain by Super-resolution Fluorescence Microscopy Hiroyuki Aoki, Kazuki Mori, Akihiko Shin, Shinzaburo Ito The direct observation of individual polymer chains would provide valuable information to understand the fundamental properties of polymer materials. Fluorescence imaging is the most effective method to detect a single molecule embedded in a bulk medium; however, the imaging of the conformation of a single chain has been impossible because of the diffraction-limited spatial resolution ($\sim$ 200 nm). In the current study, we developed a super-resolution fluorescence microscopy technique, photo-activated localization microscopy (PALM), for the direct observation of the conformation of a single polymer chain. For the PALM observation, a trace amount of poly(butyl methacrylate) (PBMA) labeled by rhodamine spiroamide was dispersed in the unlabeled PBMA matrix. The conformation of the individual PBMA chain was observed in three dimensions with the lateral spatial resolution of 20 nm and the depth resolution of 50 nm. The nanometric imaging by the super-resolution technique was applied to the conformational analysis of single polymer chain under macroscopic deformation. [Preview Abstract] |
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