Bulletin of the American Physical Society
2009 APS March Meeting
Volume 54, Number 1
Monday–Friday, March 16–20, 2009; Pittsburgh, Pennsylvania
Session A40: Proteins: Structure and Functions I |
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Sponsoring Units: DBP Chair: Ching-Hwa Kiang, Rice University Room: 412 |
Monday, March 16, 2009 8:00AM - 8:12AM |
A40.00001: Free energy landscapes of short peptide chains using adaptively biased molecular dynamics Vadzim Karpusenka, Volodymyr Babin, Christopher Roland, Celeste Sagui We present the results of a computational study of the free energy landscapes of short polypeptide chains, as a function of several reaction coordinates meant to distinguish between several known types of helices. The free energy landscapes were calculated using the recently developed adaptively biased molecular dynamics method followed up with equilibrium ``umbrella correction'' runs. Specific polypeptides investigated include small chains of pure and mixed alanine, glutamate, leucine, lysine and methionine (all amino acids with strong helix-forming propensities), as well as glycine, proline(having a low helix forming propensities), tyrosine, serine and arginine. Our results are consistent with the existing experimental and other theoretical evidence. [Preview Abstract] |
Monday, March 16, 2009 8:12AM - 8:24AM |
A40.00002: Structural and functional allostery wiring diagrams in GroEL/GroES Riina Tehver, Jie Chen, D. Thirumalai Repeated cycling between distinct allosteric states is required for the functions of numerous biological nanomachines. Determining the specific residues that are responsible for transmitting allosteric signals is needed to understand their operation. Using structural perturbation analysis and evolutionary correlations of mutations of residues, we determine networks of key residues in molecular chaperonin GroEL and its cochaperonin GroES. GroEL is a molecular machine that rescues aggregation-prone misfolded proteins. Its functional cycle consists of a series of large-scale allosteric transitions between the T, R, R' and R'' states. The corresponding structural rearrangements facilitate substrate protein capture, refolding, and release. The networks of residues we find provide a microscopic foundation for the cooperativity of the allosteric transitions and a linkage between substrate protein binding and ATPase activity of GroEL. [Preview Abstract] |
Monday, March 16, 2009 8:24AM - 8:36AM |
A40.00003: Decoupling of Protein Dynamics from the Solvent Viscosity Sheila Khodadadi, Armistead Kathleen, Alexei Sokolov Studies show that solvent viscosity has a strong influence on protein dynamics and activity, but the detailed mechanism of the solvent-protein interactions is not fully understood. Using dielectric spectroscopy we were able to identify a protein related relaxation process of myoglobin in water-glycerol and water-sucrose solutions. We demonstrate that the rate of biochemical reaction (taken from literature$^{1})$ follows the protein related relaxation observed in dielectric spectra. Also our results reveal decoupling of protein dynamics from solvent viscosity. This finding explains the known in literature decoupling of protein activity from solvent viscosity and demonstrates direct connection between protein dynamics and its functionality. Possible microscopic mechanisms of this decoupling are discussed at the end. 1. Kleinert, T.; \textit{et al}. \textit{Biochemistry}\textbf{ 1998}, $37$, 717. [Preview Abstract] |
Monday, March 16, 2009 8:36AM - 8:48AM |
A40.00004: Phosphorylation of histone H3 Thr 118 converts nucleosomes into a higher-mass complex Justin North, Michael Poirier, Michelle Ferdinand, Jennifer Ottesen The nucleosome is the fundamental unit of DNA compaction in eukaryotes by which 147 base pairs of DNA wrap 1.7 times around a protein complex called the histone octamer. Numerous chemical modifications are found in vivo that alter octamer surface charge and shape. One such modification is phosphorylation of histone H3 residue Thr 118 located in the dyad region of the nucleosome. We find that phosphorylated H3 T118 (H3 pT118) octamer, when reconstituted with DNA of about 200bp, suppresses nucleosome formation and promotes formation of a higher-mass DNA-protein complex. Coordinately, dephosphorylation of H3 pT118 octamer by phosphatase results in reconstitution of normal nucleosomes. DNAse I foot printing reveals that while DNA contacting the octamer surface in nucleosomes is less accessible than free DNA, the entire DNA strand is equally accessible in the higher-mass complex and is digested at one-third the rate of free DNA. [Preview Abstract] |
Monday, March 16, 2009 8:48AM - 9:00AM |
A40.00005: The Role of gp120 Flexibility in Binding A.J. Rader Current treatment of the human immunodeficiency virus (HIV) focuses on delivering several drugs to to a few specific viral protein targets. A complementary antiviral therapy involves targeting the process of viral entry. Viral entry is a dynamic process which involves a series of conformational changes by the HIV envelope glycoproteins (gp120 and gp41). The extraordinary conformational flexibility, glycosylation and strain variability of these proteins complicate the development of an effective vaccine. We present results from the graph theoretical analysis of flexibility and rigidity using the Floppy Inclusion and Rigid Substructure Topography (FIRST) software for all known HIV-1 gp120 structures. Comparisons between structures using this mechanical stability and intrinsic flexibility is used to identify a consensus rigid region that might serve as drug targets in a pre-complex conformation. Furthermore, analysis of structures with various binding partners illustrates the differential partitioning of mechanical flexibility and strain. We relate these differences in mechanical stability to thermodynamic differences in binding and stabilizing mutations. [Preview Abstract] |
Monday, March 16, 2009 9:00AM - 9:12AM |
A40.00006: AP helical stability in salt solutions Eliana Asciutto, Kan Xiong, Sanford Asher, Jeffry Madura Protein dynamics depends on the environment and the inclusion of salts in the simulation of folding/unfolding becomes extremely necessary when comparing energy barriers or reaction rates with experimental results. The aim of this study is to investigate the effects of three sodium salts: $NaClO_4$,$NaCl$ and $Na_2 SO_4$ on the helical stability of AP, a mainly alanine peptide. The dependence of the peptide helical stability on the environment has been studied using Replica Exchange Molecular Dynamics (REMD) simulations, Circular Dichroism (CD) and Ultraviolet Raman Resonance Spectroscopy (UVRS) experiments. It was found that $NaClO_4$ solution strongly stabilizes the helical states and that the order in which sodium salts stabilize the peptide helical states follows a reverse Hofmeister Series ($ClO_4^- < Cl^- < SO_4^{2-})$. Another interesting result found is that $ClO_4^- $ ions are attracted to the backbone; $Cl^-$ ions are repelled while $SO_4^{2-} $ ions are attracted to the positive side chains. A thorough investigation of the ion effects on the first and second solvation water along with the Kirkwood-Buff theory for solutions allowed us to explain the physical mechanisms involved in the observed ion specific effects. [Preview Abstract] |
Monday, March 16, 2009 9:12AM - 9:24AM |
A40.00007: Computational modeling of protein folding assistance by the eukaryotic chaperonin CCT Manori Jayasinghe, George Stan Chaperonins are biological nanomachines that promote protein folding using energy derived from ATP hydrolysis. Structurally, chaperonins are large oligomeric complexes that form double-ring construct, enclosing a central cavity that serves as folding chamber. Our focus is on the substrate binding mechanisms of the Eukaryotic chaperonin CCT and Archaeal chaperonin Thermosome. We contrast our results with the annealing action of the bacterial chaperonin GroEL of \textit{E. coli.}, currently the best studied for chaperonin machinery. CCT was suggested to be more selective towards the substrate recognition where as GroEL is more promiscuous due to the hydrophobic interactions. We study the interaction of CCT with Tubulin, one of its stringent substrates. Using molecular docking and molecular dynamics simulations, we probe binding of a $\beta$tubulin peptide (205-274) to the CCT$\gamma$ apical domain. We identify a versatile binding mechanism, involving mostly hydrophobic interactions with the helical region and electrostatic interactions with the helical protrusion region. This specific substrate-protein recognition mechanism is likely to be optimized for specific substrate protein-CCT subunit pairs. [Preview Abstract] |
Monday, March 16, 2009 9:24AM - 9:36AM |
A40.00008: Substrate protein recognition mechanism of archaeal and eukaryotic chaperonins. Pooja Shrestha, Manori Jayasinghe, George Stan Chaperonins are double ring-shaped biological nanomachines that assist protein folding. Spectacular conformational changes take place within each chaperonin ring using energy derived from ATP hydrolysis. These changes result in transitions from the open to the closed ring. Substrate proteins bind to the open ring and are encapsulated within the closed ring cavity. We focus on the substrate protein recognition mechanism of archaeal and eukaryotic chaperonins. We predict substrate protein binding sites using structural and bioinformatic analyses of functional states during the chaperonin cycle. Based on large changes in solvent accessible surface area and contact maps we glean the functional role of chaperonin amino acids. During the transition between open to closed chaperonin ring, the largest change in accessible surface area of amino acids is found in helical protrusion and two helices located at the cavity opening. Our calculations suggest that the helical protrusion and two helices constitute the substrate protein binding site. [Preview Abstract] |
Monday, March 16, 2009 9:36AM - 9:48AM |
A40.00009: Terahertz Dielectric Response for Cytochrome C Yunfen He, Jing-Yin Chen, Wenjun Zheng, Andrea Markelz Previously we demonstrated a large contrast in the terahertz dielectric response between oxidized and reduced cytochrome c and associated this difference with a change in the collective structural motions associated with protein flexibility (Chen et al. Phys. Rev. E Rapid 72, 040901 (2005).) We present calculations of the terahertz dielectric response of cytochrome c as a function of oxidation state and hydration. Molecular dynamics simulations are performed to equilibriate water content. Quasiharmonic analysis and dipole-dipole correlation analysis is performed after equilibriating the system. We compare the calculated results with the measurements to determine the relative contribution of correlated motions and diffusive motions to the measured dielectric response and how these two different contributions give rise to the observed large oxidation dependence and hydration dependence. [Preview Abstract] |
Monday, March 16, 2009 9:48AM - 10:00AM |
A40.00010: Micro-Spectroscopy of Proteins and Cells at Variable Pressure in a Micro-Capillary Sang Hoon Park, Silki Arora, Alfons Schulte Combining Raman microscopy with a micro-capillary compartment enables spectroscopic studies of small amounts of biological material at variable pressure. We present experiments employing a variety of optical probes over the pressure range from atmospheric pressure to 4 kBar in a micro-capillary which uses less than 100 nanoliters of sample. We investigate pressure effects on the Raman spectrum of poly(L-glutamic acid) and proteins in solution. A shift of the amide I band in poly(L-glutamic acid) to lower frequency with pressure may suggest significant change in secondary structure towards a-helical conformation. The micro-capillary also allows to enclose living cells and to optically interrogate them through a microscope. This is demonstrated by Raman spectroscopy of individual red blood cells. [Preview Abstract] |
Monday, March 16, 2009 10:00AM - 10:12AM |
A40.00011: Cross-correlated TIRF/AFM reveals asymmetry in self-assembled Myosin filaments - a Dyck paths model of asymmetry and implications for Motility Andre Brown, Alina Hategan, Daniel Safer, Yale Goldman, Dennis Discher Myosin-II's rod-like tail drives filament assembly with a head arrangement that should generate equal and opposite contractile forces on actin -- if one assumes that the filament is a symmetric bipole. Self-assembled myosin filaments are shown here to be asymmetric in physiological buffer based on cross-correlated images from both atomic force microscopy (AFM) and total internal reflection fluorescence (TIRF). Quantitative cross-correlation of these orthogonal methods produces structural information unavailable to either method alone in showing that fluorescence intensity along the filament length is proportional to height. This implies that myosin heads form a shell around the filament axis, consistent with F-actin binding. A motor density of $\sim$50-100 heads/micron is further estimated but with an average of 32\% more motors on one half of any given filament compared to the other, regardless of length. A purely entropic pyramidal lattice model is developed and mapped onto a Dyck path problem that qualitatively captures this lack of length dependence and the distribution of filament asymmetries. Such strongly asymmetric bipoles are likely to produce an imbalanced contractile force in cells and in actin-myosin gels, and thereby contribute to motility as well as cytoskeletal tension. [Preview Abstract] |
Monday, March 16, 2009 10:12AM - 10:24AM |
A40.00012: A new view on the role of intrinsic protein disorder Jintao Liu, James Faeder, Carlos Camacho Recent studies have found that many proteins do not have stable structure by themselves, i.e., are intrinsically disordered, which challenges the conventional view that structure determines protein function and interaction. We have analyzed the Human Protein Reference Database with the VSL2 protein disorder predictor, and find that the amount of disorder in a protein is the result of evolutionary pressure: catalytic proteins interact with substrates rapidly and highly specifically and thus exhibit low levels of disorder; transcription regulators often slide along DNA, which favors flexible or disordered structures; binding proteins have affinities that depend weakly on folding stability, and thus have a broad disorder distribution. Finally, our findings suggest that sequence/structural features such as phosphotyrosine are better indicators of multiple protein-protein interactions than disorder. [Preview Abstract] |
Monday, March 16, 2009 10:24AM - 10:36AM |
A40.00013: Structure-Based Prediction of Unstable Regions in Proteins: Applications to Protein Misfolding Diseases Will Guest, Neil Cashman, Steven Plotkin Protein misfolding is a necessary step in the pathogenesis of many diseases, including Creutzfeldt-Jakob disease (CJD) and familial amyotrophic lateral sclerosis (fALS). Identifying unstable structural elements in their causative proteins elucidates the early events of misfolding and presents targets for inhibition of the disease process. An algorithm was developed to calculate the Gibbs free energy of unfolding for all sequence-contiguous regions of a protein using three methods to parameterize energy changes: a modified G\={o} model, changes in solvent-accessible surface area, and solution of the Poisson-Boltzmann equation. The entropic effects of disulfide bonds and post-translational modifications are treated analytically. It incorporates a novel method for finding local dielectric constants inside a protein to accurately handle charge effects. We have predicted the unstable parts of prion protein and superoxide dismutase 1, the proteins involved in CJD and fALS respectively, and have used these regions as epitopes to prepare antibodies that are specific to the misfolded conformation and show promise as therapeutic agents. [Preview Abstract] |
Monday, March 16, 2009 10:36AM - 10:48AM |
A40.00014: Catching the cold: Can computational modeling explain the physical mechanisms behind cold denaturation Cristiano Dias Proteins assume a unique three-dimensional structure under physiological conditions. This structure becomes gradually unstable as temperature is raised or lowered. At about 60$^{\circ}$C the ordered structure of proteins becomes unstable. This phenomenon is called denaturation and is also observed at low temperatures, around -20$^{\circ}$C. While denaturation at high temperature is well understood, the mechanism behind denaturation at low temperature, i.e. cold denaturation, is still controversial. This mechanism depends strongly on the properties of the solvent in which the protein is immersed, i.e. water. In this talk, I will discuss a simplified model for water that we have recently proposed in the literature (to be published) and a microscopic mechanism for cold denaturation (Phys. Rev. Lett. 100, 118101 (2008) ). [Preview Abstract] |
Monday, March 16, 2009 10:48AM - 11:00AM |
A40.00015: Exact analytical solution in the Extended Zwanzig Model (EZM) for linear protein denaturation Luis Olivares-Quiroz The elucidation of the physical mechanisms underlying protein's folding and unfolding in a variety of physico-chemical conditions is one of the most challenging problems faced by molecular biology and biophysics. The \textit{Extended Zwanzig Model} (EZM) is a formalism that relates protein denaturation profiles with the energy spectrum \{$E_k$\} accessible to the system. In this work, an exact analytical solution for the EZM in the case of a protein following a linear denaturation profile as function of a reactive coordinate $\mathcal{C}$ is presented. The relevance for this solution is two fold. Given the complex functional form followed by the energy spectrum \{$E_k$\} in terms of the reactive coordinates, there is a lack of analytical solutions for the MEZ even in the most simplest cases. On the other hand, it is known that most proteins exhibit a sigmoidal denaturation pattern in terms of physical variables like temperature, pressure or concentration of chemical compounds. It is shown here that the sigmoidal denaturation profile can be approximated by a sum of linear terms and therefore, an approximate solution for the general denaturation profile can be generated from a superposition of exact linear cases. [Preview Abstract] |
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