Bulletin of the American Physical Society
2008 APS March Meeting
Volume 53, Number 2
Monday–Friday, March 10–14, 2008; New Orleans, Louisiana
Session U18: Focus Session: Polymer Collapse and Protein Folding |
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Sponsoring Units: GSNP DPOLY Chair: Tom Truskett, University of Texas at Austin Room: Morial Convention Center 210 |
Thursday, March 13, 2008 8:00AM - 8:36AM |
U18.00001: Folding peptides and proteins with all-atom physics: methods and applications Invited Speaker: Computational methods offer powerful tools for investigating proteins and peptides at the molecular-level; however, it has proven challenging to reproduce the long time scale folding processes of these molecules at a level that is both faithful to the atomic driving forces and attainable with modern commodity cluster computing. Alternatively, the past decade has seen significant progress in using bioinformatics-based approaches to infer the three dimensional native structures of proteins, drawing upon extensive knowledge databases of known protein structures [1]. These methods work remarkably well when a homologous protein can be found to provide a structural template for a candidate sequence. However, in cases where homology to database proteins is low, where the folding pathway is of interest, or where conformational flexibility is substantial---as in many emerging protein and peptide technologies---bioinformatics methods perform poorly. There is therefore great interest in seeing purely physics-based approaches succeed. We discuss a purely physics-based, database-free folding method, relying on proper thermal sampling (replica exchange molecular dynamics) and molecular potential energy functions. In order to surmount the tremendous computational demands of all-atom folding simulations, our approach implements a conformational search strategy based on a putative protein folding mechanism called zipping and assembly [2-4]. That is, we explicitly seek out potential folding pathways inferred from short simulations, and iteratively pursue all such routes by coaxing a polypeptide chain along them. The method is called the Zipping and Assembly Method (ZAM) and it works in two parts: (1) the full polypeptide chain is broken into small fragments that are first simulated independently and then successively re-assembled into larger segments with further sampling, and (2) consistently stable structure in fragments is detected and locked into place, in order to avoid re-sampling those degrees of freedom in subsequent steps. ZAM pursues all potential folding routes it finds, which may be mutually exclusive, and it ranks these by calculating free energies along the way. Importantly, it gives full conformational ensembles and folding pathways, features not captured by bioinformatics approaches. We also discuss ways in which the structural ensembles and folding pathways of ZAM can facilitate the rational design of peptide technologies. In particular, we examine the coupling of ZAM-produced structures with coarse-grained theories of transport and association, in order to model the interactions of peptides with membranes (for insertion processes), proteins (for binding processes), and other peptides (for aggregation processes). Importantly, this approach is able to capture highly sequence-specific effects due to the atomistic nature of the ZAM folding simulations, providing a predictive tool for targeted sequence mutations. 1. J. Moult, \textit{A decade of CASP: progress, bottlenecks and prognosis in protein structure prediction,} Curr. Opin. Struct. Biol. \textbf{15, }(2005). 2. K.M. Fiebig and K.A. Dill, \textit{Protein core assembly processes,} J. Chem. Phys. \textbf{98, }(1993). 3. S.B. Ozkan, G.H.A. Wu, J.D. Chodera, and K.A. Dill, \textit{Protein folding by zipping and assembly,} Proc. Natl. Acad. Sci. U. S. A. \textbf{104, }(2007). 4. M.S. Shell, S.B. Ozkan, V.A. Voelz, G.H.A. Wu, and K. Dill, \textit{Can molecular physics predict the native structures of globular proteins?,} \textit{under review}\textbf{, }(2007). [Preview Abstract] |
Thursday, March 13, 2008 8:36AM - 8:48AM |
U18.00002: Studies of Protein Folding in Non-Funeled Free Energy Landscapes Corey O'Hern, Gregg Lois, Jerzy Blawzdziewicz A theoretical framework is developed to understand the dynamics of protein folding. The key insight is that the search for the optimal conformation of the protein is influenced by the rate at which external parameters are adjusted to induce folding. A theory based on this insight predicts that (1) proteins with non-funneled free energy landscapes can fold reliably, (2) reliable folding can occur in equilibrium or out-of-equilibrium, and (3) reliable folding only occurs when the quench rate is below a limiting value, which can be calculated from measurements of the free energy. We test these predictions against numerical simulations of heteropolymers with hydrophobic and hydrophilic interactions and a single energy scale. [Preview Abstract] |
Thursday, March 13, 2008 8:48AM - 9:00AM |
U18.00003: Exploring HP protein models using Wang-Landau sampling Thomas Wuest, David P. Landau The hydrophobic-polar (HP) protein model has become a standard in assessing the efficiency of computational methods for protein structure prediction as well as for exploring the statistical physics of protein folding in general. Numerous methods have been proposed to address the challenges of finding minimal energy conformations within the rough energy landscape of this lattice heteropolymer model. However, only a few studies have been dedicated to the more revealing - but also more demanding - problem of estimating the density of states which allows access to thermodynamic properties of a system at any temperature. Here, we show that Wang-Landau sampling, in connection with a suitable move set (``pull moves''), provides a powerful route for the ground state search and the precise determination of the density of states for HP sequences (with up to 100 monomers) in both, two and three dimensions. Our procedure possesses an intrinsic simplicity and overcomes the inevitable limitations inherent in other more tailored approaches. The main advantage lies in its general applicability to a broad range of lattice protein models that go beyond the scope of the HP model. [Preview Abstract] |
Thursday, March 13, 2008 9:00AM - 9:12AM |
U18.00004: ABSTRACT WITHDRAWN |
Thursday, March 13, 2008 9:12AM - 9:24AM |
U18.00005: Resolution of the unfolded state. Gregory Beaucage The unfolded states in proteins and nucleic acids remain weakly understood despite their importance to protein folding; misfolding diseases (Parkinson's {\&} Alzheimer's); natively unfolded proteins ($\sim $ 30{\%} of eukaryotic proteins); and to understanding ribozymes. Research has been hindered by the inability to quantify the residual (native) structure present in an unfolded protein or nucleic acid. Here, a scaling model is proposed to quantify the \textit{degree of folding} and the unfolded state (Beaucage, 2004, 2007). The model takes a global view of protein structure and can be applied to a number of analytic methods and to simulations. Three examples are given of application to small-angle scattering from pressure induced unfolding of SNase (Panick, 1998), from acid unfolded Cyt c (Kataoka, 1993) and from folding of \textit{Azoarcus} ribozyme (Perez-Salas, 2004). These examples quantitatively show 3 characteristic unfolded states for proteins, the statistical nature of a folding pathway and the relationship between extent of folding and chain size during folding for charge driven folding in RNA. Beaucage, G., \textit{Biophys. J.}, in press (2007). Beaucage, G., \textit{Phys. Rev. E}. \textbf{70}, 031401 (2004). Kataoka, M., Y. Hagihara, K. Mihara, Y. Goto \textit{J. Mol. Biol.} \textbf{229}, 591 (1993). Panick, G., R. Malessa, R. Winter, G. Rapp, K. J. Frye, C. A. Royer \textit{J. Mol. Biol.} \textbf{275}, 389 (1998). Perez-Salas U. A., P. Rangan, S. Krueger, R. M. Briber, D. Thirumalai, S. A. Woodson, \textit{Biochemistry} \textbf{43} 1746 (2004). [Preview Abstract] |
Thursday, March 13, 2008 9:24AM - 9:36AM |
U18.00006: Crowding Effects on the Thermodynamics of Apoflavodoxin Folding. Dirar Al Homouz The thermodynamics of folding in Apoflavodoxin protein are studied using coarse-grained molecular dynamics simulations as a function of volume fraction of crowding agents. The stability of the folded state is enhanced in the presence of crowding agents as can be seen from the free energy diagrams. The changes in the transition state ensemble are analyzed under different crowding conditions. [Preview Abstract] |
Thursday, March 13, 2008 9:36AM - 9:48AM |
U18.00007: Protein Folding Simulation of Mutant Go Models of the Wild-Type Trp-cage Protein Apichart Linhananta, Junmin Liu For the past three decades, Go models of protein folding have played important roles in the understanding of how proteins fold from random conformations to their unique native structures. Unfortunately Go models reliance on known NMR or x-ray structures to construct Go interaction potentials severely limit their predictive powers. In this work, we introduce a novel method for constructing Go interaction potentials of mutant proteins based on Go interaction potentials of wild type proteins. As a template we employ the all-atom Go model of the 20-residue Trp-cage protein (A. Linhananta, J. Boer and I. MacKay, J. Chem. Phys., 2005, 122, 114901) as the wild type Go model. Trp-cage mutants are constructed by replacing a Trp-cage residue with a different residue. In particular the Pro-12 residue of the Trp-cage is substituted by Trp-12 to produce the Trp2-cage mutant, whose native structure is not yet known. Monte Carlo simulations, using CHARMM force fields, are performed to determine the ground-state structure mutant. The resulting mutant structures are used to construct the Go interaction potential of the Trp2-cage mutant Go model. [Preview Abstract] |
Thursday, March 13, 2008 9:48AM - 10:00AM |
U18.00008: Statistical features of the rough energy landscape of proteins emerging from single molecule force-clamp spectroscopy Jasna Brujic, Maxime Clusel, Eric Corwin Following the complete folding trajectories of single ubiquitin molecules opens an unique window into the detailled mechanisms of protein folding. The biological importance of this problem motivated extensive studies using macroscopic biochemistry experiments and molecular dynamics simulations at the atomic scale, while little is known about the mesoscopic mechanisms of folding. To this end, our recent experiments combined with the tools of modern statistical mechanics reveal a wealth of new information. Using this single molecule approach, we have observed physical features reminiscent of glassy systems, exemplified by a power-law distribution of the rates of protein unfolding under a stretching force [1]. To further probe the signs of complexity in protein dynamics, we investigate memory effects and the influence of force on the folding trajectories, and more specifically the mechanism of formation of native interactions. The general aim of this research is to build a self-consistent picture of the free energy landscape of proteins. [1] J. Brujic \textit{et al.}, Nature Physics, vol 2, 282 (2006). [Preview Abstract] |
Thursday, March 13, 2008 10:00AM - 10:12AM |
U18.00009: Asymmetrical collapse of charged heterogeneous macromolecules Natalia Denesyuk, John Weeks We propose a new method based on local molecular field (LMF) theory to treat Coulomb interactions in simulations of ionic fluids. This method has been tested in Langevin dynamics simulations of a model protein, which consists of a random sequence of charged hydrophilic and neutral hydrophobic monomers, in salt solution. The concentration of salt ions in the simulation box is maintained by grand canonical Monte Carlo. Our general strategy is to perform averages over an ensemble of sequences in order to identify those general properties that are sequence independent. We find that, independently of their random sequence, heterogeneous polyelectrolytes undergo the asymmetrical collapse in which one of their quadruple moments vanishes. [Preview Abstract] |
Thursday, March 13, 2008 10:12AM - 10:24AM |
U18.00010: A Model for the Thermally Induced Polymer Coil-to-Globule Transition David Simmons, Isaac Sanchez A quantitative mean-field model for the thermally-induced (heating-induced) polymer coil-to-globule transition (HCGT) is developed with no adjustable parameters. The transition temperature $\Theta $ is given for a long chain by the equation $\Theta =2T_p^{\ast} \left[ {1-\tilde {\rho }\left( \Theta \right)} \right]$ where $T_{p}^{\ast}$ is the characteristic temperature of the polymer for the lattice fluid model and $\tilde {\rho }\left( \Theta \right)$ is the reduced solvent density at the transition temperature $\Theta $. Calculated HCGT temperatures show good agreement with experimental LCSTs. The physics of the HCGT transition is shown to be consistent with the physics of the LCST transition. The predicted globular state is characterized by the dominance of attractive polymer self interactions over excluded volume interactions. This model can be easily generalized to treat cross-linked gels and their contraction-expansion characteristics. [Preview Abstract] |
Thursday, March 13, 2008 10:24AM - 10:36AM |
U18.00011: Force Induced Globule-to-Coil Transition of Single Polymer Chains. Nikhil Gunari, Gilbert Walker Force induced structural transitions of individual homopolymer chains have been studied in different solvent conditions using single molecule force spectroscopy. Single molecule mechanics in the ``fly-fishing'' mode showed a first-order like transition for polystyrene (PS) in water exhibiting a characteristic three regime force extension curve. In contrast, poly methylmethacrylate (PMMA) showed a characteristic saw-tooth pattern reminiscent of multidomain disassembly behavior similar to that seen in modular protein mechanics. The plateau force for PS and the saw-tooth pattern for PMMA disappear when measured in aqueous guanidine hydrochloride solution and in other non-solvents showing that the characteristic deformational behavior observed for the two polymers in water may be due to hydrophobic interactions . [Preview Abstract] |
Thursday, March 13, 2008 10:36AM - 10:48AM |
U18.00012: Wang-Landau sampling for homopolymer collapse Daniel T. Seaton, Steven J. Mitchell, David P. Landau We explore the behavior of a continuum-homopolymer model using the Wang-Landau algorithm, concentrating on phase transitions such as the coil-globule and solid-liquid transitions. Using the density of states generated by the Wang-Landau algorithm, we calculate various thermodynamic quantities, e.g., the internal energy and specific heat. We also study how algorithmic parameters, such as sampling boundaries (maximum and minimum energies for random walks) and the final value of the modification factor, affect these quantities. In particular, we observe how the sampling boundaries can significantly alter the transition behavior. Our results are compared with two recent studies that yielded contradictory results, one using the bond-fluctuation model and the other using a continuum model similar to our own. We find that the transitions seen in our model are much more similar to those in the bond-fluctuation study. The careful analysis of the effects of algorithmic parameters on thermodynamic quantities should be relevant to the study of other polymeric/protein models. [Preview Abstract] |
Thursday, March 13, 2008 10:48AM - 11:00AM |
U18.00013: Stimuli-Responsive, Concentrated Aqueous Solutions of DMAEMA-containing Amphiphilic Di- and Triblock Copolymers Kyle Guice, Yueh-Lin Loo Poly(dimethyoaminoethyl methacrylate), poly(DMAEMA), has generated considerable interest due to its responsiveness to changes in temperature and pH. The pendant tertiary amine groups of DMAEMA are easily protonated below its pKa, and the polymer undergoes a hydrophilic-to-hydrophobic transition when heated above its lower critical solution temperature (LCST) in water. We have investigated di- and triblock copolymers containing statistical copolymers of DMAEMA and hydroxyethyl methacrylate (HEMA), a biocompatible but nonresponsive monomer, as stimuli-responsive concentrated aqueous solutions. The swelling characteristics of these concentrated aqueous block copolymer solutions depend highly on the DMAEMA composition. Further, by selecting an appropriate hydrophobic block, we are able to design stimuli-responsive concentrated aqueous solutions that undergo reversible phase transformations over a narrow temperature window. [Preview Abstract] |
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