Bulletin of the American Physical Society
2005 APS March Meeting
Monday–Friday, March 21–25, 2005; Los Angeles, CA
Session D22: Focus Session: Protein Folding |
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Sponsoring Units: DBP Chair: Denis Rousseau, AECOM Room: LACC 409B |
Monday, March 21, 2005 2:30PM - 3:06PM |
D22.00001: Protein Folding Transition States as Eigenstates Invited Speaker: We are interested in the microscopic routes by which simple fast folding proteins fold, and the bottleneck steps. We model the process using a master equation. We find that folding differs from small molecule bond-formation kinetics in various ways. For example, simple mass-action miss important aspects of the heterogeneity of the routes. The energy landscape has a funnel shape. Also, the rate-limiting step is not a single microstructure; rather, the transition state can be characterized as an eigenstate. These observations may be useful for developing more efficient computational methods for conformational searching in protein structure prediction. \newline \newline Co-authors are Banu Ozkan (Postdoc), John Chodera (Graduate Student), and Ke Fan (Postdoc), UCSF. [Preview Abstract] |
Monday, March 21, 2005 3:06PM - 3:18PM |
D22.00002: All-Atom Folding and Characterization of the Free-Energy Landscape of the Villin Headpiece Wolfgang Wenzel, Alexander Schug, Abhinav Verma The prediction of protein tertiary structure, in particular based on sequence information alone, remains one of the outstanding problems in biophysical chemistry. According to the thermodynamic hypothesis, the native conformation of a protein can be predicted as the global optimum of its free energy surface with stochastic optimization methods[1] orders of magnitude faster than by direct simulation of the folding process. We have recently developed an all-atom free energy forcefield[2]which implements a minimal thermodynamic model based on physical interactions . Using this forcefield we could reproducibly fold several proteins[3] ranging from 20-60 amino acids in length at the all atom level, among them the 36-amino acid, three helix villin headpiece. The conformations generated in the search can be used to construct a decoy tree, which completely characterizes the low energy conformations of the protein Consistent with the ``new paradigm'' for protein folding their analysis characterizes the folding funnel and its metastable branches. \newline [1] W. Wenzel, K. Hamacher, PRL 59, 3003 (1999) \newline [2] T. Herges, W. Wenzel, Biophysical J. 87, 3100 (2004) \newline [3] A. Schug, W. Wenzel, PRL 91, 158102 (2003), EPL 67, 307 (2004), Proteins (in press), PRL (in press), JACS (in press) \newline [Preview Abstract] |
Monday, March 21, 2005 3:18PM - 3:30PM |
D22.00003: Reproducible In-Silico Folding of a Four Helix 60 Amino Acid Protein in a Transferable All-Atom Forcefield Alexander Schug, Wolfgang Wenzel For predicting the protein tertiary structure one approach describes the native state of a protein as the global minimum of an appropiate free-energy forcefield. We have recently developed such a all-atom protein forcefield (PFF01). As major challenge remains the search for the global minimum for which we developed efficient methods. Using these we were able to predict the structure of helical proteins from different families ranging in size from 20 to 60 amino acids starting with random configurations. For the four helix 60 amino acid protein \emph{Bacterial Ribosomal Protein L20} (pdb code: 1GYZ) we used a simple client-master model for distributed computing. Starting from a set of random structures three phases of different folding simulations refined this set to a final one with 50 configurations. During this process the amount of native-like structures increased strongly. Six out of the ten structures best in energy approached the native structure within 5 \AA\ backbone rmsd. The conformation with the lowest energy had a backbone rmsd value of 4.6 \AA\ therefore correctly predicting the tertiary structure of 1GYZ.\\ References\\ A.~Schug et al, Phys. Rev. Letters, 91:158102, 2003\\ A.~Schug et al, J. Am. Chem. Soc. (in press), 2004\\ [Preview Abstract] |
Monday, March 21, 2005 3:30PM - 3:42PM |
D22.00004: Effective potential for Folding Protein with Both Alpha and Beta Structures Nan-Yow Chen, Chung-Yu Mou, Zheng-Yao Su A coarse-grained off-lattice model that can fold proteins with both helix and sheet structures is proposed. To predict the native structure in a reasonable time, the model has included the essential effects of water in an unbiased effective potential. Two new ingredients, the dipole-dipole interaction and the local hydrophobic interaction, are introduced and are shown to be as crucial as the hydrogen bonding. The model allows successful folding of both helix and sheet structures for a number of proteins and may have provided important hints to the study of protein folding. [Preview Abstract] |
Monday, March 21, 2005 3:42PM - 4:18PM |
D22.00005: The Folding of Ligands upon Protein Binding Invited Speaker: Enzymes bind their substrates and then catalyze the chemical transformation of substrate to product. We understand pretty well the structures of enzymes and other proteins with and without bound ligands. But just how do proteins bind ligands? What are the steps? And how do we describe the dynamics of this folding process? Recent advances in initiating and perturbing chemical reactions on very fast time scales, as short as picoseconds, make it feasible to study a large range of chemical kinetics problems that heretofore could not be studied. One such approach is the rapid heating of water solutions using laser excitation. Using laser induced temperature jump relaxation spectroscopy, it is possible to examine and characterize atomic motion in proteins over the picosecond to minute time scales. Some general issues will be discussed followed by specific examples of our studies of the dynamical nature of ligand binding to date, specifically in lactate dehydrogenase and triosephosphate isomerase, over a wide time range. [Preview Abstract] |
Monday, March 21, 2005 4:18PM - 4:30PM |
D22.00006: Time resolved small angle x-ray scattering studies of macromolecular folding Lisa Kwok, Jessica Lamb, Hye Yoon Park, Kurt Andresen, Heather Smith, Alec Sandy, Suresh Narayanan, Lois Pollack Large biological molecules like proteins and RNA, carry out their functions by folding to well-defined three-dimensional structures. We are interested in the physical interactions that direct this self-assembly process. By combining microfabricated rapid mixers with synchrotron x-ray scattering, we have gained insight into the earliest steps of folding of the Tetrahymena ribozyme, a model for large RNAs. Previous work has shown that the first folding step involves electrostatic relaxation of the molecule. We will discuss a recent series of experiments that identify the tertiary contacts that form from within this compact state. [Preview Abstract] |
Monday, March 21, 2005 4:30PM - 4:42PM |
D22.00007: An Experimental Test of Jarzynski's Equality on Free Energy of Protein Unfolding Nolan Harris, Leiming Li, Ching-Hwa Kiang We performed an experimental test of Jarzynski's equality on the mechanical unfolding of a giant protein, human cardiac titin. Jarzynski's estimator relates the free energy difference ($\Delta G$) between two equilibrium states and the work performed in switching between those states. We used atomic force microscopy to obtain the single-molecule dynamic force spectroscopy of polyproteins consisting of identical tandem repeats of the I27 domain of titin. We found that Jarzynski's equality results in a good estimate of protein unfolding free energy from non-equilibrium measurements. [Preview Abstract] |
Monday, March 21, 2005 4:42PM - 4:54PM |
D22.00008: How does a protein fold? The effects of structure and many body interactions Steven Plotkin A theory for how a protein folds up to a biologically functional structure has occupied researchers for the last few decades. The difficulties stem from an incomplete knowledge of an accurate Hamiltonian, as well as non-trivial aspects of polymer physics that complicate the kinetics of folding. Here I will describe some recent results showing that relaxation rates increase significantly as the folding mechanism becomes increasingly heterogeneous. I will go on to discuss the role of many-body interactions in the Hamiltonian, and show how accounting for them is essential for predicting folding rates and mechanisms. [Preview Abstract] |
Monday, March 21, 2005 4:54PM - 5:06PM |
D22.00009: Folding Kinetics and Thermodynamics of a Model Alpha Helical Hairpin Peptide Prem Chapagain, Bernard Gerstman Using MC simulations, we study the folding kinetics and thermodynamics of a specially designed alpha-turn-alpha helix that forms a two-helix bundle. This protein structure contains the hierarchy of secondary and tertiary structural elements. The model protein resembles the de novo design of alpha-turn-alpha helical hairpin peptide of Fezoui et al [PNAS (91), 1994]. Because of its size and simplicity, the two-helix bundle model protein is especially valuable from the protein design and engineering point of view. We systematically study how the folding kinetics depend on variations in the helix size and the inter-helical interactions. We find that strategic placement of non-hydrophobic residues in the helical interface leads to faster protein folding and reduces the chance of misfolding due to off-set of the helices. Depending on the nature of the inter-helical side chain packing, the helix bundle can be made to behave as a two-state system, or be made to follow more complicated kinetics. [Preview Abstract] |
Monday, March 21, 2005 5:06PM - 5:18PM |
D22.00010: Entropically driven helix formation Yehuda Snir, Randall Kamien We investigate a purely entropic approach to understanding the folding of helices that exclusively relies on a local and homogeneous interaction with depleting spheres. We found that by decreasing the size of the depleting spheres for a given volume fraction the helix formed becomes tighter. In the limit of small spheres the helix becomes the optimally tight helix of pitch to radius ratio of 2.5122 often found in alpha helices of protiens. The depletion interaction can be used as a surrogate for hydrophobicity, polymer-polymer interactions, and for boundary layers in elastica and liquid crystals. [Preview Abstract] |
Monday, March 21, 2005 5:18PM - 5:30PM |
D22.00011: Unfolding designable structures Cristiano L. Dias, Martin Grant Among an infinite number of possible folds, nature has chosen only about 1000 distinct folds to form protein structures. Theoretical studies suggest that selected folds are intrinsically more ``designable'' than others; these selected folds are unusually stable, a property called the designability principle. In this talk we use the 2D hydrophobic-polar lattice model to classify structures according to their designability, and molecular dynamics to account for their time evolution under a gradient of force. We demonstrate that, among all possible folds, the more designable ones require lower gradient of forces to unfold due to their large number of surface-core bonds. Therefore the reduced set of selected folds are, on average, more sensitive to external forces than other folds. This dynamical property might be related to the functional flexibility expected from real protein folds. [Preview Abstract] |
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D22.00012: Excluded volume entropic effects on protein unfolding times and intermediary stability Prem Chapagain, Bernard Gerstman The dynamics of protein folding result from both enthalpic and entropic contributions to the free energy. In this paper we focus on entropic volume exclusion effects. We carry out computer simulations using a model that allows us to independently change the size or biochemical properties of amino acid residues. To determine the importance of excluded volume effects, we investigate the effects of changing the size of side chains on the unfolding dynamics of a model four-helix bundle protein. In addition, we also investigate the effects of changing the thickness of the chain's backbone. This has relevance to the behaviour of synthetic polymers where the size of the constituent units can be varied. We find that entropic excluded volume effects are crucially important for stabilizing the organized native state relative to the molten globule. [Preview Abstract] |
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D22.00013: Roles of Hinges and Linkers in Protein Extension Dennis Discher, Nishant Bhasin, Vanessa Ortiz, Michael F. Klein In many multi-repeat proteins, linkers between repeats have little secondary structure and place few constraints on folding or unfolding. However, the large family of spectrin-like proteins -- including $\alpha $-actinin, spectrin, and dystrophin -- share repeats of 3-helix bundles that appear in crystal structures to be linked by long helices. Some of these proteins also have praline-rich hinge regions. Regardless, these proteins are regularly subjected to mechanical stress, and recent single molecule AFM experiments show the simultaneous unfolding of tandem repeats at high frequency. This suggests the contiguous helix between spectrin repeats often propagates a cooperative helix-to-coil transition. Here we describe further experiments and all-atom steered molecular dynamics (SMD) simulations of tandem spectrin repeats in explicit water. The results reveal several rate-dependent pathways, with one pathway (in SMD) showing distinct unfolding of the linker between repeats. The forced unfolding mechanism begins with a splay distortion of proximal loops away from hydrophobic contacts with the linker. This is followed by linker destabilization via stretch-splay unwinding and increased hydration of the backbone. \textbf{The end result is an unfolded helix that mechanically decouples tandem repeats. } [Preview Abstract] |
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