After decades of largely independent experimental and theoretical work, the field of protein folding is entering a mature age in which the two are converging. Experimental techniques have become sophisticated enough to probe the folding of small, fast-folding proteins and protein elements, while computational power and algorithms have reached a level at which simulating these events is tractable. The central goal our eCheminfo "Protein Folding and Dynamics" program is to bring together researchers working on both theoretical and experimental fronts of the protein folding field, and have them present recent cutting-edge research results.
We will be holding the “Protein Folding and Dynamics" InterAction Meeting session in Basel, Switzerland on 9 November 2005. The purpose of the meeting is to bring together world-class researchers to present and discuss recent and new approaches and results in research areas relevant to both basic protein research and applications relevant to Alzheimer’s, Huntington’s Disease, and other diseases. The emphasis of the meeting activity is on communication and open discussion, which we hope will lead to new ideas and collaborations towards progress and innovation in the areas discussed. A significant amount of time at the meeting will be devoted to question time and panel and group discussions towards this goal.
A description of the session and invited speaker presentations follows:
eCheminfo InterAction Meeting Session, Basel, 9 November 2005
Protein Folding and Dynamics
chaired by chaired by Wilfred van Gunsteren (ETH-Zurich)
eCheminfo and InnovationWell 2005 InterAction Meetings, 9-10 November 2005, Basel, Switzerland
Program Updates loaded in the Program Areas on http://echeminfo.com/ and http://innovationwell.net/
Invited Speakers and Discussion Leaders:
Jeremy Smith (University of Heidelberg), Wolfgang Wenzel (University of Karslruhe), Thomas Kiefhaber (University of Basel), Xavier Daura (University of Barcelona), Nikolay V. Dokholyan (University of North Carolina) and Michele Vendruscolo (University of Cambridge)
Presentation Abstracts:
Dynamics of Protein Binding, Reaction and Structural Change
Jeremy C. Smith, Computational Molecular Biophysics, Faculties of Biological Science and Physics/Astronomy, Heidelberg University, Germany
Computer simulation results on dynamical effects influencing ligand binding, reactions and the mechanics of large-scale conformational change in proteins will be discussed. Among the questions to be examined are the thermodynamic consequences of vibrational changes on ligand binding, the protein glass transition and function, proton transfer reactions in the light-driven proton pump protein, bacteriorhodopsin, and the mechanics of the power stroke of muscle contraction.
Aspects of beta-peptide folding from molecular-dynamics simulation
Xavier Daura, Catalan Institution for Research and Advanced Studies (ICREA) and Institute of Biotechnology and Biomedicine (IBB), Universitat Autònoma de Barcelona, E-08193 Bellaterra (Barcelona), Spain
Due mostly to work from the groups of D. Seebach at ETH Zürich and S. H. Gellman at University of Wisconsin, there is now considerable knowledge on the chemistry and "biology" –the possible biomedical and biotechnological applications– of beta-peptides. Since 1997, stimulated by D. Seebach and co-workers, we have been working on several aspects of beta-peptide structure and dynamics, including folding thermodynamics and kinetics. My presentation will be centred around two such aspects, which we have been recently investigating. The first one refers to the accessible conformational spaces of two beta-peptides in methanol at different temperatures, which we have analysed in terms of network theory. Here, the populated conformational states are determined by clustering peptide structures sampled at regular time intervals during the simulation. Each conformational state represents, thereafter, a node in the graph –network–. Links between nodes correspond to bidirectional transitions between conformational states –clusters– sampled during the simulation. Comparison of the resulting graphs to theoretical models gives us information on the properties of the conformational free-enthalpy landscape of the peptides. The second one refers to the energetics of one of these two peptides, which we have analysed using classical-thermodynamics formulae that relate free-enthalpy and entropy differences over a temperature range to enthalpies and heat capacities at constant pressure. Two of the conclusions from this work were unexpected.
All-atom protein folding with stochastic optimization methods
A. Schug , A. Verma and W. Wenzel, Forschungszentrum Karlsruhe, Institut für Nanotechnologie, Karlsruhe, Germany
The prediction of protein tertiary structure, in particular based on sequence information alone, remains one of the outstanding problems in biophysical chemistry. We have recently developed an all-atom free energy forcefield (PFF01) which implements a minimal thermodynamic model based on physical interactions and an implict solvent model. We could demonstrate that PFF01 stabilizes the native conformation of several helical proteins as the global optimum of its free energy surface. In addition we were able to reproducibly fold several helical proteins, ranging 20-60 amino acids in size from random starting conditions. We used several stochastic optimization methods: the stochastic tunneling method, an adapted version of parallel tempering, basin hopping techniques and distributed evolutionary optimization strategies. We will discuss advantages and limitations with respect to further improvements of this approach to in-silico all-atom protein structure prediction.
Structure determination of native and non-native protein conformations using NMR-derived restraints
Michele Vendruscolo, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
In recent years increasingly detailed information about the structures and dynamics of protein molecules has been obtained by innovative applications of NMR techniques and of theoretical methods, in particular molecular dynamics simulations. I will discuss how such approaches can be combined by incorporating a wide range of different types of experimental data as restraints in computer simulations to provide unprecedented detail about the ensembles of structures that describe proteins in a wide variety of states from the native structure to highly unfolded species. This strategy has provided, in particular, new insights into the mechanism by which proteins are able to fold into their native states, or by which they fail to do so and give rise to harmful aggregates that are associated with a wide range of debilitating human diseases.
Simple yet Predictive Protein Models
Nikolay V. Dokholyan, University of North Carolina at Chapel Hill, School of Medicine, Campus Box 7260, Chapel Hill, NC 27599, USA
The traditional approach to computational biophysics studies of molecular systems is brute force molecular dynamics simulations under conditions of interest. The disadvantages of this traditional approach are that the time and length scales accessible to computer simulations often do not reach biologically-relevant scales. An alternative approach, which we call intuitive modeling, is hypothesis-driven and is based on tailoring simplified protein models to the systems of interest. Using intuitive modeling, the length and time scales that are achievable using simplified protein models by far exceed those of the traditional molecular dynamics simulations. We will describe several recent studies that signify the predictive power of simplified protein models within the intuitive modeling approach.
Protein Dynamics Measured by Triplet-Triplet Energy Transfer
Thomas Kiefhaber, Biozentrum der Universität Basel, Division of Biophysical Chemistry
Klingelbergstr. 70, CH-4056 Basel, Switzerland
The rate at which a protein can explore conformational space during folding is limited by intrachain diffusion processes. The maximum rate for protein folding can not exceed the rates of intramolecular contact formation [1]. To understand the dynamics of unfolded polypeptide chains we studied contact formation between individual amino acid residues using diffusion controlled triplet-triplet energy transfer (TTET) [2]. We attached xanthone as triplet donor and naphtylalanine as triplet acceptor at the ends of polypeptide chains with different sequence and varied the distance between donor and acceptor from 3 to 60 amino acids. We observed single exponential kinetics for end-to-end diffusion in all peptides. In flexible poly(Gly-Ser) chains the time constant for contact formation reaches an upper limit of about 5 ns, which sets the speed limit for protein folding. This value is nearly independent of chain length for short donor-acceptor distances (N<8; N=number of peptide bonds between donor and acceptor). In the limit of long chains (N>20) the rate of end-to-end diffusion scales with N^(-1.7). We found only little effect of the amino acid sequence on local chain dynamics. In host-guest peptides the stiffest side chain (Pro) showed only about 8-fold slower chain dynamics compared to the most flexible amino acid (Gly) [3].
During protein folding most interactions are formed between amino acids in the interior of the polypeptide chain. To test for differences in the dynamics of intrachain diffusion compared to end-to-end diffusion we studied contact formation in a series of peptides that had either one end or both ends extended beyond the position of the triplet donor/acceptor. We observed significantly decreased contact rates with increasing mass/surface of the additional tails until a limiting value is reached.
To compare the results obtained from homo-polypetides with natural protein sequences we measured dynamics in various loops from carp-parvalbumin and in the GB1 hairpin [4]. The results are in agreement with the dynamics expected from the host-guest peptides. Interestingly, intrachain diffusion in the natural sequences showed significant activation energies, which were similar to activation energies found for protein folding reactions (15-20 kJ/mol). Studies on helical peptides further revealed that TTET can be used to measure unfolding dynamics of protein secondary structures.
References:
1. Bieri, O., Kiefhaber, T., Biol. Chem. 380 (1999) 923.
2. Bieri, O., Wirz, J., Hellrung, B., Schutkowski, M., Drewello, M., Kiefhaber, T., Proc.
Natl. Acad. Sci. USA 96 (1999) 9597.
3. Krieger, F., Fierz, B., Bieri, O., Drewello, M., Kiefhaber, T., J. Mol. Biol. 332 (2003)
265.
4. Krieger, F., Fierz, B., Axthelm, F., Joder, K., Meyer, D., Kiefhaber, T., Chemical
Physics (2004) in press.
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