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| 2. |
- Irbäck, Anders, et al.
(författare)
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An effective all-atom potential for proteins
- 2009
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Ingår i: Food Biophysics. - : Springer Science and Business Media LLC. - 1557-1866. ; 2:1, s. 2-2
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Tidskriftsartikel (refereegranskat)abstract
- We describe and test an implicit solvent all-atom potential for simulations of protein folding and aggregation. The potential is developed through studies of structural and thermodynamic properties of 17 peptides with diverse secondary structure. Results obtained using the final form of the potential are presented for all these peptides. The same model, with unchanged parameters, is furthermore applied to a heterodimeric coiled-coil system, a mixed alpha/beta protein and a three-helix-bundle protein, with very good results. The computational efficiency of the potential makes it possible to investigate the free-energy landscape of these 49-67-residue systems with high statistical accuracy, using only modest computational resources by today's standards.PACS Codes: 87.14.E-, 87.15.A-, 87.15.Cc.
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| 3. |
- Irbäck, Anders, et al.
(författare)
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Dissecting the mechanical unfolding of ubiquitin
- 2005
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 102:38, s. 13427-13432
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Tidskriftsartikel (refereegranskat)abstract
- The unfolding behavior of ubiquitin under the influence of a stretching force recently was investigated experimentally by single-molecule constant-force methods. Many observed unfolding traces had a simple two-state character, whereas others showed clear evidence of intermediate states. Here, we use Monte Carlo simulations to investigate the force-induced unfolding of ubiquitin at the atomic level. In agreement with experimental data, we find that the unfolding process can occur either in a single step or through intermediate states. In addition to this randomness, we find that many quantities, such as the frequency of occurrence of intermediates, show a clear systematic dependence on the strength of the applied force. Despite this diversity, one common feature can be identified in the simulated unfolding events, which is the order in which the secondary-structure elements break. This order is the same in two and three-state events and at the different forces studied. The observed order remains to be verified experimentally but appears physically reasonable.
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| 4. |
- Irbäck, Anders, et al.
(författare)
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Folding thermodynamics of peptides
- 2005
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Ingår i: Biophysical Journal. - : Elsevier BV. - 1542-0086 .- 0006-3495. ; 88:3, s. 1560-1569
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Tidskriftsartikel (refereegranskat)abstract
- A simplified interaction potential for protein folding studies at the atomic level is discussed and tested on a set of peptides with; 20 residues each. The test set contains both alpha-helical ( Trp cage, F-s) and beta-sheet ( GB1p, GB1m2, GB1m3, Betanova, LLM) peptides. The model, which is entirely sequence-based, is able to fold these different peptides for one and the same choice of model parameters. Furthermore, the melting behavior of the peptides is in good quantitative agreement with experimental data. Apparent folded populations obtained using different observables are compared, and are found to be very different for some of the peptides ( e. g., Betanova). In other cases ( in particular, GB1m2 and GB1m3), the different estimates agree reasonably well, indicating a more two-state-like melting behavior.
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| 5. |
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| 6. |
- Irbäck, Anders
(författare)
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Peptide folding and aggregation studied using a simplified atomic model
- 2005
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Ingår i: Journal of Physics: Condensed Matter. - : IOP Publishing. - 1361-648X .- 0953-8984. ; 17:18, s. 1553-1564
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Tidskriftsartikel (refereegranskat)abstract
- Using an atomic model with a simplified-sequence-based potential, the folding properties of several different peptides are studied. Both alpha-helical (Trp cage, F-s) and beta-sheet(GB1p, GB1m2, GB1m3, Betanova, LLM) peptides are considered. The model is able to fold these different peptides for one and the same choice of;parameters, and the melting behaviour of the peptides (folded population against temperature) is in very good agreement with experimental data. Furthermore, using the same model with unchanged parameters, the aggregation behaviour of a fibril-forming fragment of the Alzheimer's A beta peptide is studied, with very promising results.
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| 7. |
- Irbäck, Anders, et al.
(författare)
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PROFASI: A Monte Carlo simulation package for protein folding and aggregation
- 2006
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Ingår i: Journal of Computational Chemistry. - : Wiley. - 1096-987X .- 0192-8651. ; 27:13, s. 1548-1555
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Tidskriftsartikel (refereegranskat)abstract
- We present a flexible and efficient program package written in C++, PROFASI, for simulating protein folding and aggregation. The systems are modeled using an all-atom description of the protein chains with only torsional degrees of freedom, and implicit water. The program package has a modular structure that makes the interaction potential easy to modify. The currently implemented potential is able to fold several peptides with about 20 residues, and has also been used to study aggregation and force-induced unfolding. The simulation methods implemented in PROFASI are Monte Carlo-based and include a semilocal move and simulated tempering. Adding new updates is easy. The code runs fast in both single- and multi-chain applications, as is illustrated by several examples. (C) 2006 Wiley Periodicals, Inc.
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| 8. |
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| 9. |
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| 10. |
- Irbäck, Anders, et al.
(författare)
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Spontaneous beta-barrel formation: an all-atom study of Abeta(16-22) oligomerization
- 2008
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Ingår i: Proteins. - : Wiley. - 0887-3585. ; 71:1, s. 207-214
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Tidskriftsartikel (refereegranskat)abstract
- Using all-atom Monte Carlo simulations with implicit water, combined with a cluster size analysis, we study the aggregation of A16-22, a peptide capable of forming amyloid fibrils. We consider a system of six initially randomly oriented A16-22 peptides, and investigate the thermodynamics and structural properties of aggregates formed by this system. The system is unaggregated without ordered secondary structure at high temperature, and forms -sheet rich aggregates at low temperature. At the crossover between these two regimes, we find that clusters of all sizes occur, whereas the -strand content is low. In one of several runs, we observe the spontaneous formation of a -barrel with six antiparallel strands. The -barrel stands out as the by far most long-lived aggregate seen in our simulations.
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| 11. |
- Irbäck, Anders, et al.
(författare)
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Thermal versus mechanical unfolding of ubiquitin
- 2006
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Ingår i: Proteins. - : Wiley. - 0887-3585. ; 65:3, s. 759-766
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Tidskriftsartikel (refereegranskat)abstract
- The authors studied the temperature-induced unfolding of ubiquitin by all-atom Monte Carlo simulations. The unfolding behavior is compared with that seen in previous simulations of the mechanical unfolding of this protein, based on the same model. In mechanical unfolding, secondary-structure elements were found to break in a quite well-defined order. In thermal unfolding, the authors saw somewhat larger event-to-event fluctuations, but the unfolding pathway, was still far from random. Two long-lived secondary-structure elements could be identified in the simulations. These two elements have been found experimentally to be the thermally most stable ones. Interestingly, one of these long-lived elements, the first P-hairpin, was found to break early in the mechanical unfolding simulations. Their combined simulation results thus enable the authors to predict in detail important differences between the thermal and mechanical unfolding behaviors of ubiquitin.
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| 12. |
- Li, Da-Wei, et al.
(författare)
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Formation and Growth of Oligomers: A Monte Carlo Study of an Amyloid Tau Fragment
- 2008
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Ingår i: PLoS Computational Biology. - : Public Library of Science (PLoS). - 1553-7358. ; 4:12
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Tidskriftsartikel (refereegranskat)abstract
- Small oligomers formed early in the process of amyloid fibril formation may be the major toxic species in Alzheimer's disease. We investigate the early stages of amyloid aggregation for the tau fragment AcPHF6 (Ac-VQIVYK-NH2) using an implicit solvent all-atom model and extensive Monte Carlo simulations of 12, 24, and 36 chains. A variety of small metastable aggregates form and dissolve until an aggregate of a critical size and conformation arises. However, the stable oligomers, which are beta-sheet-rich and feature many hydrophobic contacts, are not always growth-ready. The simulations indicate instead that these supercritical oligomers spend a lengthy period in equilibrium in which considerable reorganization takes place accompanied by exchange of chains with the solution. Growth competence of the stable oligomers correlates with the alignment of the strands in the beta-sheets. The larger aggregates seen in our simulations are all composed of two twisted beta-sheets, packed against each other with hydrophobic side chains at the sheet-sheet interface. These beta-sandwiches show similarities with the proposed steric zipper structure for PHF6 fibrils but have a mixed parallel/antiparallel beta-strand organization as opposed to the parallel organization found in experiments on fibrils. Interestingly, we find that the fraction of parallel beta-sheet structure increases with aggregate size. We speculate that the reorganization of the beta-sheets into parallel ones is an important rate-limiting step in the formation of PHF6 fibrils.
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| 13. |
- Mitternacht, Simon, et al.
(författare)
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Changing the Mechanical Unfolding Pathway of FnIII(10) by Tuning the Pulling Strength
- 2009
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Ingår i: Biophysical Journal. - : Elsevier BV. - 1542-0086 .- 0006-3495. ; 96:2, s. 429-441
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Tidskriftsartikel (refereegranskat)abstract
- We investigate the mechanical unfolding of the tenth type III domain from fibronectin (FnIII(10)) both at constant force and at constant pulling velocity, by all-atom Monte Carlo simulations. We observe both apparent two-state unfolding and several unfolding pathways involving one of three major, mutually exclusive intermediate states. All three major intermediates lack two of seven native beta-strands, and share a quite similar extension. The unfolding behavior is found to depend strongly on the pulling conditions. In particular, we observe large variations in the relative frequencies of occurrence for the intermediates. At low constant force or low constant velocity, all three major intermediates occur with a significant frequency. At high constant force or high constant velocity, one of them, with the N- and C-terminal beta-strands detached, dominates over the other two. Using the extended Jarzynski equality, we also estimate the equilibrium free-energy landscape, calculated as a function of chain extension. The application of a constant pulling force leads to a free-energy profile with three major local minima. Two of these correspond to the native and fully unfolded states, respectively, whereas the third one can be associated with the major unfolding intermediates.
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| 14. |
- Mitternacht, Simon, et al.
(författare)
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Differences in solution behavior among four semiconductor-binding peptides
- 2007
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Ingår i: The Journal of Physical Chemistry Part B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 111:17, s. 4355-4360
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Tidskriftsartikel (refereegranskat)abstract
- Recent experiments have identified peptides that adhere to GaAs and Si surfaces. Here, we use all-atom Monte Carlo simulations with implicit solvent to investigate the behavior in aqueous solution of four such peptides, all with 12 residues. At room temperature, we find that all four peptides are largely unstructured, which is consistent with experimental data. At the same time, we find that one of the peptides is structurally different and more flexible, as compared to the others. This finding points at structural differences as a possible explanation for differences in adhesion properties among these peptides. By also analyzing designed mutants of two of the peptides, an experimental test of this hypothesis is proposed.
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