| 1. |
- 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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| 2. |
- 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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| 3. |
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| 4. |
- 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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| 5. |
- 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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| 6. |
- Jonsson, Sigurdur, et al.
(författare)
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Mechanical resistance in unstructured proteins.
- 2013
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Ingår i: Biophysical Journal. - : Elsevier BV. - 1542-0086 .- 0006-3495. ; 104:12, s. 2725-2732
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Tidskriftsartikel (refereegranskat)abstract
- Single-molecule pulling experiments on unstructured proteins linked to neurodegenerative diseases have measured rupture forces comparable to those for stable folded proteins. To investigate the structural mechanisms of this unexpected force resistance, we perform pulling simulations of the amyloid β-peptide (Aβ) and α-synuclein (αS), starting from simulated conformational ensembles for the free monomers. For both proteins, the simulations yield a set of rupture events that agree well with the experimental data. By analyzing the conformations occurring shortly before rupture in each event, we find that the mechanically resistant structures share a common architecture, with similarities to the folds adopted by Aβ and αS in amyloid fibrils. The disease-linked Arctic mutation of Aβ is found to increase the occurrence of highly force-resistant structures. Our study suggests that the high rupture forces observed in Aβ and αS pulling experiments are caused by structures that might have a key role in amyloid formation.
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| 7. |
- Luccioli, Stefano, et al.
(författare)
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Unfolding times for proteins in a force clamp
- 2010
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Ingår i: Physical Review E (Statistical, Nonlinear, and Soft Matter Physics). - 1539-3755. ; 81:1
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Tidskriftsartikel (refereegranskat)abstract
- The escape process from the native valley for proteins subjected to a constant stretching force is examined using a model for a beta barrel. For a wide range of forces, the unfolding dynamics can be treated as one-dimensional diffusion, parametrized in terms of the end-to-end distance. In particular, the escape times can be evaluated as first passage times for a Brownian particle moving on the protein free-energy landscape, using the Smoluchowski equation. At strong forces, the unfolding process can be viewed as a diffusive drift away from the native state, while at weak forces thermal activation is the relevant mechanism. An escape-time analysis within this approach reveals a crossover from an exponential to an inverse Gaussian escape-time distribution upon passing from weak to strong forces. Moreover, a single expression valid at weak and strong forces can be devised both for the average unfolding time as well as for the corresponding variance. The analysis offers a possible explanation of recent experimental findings for the proteins ddFLN4 and ubiquitin.
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| 8. |
- 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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| 9. |
- Mitternacht, Simon, et al.
(författare)
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Comparing the folding free-energy landscapes of Abeta42 variants with different aggregation properties.
- 2010
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Ingår i: Proteins. - : Wiley. - 0887-3585 .- 1097-0134. ; 78:12, s. 2600-2608
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Tidskriftsartikel (refereegranskat)abstract
- The properties of the amyloid-beta peptide that lead to aggregation associated with Alzheimer's disease are not fully understood. This study aims at identifying conformational differences among four variants of full-length Abeta42 that are known to display very different aggregation properties. By extensive all-atom Monte Carlo simulations, we find that a variety of beta-sheet structures with distinct turns are readily accessible for full-length Abeta42. In the simulations, wild type (WT) Abeta42 preferentially populates two major classes of conformations, either extended with high beta-sheet content or more compact with lower beta-sheet content. The three mutations studied alter the balance between these classes. Strong mutational effects are observed in a region centered at residues 23-26, where WT Abeta42 tends to form a turn. The aggregation-accelerating E22G mutation associated with early onset of Alzheimer's disease makes this turn region conformationally more diverse, whereas the aggregation-decelerating F20E mutation has the reverse effect, and the E22G/I31E mutation reduces the turn population. Comparing results for the four Abeta42 variants, we identify specific conformational properties of residues 23-26 that might play a key role in aggregation. Proteins 2010. (c) 2010 Wiley-Liss, Inc.
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| 10. |
- 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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| 11. |
- Mitternacht, Simon, et al.
(författare)
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Monte Carlo Study of the Formation and Conformational Properties of Dimers of Aβ42 Variants.
- 2011
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 1089-8638 .- 0022-2836. ; 410:2, s. 357-367
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Tidskriftsartikel (refereegranskat)abstract
- Small soluble oligomers, as well as dimers in particular, of the amyloid β-peptide (Aβ) are believed to play an important pathological role in Alzheimer's disease. Here, we investigate the spontaneous dimerization of Aβ42, with 42 residues, by implicit solvent all-atom Monte Carlo simulations, for the wild-type peptide and the mutants F20E, E22G and E22G/I31E. The observed dimers of these variants share many overall conformational characteristics but differ in several aspects at a detailed level. In all four cases, the most common type of secondary structure is intramolecular antiparallel β-sheets. Parallel, in-register β-sheet structure, as in models for Aβ fibrils, is rare. The primary force driving the formation of dimers is hydrophobic attraction. The conformational differences that we do see involve turns centered in the 20-30 region. The probability of finding turns centered in the 25-30 region, where there is a loop in Aβ fibrils, is found to increase upon dimerization and to correlate with experimentally measured rates of fibril formation for the different Aβ42 variants. Our findings hint at reorganization of this part of the molecule as a potentially critical step in Aβ aggregation.
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| 12. |
- Mitternacht, Simon
(författare)
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Protein dynamics: aggregation and mechanical unfolding
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The subject of this thesis is protein dynamics. Papers I--IV and VI study either of two different processes: mechanical unfolding and aggregation. Paper V presents a computationally efficient all-atom model for proteins, variants of which are used to perform Monte Carlo simulations in the other papers. Mechanical unfolding experiments probe properties of proteins at the single molecule level. The only information obtained the experiments is the extension and resisting force of the molecule. We perform all-atom simulations to generate a detailed description of the unfolding process. Papers I and II discuss the mechanical and thermal unfolding of the protein ubiquitin. The principal finding of Paper I is that ubiquitin unfolds through a well-defined pathway and that the experimentally observed non-obligatory unfolding intermediate lies on this pathway. Paper II compares mechanical unfolding pathways with thermal unfolding pathways. In Paper IV we study the mechanical unfolding of the protein FNIII-10 and find that it has three important, mutually exclusive, unfolding pathways and that the balance between the three can be shifted by changing the pulling strength. Paper III describes oligomerization of six-chain systems of the disease-related peptide Abeta(16-22). We find that disordered oligomers of different sizes dominate at high temperatures and as temperature is lowered, larger, more structured, oligomers form. In particular a very stable beta-barrel structure forms. Paper VI is an investigation of the effect of mutations on the folding properties of the peptide Abeta42 from Alzheimer's disease. Small aggregates of this peptide are believedto be important toxic agents. We find that a disease-related mutant peptide, with an elevated aggregation propensity, has a larger conformational diversity than the wild-type peptide, whereas a mutation that is known to inhibit aggregation has the opposite effect.
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| 13. |
- Mohanty, Sandipan, et al.
(författare)
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Protein folding, aggregation and unfolding in Monte Carlo Simulations
- 2010
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Ingår i: Physics Procedia. - : Elsevier BV. - 1875-3892. ; 7, s. 68-71
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Konferensbidrag (refereegranskat)abstract
- An implicit water all-atom model is used to study folding, aggregation and mechanical unfolding of small proteins. Physically reasonable results obtained for a variety of applications indicate healthy global properties of the interaction potential.
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