| 1. |
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| 2. |
- Bille, Anna, et al.
(författare)
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Local Unfolding and Aggregation Mechanisms of SOD1: A Monte Carlo Exploration.
- 2013
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Ingår i: The Journal of Physical Chemistry Part B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 117:31, s. 9194-9202
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Tidskriftsartikel (refereegranskat)abstract
- Copper, zinc superoxide dismutase 1 (SOD1) is a ubiquitous homodimeric enzyme, whose misfolding and aggregation play a potentially key role in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). SOD1 aggregation is thought to be preceded by dimer dissociation and metal loss, but the mechanisms by which the metal-free monomer aggregates remain incompletely understood. Here we use implicit solvent all-atom Monte Carlo (MC) methods to investigate the local unfolding dynamics of the β-barrel-forming SOD1 monomer. Although event-to-event variations are large, on average, we find clear differences in dynamics among the eight strands forming the β-barrel. Most dynamic is the eighth strand, β8, which is located in the dimer interface of native SOD1. For the four strands in or near the dimer interface (β1, β2, β7, and β8), we perform aggregation simulations to assess the propensity of these chain segments to self-associate. We find that β1 and β2 readily self-associate to form intermolecular parallel β-sheets, whereas β8 shows a very low aggregation propensity.
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| 3. |
- Holzgräfe, Christian, et al.
(författare)
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Hybrid Monte Carlo with non-uniform step size
- 2014
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 140:4
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Tidskriftsartikel (refereegranskat)abstract
- The Hybrid Monte Carlo method offers a rigorous and potentially efficient approach to the simulation of dense systems, by combining numerical integration of Newton's equations of motion with a Metropolis accept-or-reject step. The Metropolis step corrects for sampling errors caused by the discretization of the equations of motion. The integration is usually performed using a uniform step size. Here, we present simulations of the Lennard-Jones system showing that the use of smaller time steps in the tails of each integration trajectory can reduce errors in energy. The acceptance rate is 10-15 percentage points higher in these runs, compared to simulations with the same trajectory length and the same number of integration steps but a uniform step size. We observe similar effects for the harmonic oscillator and a coarse-grained peptide model, indicating generality of the approach. (C) 2014 AIP Publishing LLC.
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| 4. |
- Holzgräfe, Christian, et al.
(författare)
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Mutation-induced fold switching among lattice proteins.
- 2011
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 135:19
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Tidskriftsartikel (refereegranskat)abstract
- Recent experiments uncovered a mutational pathway between two proteins, along which a single mutation causes a switch in fold. Searching for such paths between real proteins remains, despite this achievement, a true challenge. Here, we analyze fold switching in the minimalistic hydrophobic/polar model on a square lattice. For this analysis, we generate a comprehensive sequence-structure database for chains of length ≤ 30, which exceeds previous work by five units. Single-mutation-induced fold switching turns out to be quite common in the model. The switches define a fold network, whose topology is roughly similar to what one would expect for a set of randomly connected nodes. In the combinatorially challenging search for fold switches between two proteins, a tempting strategy is to only consider paths containing the minimum number of mutations. Such a restricted search fails to correctly identify 40% of the single-mutation-linked fold pairs that we observe. The thermodynamic stability is correlated with mutational stability and is, on average, markedly reduced at the observed fold switches.
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| 5. |
- Irbäck, Anders, et al.
(författare)
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Aggregate geometry in amyloid fibril nucleation.
- 2013
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Ingår i: Physical Review Letters. - 1079-7114. ; 110:5
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Tidskriftsartikel (refereegranskat)abstract
- We present and study a minimal structure-based model for the self-assembly of peptides into ordered β-sheet-rich fibrils. The peptides are represented by unit-length sticks on a cubic lattice and interact by hydrogen bonding and hydrophobicity forces. Using Monte Carlo simulations with >10^{5} peptides, we show that fibril formation occurs with sigmoidal kinetics in the model. To determine the mechanism of fibril nucleation, we compute the joint distribution in length and width of the aggregates at equilibrium, using an efficient cluster move and flat-histogram techniques. This analysis, based on simulations with 256 peptides in which aggregates form and dissolve reversibly, shows that the main free-energy barriers that a nascent fibril has to overcome are associated with changes in width.
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| 6. |
- Irbäck, Anders, et al.
(författare)
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All-atom Monte Carlo simulations of protein folding and aggregation
- 2013
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Ingår i: Computational methods to study the structure and dynamics of biomolecules and biomolecular processes: from bioinformatics to molecular quantum mechanics. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 2193-9357 .- 2193-9349. - 9783642285530 - 9783642285547 ; 1, s. 433-444
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Bokkapitel (refereegranskat)
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| 7. |
- Irbäck, Anders, et al.
(författare)
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Effective all-atom potentials for proteins
- 2011
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Ingår i: Multiscale approaches to protein modeling. - New York, NY : Springer New York. - 9781441968883 - 9781441968890 ; , s. 111-126
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Bokkapitel (refereegranskat)
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| 8. |
- Jonsson, Sigurdur, et al.
(författare)
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Accelerating atomic-level protein simulations by flat-histogram techniques.
- 2011
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 135:12
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Tidskriftsartikel (refereegranskat)abstract
- Flat-histogram techniques provide a powerful approach to the simulation of first-order-like phase transitions and are potentially very useful for protein studies. Here, we test this approach by implicit solvent all-atom Monte Carlo (MC) simulations of peptide aggregation, for a 7-residue fragment (GIIFNEQ) of the Cu/Zn superoxide dismutase 1 protein (SOD1). In simulations with 8 chains, we observe two distinct aggregated/non-aggregated phases. At the midpoint temperature, these phases coexist, separated by a free-energy barrier of height 2.7 k(B)T. We show that this system can be successfully studied by carefully implemented flat-histogram techniques. The frequency of barrier crossing, which is low in conventional canonical simulations, can be increased by turning to a two-step procedure based on the Wang-Landau and multicanonical algorithms.
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| 9. |
- Jonsson, Sigurdur, et al.
(författare)
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Distinct phases of free α-synuclein - A Monte Carlo study.
- 2012
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Ingår i: Proteins. - : Wiley. - 0887-3585. ; 80:9, s. 2169-2177
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Tidskriftsartikel (refereegranskat)abstract
- The α-synuclein protein (αS), implicated in Parkinson's disease (PD), shows conformational versatility. It aggregates into β-sheet-rich fibrils, occurs in helical membrane-bound forms, is disordered as a free monomer, and has recently been suggested to have a folded helical tetramer as its main physiological form. Here we use implicit solvent all-atom Monte Carlo (MC) methods to explore the conformational ensemble sampled by the free αS monomer. We analyze secondary-structure propensities, size and topological properties, and compare with existing experimental data. Our study suggests that free αS has two distinct phases. One phase has the expected disordered character. The other phase also shows large conformational variability. However, in this phase, the β-strand content is substantial, and the backbone fold shows statistical similarities with that in αS fibrils. Presence of this phase is consistent with data from low-temperature experiments. Conversion of disordered αS to this fibril-like form requires the crossing of a rather large apparent free-energy barrier. Proteins 2012. © 2012 Wiley Periodicals, Inc.
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| 10. |
- 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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| 11. |
- Jonsson, Sigurdur, et al.
(författare)
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Monte Carlo studies of protein aggregation
- 2012
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Ingår i: Physics Procedia. - : Elsevier BV. - 1875-3892. ; 34, s. 49-54
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Konferensbidrag (refereegranskat)abstract
- The disease-linked amyloid beta (A beta) and alpha-synuclein (alpha S) proteins are both fibril-forming and natively unfolded in free monomeric form. Here, we discuss two recent studies, where we used extensive implicit solvent all-atom Monte Carlo (MC) simulations to elucidate the conformational ensembles sampled by these proteins. For alpha S, we somewhat unexpectedly observed two distinct phases, separated by a clear free-energy barrier. The presence of the barrier makes alpha S, with 140 residues, a challenge to simulate. By using a two-step simulation procedure based on flat-histogram techniques, it was possible to alleviate this problem. The barrier may in part explain why fibril formation is much slower for alpha S than it is for A beta.
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| 12. |
- 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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| 13. |
- 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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| 14. |
- 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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| 15. |
- 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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| 16. |
- Petrlova, Jitka, et al.
(författare)
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Conformational and aggregation properties of the 1-93 fragment of apolipoprotein A-I
- 2014
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Ingår i: Protein Science. - : Wiley. - 1469-896X .- 0961-8368. ; 23:11, s. 71-1559
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Tidskriftsartikel (refereegranskat)abstract
- Several disease-linked mutations of apolipoprotein A-I, the major protein in high-density lipoprotein (HDL), are known to be amyloidogenic, and the fibrils often contain N-terminal fragments of the protein. Here, we present a combined computational and experimental study of the fibril-associated disordered 1-93 fragment of this protein, in wild-type and mutated (G26R, S36A, K40L, W50R) forms. In atomic-level Monte Carlo simulations of the free monomer, validated by circular dichroism spectroscopy, we observe changes in the position-dependent β-strand probability induced by mutations. We find that these conformational shifts match well with the effects of these mutations in thioflavin T fluorescence and transmission electron microscopy experiments. Together, our results point to molecular mechanisms that may have a key role in disease-linked aggregation of apolipoprotein A-I.
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| 17. |
- Tian, Pengfei, et al.
(författare)
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Robust Estimation of Diffusion-Optimized Ensembles for Enhanced Sampling
- 2014
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 10:2, s. 543-553
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Tidskriftsartikel (refereegranskat)abstract
- The multicanonical, or flat-histogram, method is a common technique to improve the sampling efficiency of molecular simulations. The idea is that free-energy barriers in a simulation can be removed by simulating from a distribution where all values of a reaction coordinate are equally likely, and subsequently reweight the obtained statistics to recover the Boltzmann distribution at the temperature of interest. While this method has been successful in practice, the choice of a flat distribution is not necessarily optimal. Recently, it was proposed that additional performance gains could be obtained by taking the position-dependent diffusion coefficient into account, thus placing greater emphasis on regions diffusing slowly. Although some promising examples of applications of this approach exist, the practical usefulness of the method has been hindered by the difficulty in obtaining sufficiently accurate estimates of the diffusion coefficient. Here, we present a simple, yet robust solution to this problem. Compared to current state-of-the-art procedures, the new estimation method requires an order of magnitude fewer data to obtain reliable estimates, thus broadening the potential scope in which this technique can be applied in practice.
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