| 1. |
|
|
| 2. |
|
|
| 3. |
- Bille, Anna, et al.
(författare)
-
Equilibrium simulation of trp-cage in the presence of protein crowders.
- 2015
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 143:17
-
Tidskriftsartikel (refereegranskat)abstract
- While steric crowders tend to stabilize globular proteins, it has been found that protein crowders can have an either stabilizing or destabilizing effect, where a destabilization may arise from nonspecific attractive interactions between the test protein and the crowders. Here, we use Monte Carlo replica-exchange methods to explore the equilibrium behavior of the miniprotein trp-cage in the presence of protein crowders. Our results suggest that the surrounding crowders prevent trp-cage from adopting its global native fold, while giving rise to a stabilization of its main secondary-structure element, an α-helix. With the crowding agent used (bovine pancreatic trypsin inhibitor), the trp-cage-crowder interactions are found to be specific, involving a few key residues, most of which are prolines. The effects of these crowders are contrasted with those of hard-sphere crowders.
|
|
| 4. |
- Bille, Anna, et al.
(författare)
-
Local Unfolding and Aggregation Mechanisms of SOD1: A Monte Carlo Exploration.
- 2013
-
Ingår i: The Journal of Physical Chemistry Part B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 117:31, s. 9194-9202
-
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.
|
|
| 5. |
- Bille, Anna, et al.
(författare)
-
Peptide folding in the presence of interacting protein crowders
- 2016
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 144:17
-
Tidskriftsartikel (refereegranskat)abstract
- Using Monte Carlo methods, we explore and compare the effects of two protein crowders, BPTI and GB1, on the folding thermodynamics of two peptides, the compact helical trp-cage and the β-hairpin-forming GB1m3. The thermally highly stable crowder proteins are modeled using a fixed backbone and rotatable side-chains, whereas the peptides are free to fold and unfold. In the simulations, the crowder proteins tend to distort the trp-cage fold, while having a stabilizing effect on GB1m3. The extent of the effects on a given peptide depends on the crowder type. Due to a sticky patch on its surface, BPTI causes larger changes than GB1 in the melting properties of the peptides. The observed effects on the peptides stem largely from attractive and specific interactions with the crowder surfaces, and differ from those seen in reference simulations with purely steric crowder particles.
|
|
| 6. |
- Bille, Anna, et al.
(författare)
-
Stability and Local Unfolding of SOD1 in the Presence of Protein Crowders
- 2019
-
Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 123:9, s. 1920-1930
-
Tidskriftsartikel (refereegranskat)abstract
- Using NMR and Monte Carlo (MC) methods, we investigate the stability and dynamics of superoxide dismutase 1 (SOD1) in homogeneous crowding environments, where either bovine pancreatic trypsin inhibitor (BPTI) or the B1 domain of streptococcal protein G (PGB1) serves as a crowding agent. By NMR, we show that both crowders, and especially BPTI, cause a drastic loss in the overall stability of SOD1 in its apo monomeric form. Additionally, we determine chemical shift perturbations indicating that SOD1 interacts with the crowder proteins in a residue-specific manner that further depends on the identity of the crowding protein. Furthermore, the specificity of SOD1-crowder interactions is reciprocal: chemical shift perturbations on BPTI and PGB1 identify regions that interact preferentially with SOD1. By MC simulations, we investigate the local unfolding of SOD1 in the absence and presence of the crowders. We find that the crowders primarily interact with the long flexible loops of the folded SOD1 monomer. The basic mechanisms by which the SOD1 β-barrel core unfolds remain unchanged when adding the crowders. In particular, both with and without the crowders, the second β-sheet of the barrel is more dynamic and unfolding-prone than the first. Notably, the MC simulations (exploring the early stages of SOD1 unfolding) and the NMR experiments (under equilibrium conditions) identify largely the same set of PGB1 and BPTI residues as prone to form SOD1 contacts. Thus, contacts stabilizing the unfolded state of SOD1 in many cases appear to form early in the unfolding reaction.
|
|
| 7. |
- Favrin, Giorgio, et al.
(författare)
-
Folding of a small helical protein using hydrogen bonds and hydrophobicity forces.
- 2002
-
Ingår i: Proteins. - : Wiley. - 0887-3585. ; 47:2, s. 99-105
-
Tidskriftsartikel (refereegranskat)abstract
- A reduced protein model with five to six atoms per amino acid and five amino acid types is developed and tested on a three-helix-bundle protein, a 46-amino acid fragment from staphylococcal protein A. The model does not rely on the widely used Go approximation, which ignores non-native interactions. We find that the collapse transition is considerably more abrupt for the protein A sequence than for random sequences with the same composition. The chain collapse is found to be at least as fast as helix formation. Energy minimization restricted to the thermodynamically favored topology gives a structure that has a root-mean-square deviation of 1.8 A from the native structure. The sequence-dependent part of our potential is pairwise additive. Our calculations suggest that fine-tuning this potential by parameter optimization is of limited use.
|
|
| 8. |
- Favrin, Giorgio, et al.
(författare)
-
Monte Carlo update for chain molecules: Biased Gaussian steps in torsional space
- 2001
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 114:8, s. 8154-8158
-
Tidskriftsartikel (refereegranskat)abstract
- We develop a new elementary move for simulations of polymer chains in torsion angle space. The method is flexible and easy to implement. Tentative updates are drawn from a (conformation-dependent) Gaussian distribution that favors approximately local deformations of the chain. The degree of bias is controlled by a parameter b. The method is tested on a reduced model protein with 54 amino acids and the Ramachandran torsion angles as its only degrees of freedom, for different b. Without excessive fine tuning, we find that the effective step size can be increased by a factor of 3 compared to the unbiased b = 0 case. The method may be useful for kinetic studies, too.
|
|
| 9. |
- Favrin, Giorgio, et al.
(författare)
-
Oligomerization of amyloid A beta(16-22) peptides using hydrogen bonds and hydrophobicity forces
- 2004
-
Ingår i: Biophysical Journal. - : Elsevier BV. - 1542-0086 .- 0006-3495. ; 87:6, s. 3657-3664
-
Tidskriftsartikel (refereegranskat)abstract
- The 16 - 22 amino-acid fragment of the beta-amyloid peptide associated with the Alzheimer's disease, Abeta, is capable of forming amyloid fibrils. Here we study the aggregation mechanism of Abeta(16-22) peptides by unbiased thermodynamic simulations at the atomic level for systems of one, three, and six Abeta(16-22) peptides. We find that the isolated Abeta(16-22) peptide is mainly a random coil in the sense that both the alpha-helix and beta-strand contents are low, whereas the three- and six-chain systems form aggregated structures with a high beta-sheet content. Furthermore, in agreement with experiments on Abeta(16-22) fibrils, we find that large parallel beta-sheets are unlikely to form. For the six-chain system, the aggregated structures can have many different shapes, but certain particularly stable shapes can be identified.
|
|
| 10. |
- Favrin, Giorgio, et al.
(författare)
-
Sequence-based study of two related proteins with different folding behaviors
- 2004
-
Ingår i: Proteins. - : Wiley. - 0887-3585. ; 54:1, s. 8-12
-
Tidskriftsartikel (refereegranskat)abstract
- Z(SPA-1) is an engineered protein that binds to its parent, the three-helix-bundle Z domain of staphylococcal protein A. Uncomplexed Z(SPA-1) shows a reduced helix content and a melting behavior that is less cooperative, compared with the wild-type Z domain. Here we show that the difference in folding behavior between these two sequences can be partly understood in terms of an off-lattice model with 5-6 atoms per amino acid and a minimalistic potential, in which folding is driven by backbone hydrogen bonding and effective hydrophobic attraction. (C) 2003 Wiley-Liss, Inc.
|
|
| 11. |
- Favrin, Giorgio, et al.
(författare)
-
Two-state folding over a weak free-energy barrier
- 2003
-
Ingår i: Biophysical Journal. - 1542-0086. ; 85:3, s. 1457-1465
-
Tidskriftsartikel (refereegranskat)abstract
- We present a Monte Carlo study of a model protein with 54 amino acids that folds directly to its native three-helix-bundle state without forming any well-defined intermediate state. The free-energy barrier separating the native and unfolded states of this protein is found to be weak, even at the folding temperature. Nevertheless, we find that melting curves to a good approximation can be described in terms of a simple two-state system, and that the relaxation behavior is close to single exponential. The motion along individual reaction coordinates is roughly diffusive on timescales beyond the reconfiguration time for a single helix. A simple estimate based on diffusion in a square-well potential predicts the relaxation time within a factor of two.
|
|
| 12. |
- Gupta, N, et al.
(författare)
-
Coupled folding-binding versus docking: A lattice model study
- 2004
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 120:8, s. 3983-3989
-
Tidskriftsartikel (refereegranskat)abstract
- Using a simple hydrophobic/polar protein model, we perform a Monte Carlo study of the thermodynamics and kinetics of binding to a target structure for two closely related sequences, one of which has a unique folded state while the other is unstructured. We obtain significant differences in their binding behavior. The stable sequence has rigid docking as its preferred binding mode, while the unstructured chain tends to first attach to the target and then fold. The free-energy profiles associated with these two binding modes are compared. (C) 2004 American Institute of Physics.
|
|
| 13. |
- Holzgräfe, Christian, et al.
(författare)
-
Hybrid Monte Carlo with non-uniform step size
- 2014
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 140:4
-
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.
|
|
| 14. |
- Holzgräfe, Christian, et al.
(författare)
-
Mutation-induced fold switching among lattice proteins.
- 2011
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 135:19
-
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.
|
|
| 15. |
- Irbäck, Anders
(författare)
-
A minimalistic all-atom approach to protein folding
- 2003
-
Ingår i: Journal of Physics: Condensed Matter. - : IOP Publishing. - 1361-648X .- 0953-8984. ; 15:18, s. 1797-1807
-
Tidskriftsartikel (refereegranskat)abstract
- Using simple sequence-based potentials, the folding properties of a designed three-helix-bundle protein, an alpha-helix and a beta-hairpin are studied. The three-helix-bundle protein is modelled using 5-6 atoms per amino acid and is found to undergo a first-order-like folding transition in which chain collapse and helix formation cannot be separated, which is in-accord with experimental data. The other two sequences are studied using a model that contains all atoms and are indeed found to make an alpha-helix and a beta-hairpin, respectively, for exactly the same choice of parameters. The calculated melting curves are, moreover, in reasonable quantitative agreement with experimental data, for both peptides. The melting curves are found to be quite well described by a simple two-state model, although the energy distributions lack a clear bimodal shape.
|
|
| 16. |
- Irbäck, Anders, et al.
(författare)
-
Aggregate geometry in amyloid fibril nucleation.
- 2013
-
Ingår i: Physical Review Letters. - 1079-7114. ; 110:5
-
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.
|
|
| 17. |
- Irbäck, Anders, et al.
(författare)
-
All-atom Monte Carlo simulations of protein folding and aggregation
- 2013
-
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
-
Bokkapitel (refereegranskat)
|
|
| 18. |
- Irbäck, Anders, et al.
(författare)
-
An effective all-atom potential for proteins
- 2009
-
Ingår i: Food Biophysics. - : Springer Science and Business Media LLC. - 1557-1866. ; 2:1, s. 2-2
-
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.
|
|
| 19. |
- Irbäck, Anders, et al.
(författare)
-
Dissecting the mechanical unfolding of ubiquitin
- 2005
-
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
-
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.
|
|
| 20. |
- Irbäck, Anders, et al.
(författare)
-
Effective all-atom potentials for proteins
- 2011
-
Ingår i: Multiscale approaches to protein modeling. - New York, NY : Springer New York. - 9781441968883 - 9781441968890 ; , s. 111-126
-
Bokkapitel (refereegranskat)
|
|
| 21. |
|
|
| 22. |
- Irbäck, Anders, et al.
(författare)
-
Folding thermodynamics of peptides
- 2005
-
Ingår i: Biophysical Journal. - : Elsevier BV. - 1542-0086 .- 0006-3495. ; 88:3, s. 1560-1569
-
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.
|
|
| 23. |
- Irbäck, Anders, et al.
(författare)
-
Folding thermodynamics of three beta-sheet peptides: A model study
- 2004
-
Ingår i: Proteins. - : Wiley. - 0887-3585. ; 56:1, s. 110-116
-
Tidskriftsartikel (refereegranskat)abstract
- We study the folding thermodynamics of a beta-hairpin and two three-stranded beta-sheet peptides using a simplified sequence-based all-atom model, in which folding is driven mainly by backbone hydrogen bonding and effective hydrophobic attraction. The native populations obtained for these three sequences are in good. agreement with experimental data. We also show that the apparent native population depends on which observable is studied; the hydrophobicity energy and the number of native hydrogen bonds give different results. The magnitude of this dependence matches well with the results obtained in two different experiments on the beta-hairpin. (C) 2004 Wiley-Liss, Inc.
|
|
| 24. |
|
|
| 25. |
- Irbäck, Anders, et al.
(författare)
-
Identification of amino acid sequences with good folding properties in an off-lattice model
- 1997
-
Ingår i: Physical Review E. - 1063-651X. ; 55:1 SUPPL. B, s. 860-867
-
Tidskriftsartikel (refereegranskat)abstract
- Folding properties of a two-dimensional toy protein model containing only two amino acid types, hydrophobic and hydrophilic, respectively, are analyzed. An efficient Monte Carlo procedure is employed to ensure that the ground states are found. The thermodynamic properties are found to be strongly sequence dependent in contrast to the kinetic ones. Hence, criteria for good folders are defined entirely in terms of thermodynamic fluctuations. With these criteria sequence patterns that fold well are isolated. For 300 chains with 20 randomly chosen binary residues approximately 10% meet these criteria. Also, an analysis is performed by means of statistical and artificial neural network methods from which it is concluded that the folding properties can be predicted to a certain degree given the binary numbers characterizing the sequences.
|
|
| 26. |
- Irbäck, Anders, et al.
(författare)
-
Local interactions and protein folding : A model study on the square and triangular lattices
- 1998
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 108:5, s. 2245-2250
-
Tidskriftsartikel (refereegranskat)abstract
- We study a simple heteropolymer model containing sequence-independent local interactions on both square and triangular lattices. Sticking to a two-letter code, we investigate the model for varying strength κ of the local interactions; κ=0 corresponds to the well-known HP model [K. F. Lau and K. A. Dill, Macromolecules 22, 3986 (1989)]. By exhaustive enumerations for short chains, we obtain all structures which act as a unique and pronounced energy minimum for at least one sequence. We find that the number of such designable structures depends strongly on κ. Also, we find that the number of designable structures can differ widely for the two lattices at a given κ. This is the case, for example, at κ=0, which implies that the HP model exhibits different behavior on the two lattices. Our findings clearly show that sequence-independent local properties of the chains can play an important rote in the formation of unique minimum energy structures.
|
|
| 27. |
- Irbäck, Anders, et al.
(författare)
-
Local interactions and protein folding : A three-dimensional off-lattice approach
- 1997
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 107:1, s. 273-282
-
Tidskriftsartikel (refereegranskat)abstract
- The thermodynamic behavior of a three-dimensional off-lattice model for protein folding is probed. The model has only two types of residues, hydrophobia and hydrophilic. In absence of local interactions, native structure formation does not occur for the temperatures considered. By including sequence independent local interactions, which qualitatively reproduce local properties of functional proteins, the dominance of a native state for many sequences is observed. As in lattice model approaches, folding takes place by gradual compactification, followed by a sequence dependent folding transition. Our results differ from lattice approaches in that bimodal energy distributions are not observed and that high folding temperatures are accompanied by relatively low temperatures for the peak of the specific heat. Also, in contrast to earlier studies using lattice models, our results convincingly demonstrate that one does not need more than two types of residues to generate sequences with good thermodynamic folding properties in three dimensions.
|
|
| 28. |
- Irbäck, Anders, et al.
(författare)
-
Monte Carlo procedure for protein design
- 1998
-
Ingår i: Physical Review E. - 1063-651X. ; 58:5
-
Tidskriftsartikel (refereegranskat)abstract
- A method for sequence optimization in protein models is presented. The approach, which has inherited its basic philosophy from recent work by Deutsch and Kurosky [Phys. Rev. Lett. 76, 323 (1996)] by maximizing conditional probabilities rather than minimizing energy functions, is based upon a different and very efficient multisequence Monte Carlo scheme. By construction, the method ensures that the designed sequences represent good folders thermodynamically. A bootstrap procedure for the sequence space search is devised making very large chains feasible. The algorithm is successfully explored on the two-dimensional HP model [K. F. Lau and K. A. Dill, Macromolecules 32, 3986 (1989)] with chain lengths N= 16, 18, and 32.
|
|
| 29. |
- Irbäck, Anders, et al.
(författare)
-
Monte Carlo study of the phase structure of compact polymer chains
- 1999
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 110:24, s. 12256-12262
-
Tidskriftsartikel (refereegranskat)abstract
- We study the phase behavior of single homopolymers in a simple hydrophobic/hydrophilic off-lattice model with sequence independent local interactions. The specific heat is, not unexpectedly, found to exhibit a pronounced peak well below the collapse temperature, signalling a possible low-temperature phase transition. The system size dependence at this maximum is investigated both with and without the local interactions, using chains with up to 50 monomers. The size dependence is found to be weak. The specific heat itself seems not to diverge. The homopolymer results are compared with those for two nonuniform sequences. Our calculations are performed using the methods of simulated and parallel tempering. The performances of these algorithms are discussed, based on careful tests for a small system.
|
|
| 30. |
|
|
| 31. |
- Irbäck, Anders
(författare)
-
Peptide folding and aggregation studied using a simplified atomic model
- 2005
-
Ingår i: Journal of Physics: Condensed Matter. - : IOP Publishing. - 1361-648X .- 0953-8984. ; 17:18, s. 1553-1564
-
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.
|
|
| 32. |
- Irbäck, Anders, et al.
(författare)
-
PROFASI: A Monte Carlo simulation package for protein folding and aggregation
- 2006
-
Ingår i: Journal of Computational Chemistry. - : Wiley. - 1096-987X .- 0192-8651. ; 27:13, s. 1548-1555
-
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.
|
|
| 33. |
|
|
| 34. |
- Irbäck, Anders
(författare)
-
Protein folding in the absence of a clear free-energy barrier
- 2003
-
Ingår i: Acta Physica Polonica. Series B: Elementary Particle Physics, Nuclear Physics, Statistical Physics, Theory of Relativity, Field Theory. - 0587-4254. ; 34:10, s. 4867-4878
-
Tidskriftsartikel (refereegranskat)abstract
- Many small proteins fold in a two-state manner, the rate-limiting step being the passage of the free-energy barrier separating the unfolded state from the native one. The free-energy barrier is, however, weak or absent for the fastest-folding proteins. Here a simple diffusion picture for such proteins is discussed. It is tested on a model protein that makes a three-helix bundle. Assuming the motion along individual reaction coordinates to be diffusive on timescales beyond the reconfiguration time for a single helix, it is found that the relaxation time can be predicted within a factor of two. It is also shown that melting curves for this protein to a good approximation can be described in terms of a simple two-state system, despite the absence of a clear free-energy barrier.
|
|
| 35. |
|
|
| 36. |
- Irbäck, Anders, et al.
(författare)
-
Protein folding/unfolding in the presence of interacting macromolecular crowders
- 2017
-
Ingår i: European Physical Journal: Special Topics. - : Springer Science and Business Media LLC. - 1951-6355 .- 1951-6401. ; 226:4, s. 627-638
-
Forskningsöversikt (refereegranskat)abstract
- Recent years have seen an increasing number of biophysical studies of proteins being conducted in cells and concentrated protein solutions. In these experiments, compared to dilute-solution data, both stabilization and destabilization of globular proteins have been observed, which cannot be explained in terms of volume exclusion alone. For a fundamental understanding of the observed effects, there is a need for computational modeling beyond the level of hard-sphere crowders. This mini-review discusses recent efforts to simulate folding/unfolding properties of proteins in the presence of explicit macromolecular crowders. A Monte Carlo-based approach by us is described, which we recently applied to study the equilibrium folding thermodynamics of two peptides in the presence of explicit protein crowders.
|
|
| 37. |
- Irbäck, Anders, et al.
(författare)
-
Sequence dependence of self-interacting random chains
- 1995
-
Ingår i: Journal of Physics A: Mathematical and General. - : IOP Publishing. - 0305-4470 .- 1361-6447. ; 28:8, s. 2121-2132
-
Tidskriftsartikel (refereegranskat)abstract
- We study the thermodynamic behaviour of the random chain model proposed by Iori, Marinari and Parisi and how this behaviour depends on the actual sequence of interactions along the chain. The properties of randomly chosen sequences are compared to those of designed sequences obtained through a simulated annealing procedure in sequence space. We show that for designed sequences the transition to the folded phase takes place at a smaller strength of the quenched disorder. As a result, folding can be relatively fast for these sequences.
|
|
| 38. |
- Irbäck, Anders
(författare)
-
Sequence design in coarse-grained protein models
- 2000
-
Ingår i: Progress of Theoretical Physics Supplement. ; 138, s. 273-281
-
Konferensbidrag (refereegranskat)abstract
- Designing amino acid sequences that are stable in a given target structure amounts to maximizing a conditional probability. A straightforward approach to accomplish this is a nested Monte Carlo where the conformation space is explored over and over again for different fixed sequences. In this paper we discuss an alternative Monte Carlo approach, multisequence design, where conformation and sequence degrees of freedom are simultaneously probed. The method is explored on hydrophobic/polar models. A statistical analysis of sequence correlations is also discussed. It is found that hydrophobic/polar model sequences and enzymes display hydrophobicity correlations that are qualitatively similar.
|
|
| 39. |
- Irbäck, Anders, et al.
(författare)
-
Spontaneous beta-barrel formation: an all-atom study of Abeta(16-22) oligomerization
- 2008
-
Ingår i: Proteins. - : Wiley. - 0887-3585. ; 71:1, s. 207-214
-
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.
|
|
| 40. |
- Irbäck, Anders, et al.
(författare)
-
Studies of an off-lattice model for protein folding : Sequence dependence and improved sampling at finite temperature
- 1995
-
Ingår i: Journal of Chemical Physics. - 0021-9606. ; 103:23, s. 10298-10305
-
Tidskriftsartikel (refereegranskat)abstract
- We study the thermodynamic behavior of a simple off-lattice model for protein folding. The model is two dimensional and has two different "amino acids." Using numerical simulations of all chains containing eight or ten monomers, we examine the sequence dependence at a fixed temperature. It is shown that only a few of the chains exist in unique folded state at this temperature, and the energy level spectra of chains with different types of behavior are compared. Furthermore, we use this model as a testbed for two improved Monte Carlo algorithms. Both algorithms are based on letting some parameter of the model become a dynamical variable; one of the algorithms uses a fluctuating temperature and the other a fluctuating monomer sequence. We find that by these algorithms one gains large factors in efficiency in comparison with conventional methods.
|
|
| 41. |
- Irbäck, Anders, et al.
(författare)
-
Thermal versus mechanical unfolding of ubiquitin
- 2006
-
Ingår i: Proteins. - : Wiley. - 0887-3585. ; 65:3, s. 759-766
-
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.
|
|
| 42. |
- Irbäck, Anders, et al.
(författare)
-
Thermodynamics of amyloid formation and the role of intersheet interactions
- 2015
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 143:10
-
Tidskriftsartikel (refereegranskat)abstract
- The self-assembly of proteins into beta-sheet-rich amyloid fibrils has been observed to occur with sigmoidal kinetics, indicating that the system initially is trapped in a metastable state. Here, we use a minimal lattice-based model to explore the thermodynamic forces driving amyloid formation in a finite canonical (NVT) system. By means of generalized-ensemble Monte Carlo techniques and a semi-analytical method, the thermodynamic properties of this model are investigated for different sets of intersheet interaction parameters. When the interactions support lateral growth into multi-layered fibrillar structures, an evaporation/condensation transition is observed, between a supersaturated solution state and a thermodynamically distinct state where small and large fibril-like species exist in equilibrium. Intermediate-size aggregates are statistically suppressed. These properties do not hold if aggregate growth is one-dimensional. (C) 2015 AIP Publishing LLC.
|
|
| 43. |
- Irbäck, Anders, et al.
(författare)
-
Thermodynamics of α- and β-structure formation in proteins
- 2003
-
Ingår i: Biophysical Journal. - 1542-0086. ; 85:3, s. 1466-1473
-
Tidskriftsartikel (refereegranskat)abstract
- An atomic protein model with a minimalistic potential is developed and then tested on an α-helix and a β-hairpin, using exactly the same parameters for both peptides. We find that melting curves for these sequences to a good approximation can be described by a simple two-state model, with parameters that are in reasonable quantitative agreement with experimental data. Despite the apparent two-state character of the melting curves, the energy distributions are found to lack a clear bimodal shape, which is discussed in some detail. We also perform a Monte Carlo-based kinetic study and find, in accord with experimental data, that the α-helix forms faster than the β-hairpin.
|
|
| 44. |
- Jonsson, Sigurdur, et al.
(författare)
-
Accelerating atomic-level protein simulations by flat-histogram techniques.
- 2011
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 135:12
-
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.
|
|
| 45. |
- Jonsson, Sigurdur, et al.
(författare)
-
Distinct phases of free α-synuclein - A Monte Carlo study.
- 2012
-
Ingår i: Proteins. - : Wiley. - 0887-3585. ; 80:9, s. 2169-2177
-
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.
|
|
| 46. |
- Jonsson, Sigurdur, et al.
(författare)
-
Mechanical resistance in unstructured proteins.
- 2013
-
Ingår i: Biophysical Journal. - : Elsevier BV. - 1542-0086 .- 0006-3495. ; 104:12, s. 2725-2732
-
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.
|
|
| 47. |
- Jonsson, Sigurdur, et al.
(författare)
-
Monte Carlo studies of protein aggregation
- 2012
-
Ingår i: Physics Procedia. - : Elsevier BV. - 1875-3892. ; 34, s. 49-54
-
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.
|
|
| 48. |
- Li, Da-Wei, et al.
(författare)
-
Formation and Growth of Oligomers: A Monte Carlo Study of an Amyloid Tau Fragment
- 2008
-
Ingår i: PLoS Computational Biology. - : Public Library of Science (PLoS). - 1553-7358. ; 4:12
-
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.
|
|
| 49. |
- Li, Yuan, et al.
(författare)
-
When a foreign gene meets its native counterpart : computational biophysics analysis of two PgiC loci in the grass Festuca ovina
- 2020
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Duplicative horizontal gene transfer may bring two previously separated homologous genes together, which may raise questions about the interplay between the gene products. One such gene pair is the “native” PgiC1 and “foreign” PgiC2 in the perennial grass Festuca ovina. Both PgiC1 and PgiC2 encode cytosolic phosphoglucose isomerase, a dimeric enzyme whose proper binding is functionally essential. Here, we use biophysical simulations to explore the inter-monomer binding of the two homodimers and the heterodimer that can be produced by PgiC1 and PgiC2 in F. ovina. Using simulated native-state ensembles, we examine the structural properties and binding tightness of the dimers. In addition, we investigate their ability to withstand dissociation when pulled by a force. Our results suggest that the inter-monomer binding is tighter in the PgiC2 than the PgiC1 homodimer, which could explain the more frequent occurrence of the foreign PgiC2 homodimer in dry habitats. We further find that the PgiC1 and PgiC2 monomers are compatible with heterodimer formation; the computed binding tightness is comparable to that of the PgiC1 homodimer. Enhanced homodimer stability and capability of heterodimer formation with PgiC1 are properties of PgiC2 that may contribute to the retaining of the otherwise redundant PgiC2 gene.
|
|
| 50. |
- Luccioli, Stefano, et al.
(författare)
-
Unfolding times for proteins in a force clamp
- 2010
-
Ingår i: Physical Review E (Statistical, Nonlinear, and Soft Matter Physics). - 1539-3755. ; 81:1
-
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.
|
|
