Biomedical subjects

Anders Irbäck

Publications and source records attributed to Anders Irbäck.

11 recordsLinked to original sources

PubMed2006

Thermal versus mechanical unfolding of ubiquitin.

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 beta-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.

Monte Carlo Method↗

PubMed2006

PROFASI: A Monte Carlo simulation package for protein folding and aggregation.

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.

Algorithms↗

PubMed2005

Dissecting the mechanical unfolding of ubiquitin.

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.

Models, Molecular↗

PubMed2004

Folding thermodynamics of peptides.

A simplified interaction potential for protein folding studies at the atomic level is discussed and tested on a set of peptides with approximately 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.

Computer Simulation↗

PubMed2004

Oligomerization of amyloid Abeta16-22 peptides using hydrogen bonds and hydrophobicity forces.

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 Abeta16-22 peptides by unbiased thermodynamic simulations at the atomic level for systems of one, three, and six Abeta16-22 peptides. We find that the isolated Abeta16-22 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 Abeta16-22 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.

Amyloid beta-Peptides↗

PubMed2004

Folding thermodynamics of three beta-sheet peptides: a model study.

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.

Hydrogen Bonding↗

PubMed2004

Coupled folding-binding versus docking: a lattice model study.

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.

Journal Article↗

PubMed2004

Sequence-based study of two related proteins with different folding behaviors.

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.

Amino Acid Sequence↗

PubMed2003

Two-state folding over a weak free-energy barrier.

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.

Amino Acids↗

PubMed2003

Thermodynamics of alpha- and beta-structure formation in proteins.

An atomic protein model with a minimalistic potential is developed and then tested on an alpha-helix and a beta-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 alpha-helix forms faster than the beta-hairpin.

Hydrogen Bonding↗

PubMed2002

Folding of a small helical protein using hydrogen bonds and hydrophobicity forces.

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.

Amino Acid Sequence↗