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- Keasar, Chen, et al.
(författare)
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An analysis and evaluation of the WeFold collaborative for protein structure prediction and its pipelines in CASP11 and CASP12
- 2018
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Every two years groups worldwide participate in the Critical Assessment of Protein Structure Prediction (CASP) experiment to blindly test the strengths and weaknesses of their computational methods. CASP has significantly advanced the field but many hurdles still remain, which may require new ideas and collaborations. In 2012 a web-based effort called WeFold, was initiated to promote collaboration within the CASP community and attract researchers from other fields to contribute new ideas to CASP. Members of the WeFold coopetition (cooperation and competition) participated in CASP as individual teams, but also shared components of their methods to create hybrid pipelines and actively contributed to this effort. We assert that the scale and diversity of integrative prediction pipelines could not have been achieved by any individual lab or even by any collaboration among a few partners. The models contributed by the participating groups and generated by the pipelines are publicly available at the WeFold website providing a wealth of data that remains to be tapped. Here, we analyze the results of the 2014 and 2016 pipelines showing improvements according to the CASP assessment as well as areas that require further adjustments and research.
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| 4. |
- Lensink, Marc F., et al.
(författare)
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Impact of AlphaFold on structure prediction of protein complexes: The CASP15-CAPRI experiment
- 2023
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Ingår i: Proteins. - : WILEY. - 0887-3585 .- 1097-0134.
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Tidskriftsartikel (refereegranskat)abstract
- We present the results for CAPRI Round 54, the 5th joint CASP-CAPRI protein assembly prediction challenge. The Round offered 37 targets, including 14 homodimers, 3 homo-trimers, 13 heterodimers including 3 antibody-antigen complexes, and 7 large assemblies. On average similar to 70 CASP and CAPRI predictor groups, including more than 20 automatics servers, submitted models for each target. A total of 21 941 models submitted by these groups and by 15 CAPRI scorer groups were evaluated using the CAPRI model quality measures and the DockQ score consolidating these measures. The prediction performance was quantified by a weighted score based on the number of models of acceptable quality or higher submitted by each group among their five best models. Results show substantial progress achieved across a significant fraction of the 60+ participating groups. High-quality models were produced for about 40% of the targets compared to 8% two years earlier. This remarkable improvement is due to the wide use of the AlphaFold2 and AlphaFold2-Multimer software and the confidence metrics they provide. Notably, expanded sampling of candidate solutions by manipulating these deep learning inference engines, enriching multiple sequence alignments, or integration of advanced modeling tools, enabled top performing groups to exceed the performance of a standard AlphaFold2-Multimer version used as a yard stick. This notwithstanding, performance remained poor for complexes with antibodies and nanobodies, where evolutionary relationships between the binding partners are lacking, and for complexes featuring conformational flexibility, clearly indicating that the prediction of protein complexes remains a challenging problem.
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- Chrabaszczewska, Magdalena, et al.
(författare)
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Structural characterization of covalently stabilized human cystatin c oligomers
- 2020
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 21:16
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Tidskriftsartikel (refereegranskat)abstract
- Human cystatin C (HCC), a cysteine-protease inhibitor, exists as a folded monomer under physiological conditions but has the ability to self-assemble via domain swapping into multimeric states, including oligomers with a doughnut-like structure. The structure of the monomeric HCC has been solved by X-ray crystallography, and a covalently linked version of HCC (stab-1 HCC) is able to form stable oligomeric species containing 10–12 monomeric subunits. We have performed molecular modeling, and in conjunction with experimental parameters obtained from atomic force microscopy (AFM), transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS) measurements, we observe that the structures are essentially flat, with a height of about 2 nm, and the distance between the outer edge of the ring and the edge of the central cavity is ~5.1 nm. These dimensions correspond to the height and diameter of one stab-1 HCC subunit and we present a dodecamer model for stabilized cystatin C oligomers using molecular dynamics simulations and experimentally measured parameters. Given that oligomeric species in protein aggregation reactions are often transient and very highly heterogeneous, the structural information presented here on these isolated stab-1 HCC oligomers may be useful to further explore the physiological relevance of different structural species of cystatin C in relation to protein misfolding disease.
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- Liwo, Jozef A., et al.
(författare)
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Origin of the Architecture of Biological Macromolecules - A Mean-Field Perspective
- 2014
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Ingår i: Biophysical Journal. - : Elsevier BV. - 0006-3495 .- 1542-0086. ; 106:2, s. 256A-256A
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The structures of the key classes of biological macromolecules: proteins, nucleic acids and polysaccharides can be dissected into very regular motifs, which are alpha-, beta, and double helices and sheets. In this communication we demonstrate that these regular patterns arise as a result of dipole-dipole interactions of the polar groups (peptide, nucleic-acid-base or sugar-ring groups) and the coupling of these interactions with backbone-local interactions, described at the mean-field level; the averaging is carried out by rotating the dipole of a polar unit about its virtual-bond axis.
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- Peng, Xubiao, et al.
(författare)
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Collective motions and structural self-organisation along the myoglobin folding pathway
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We develop a highly predictive energy function to describe the low temperature crystallographic structure of myoglobin with sub-\AA ngstr\"om precision. We use the energy function to investigate the way how myoglobin folds.For this we employ the Glauber protocol, with a variable ambient temperature. We first increase the temperature so that the structure unfolds into a random coil. We then lower thetemperature back to its original value, and monitor how the myoglobin folds towards its native state.We find that the folding proceeds by $\alpha$-helix nucleation, and that the ordering of helix formation parallels experimental observations. There is also a molten globule folding intermediate, with a radius of gyration that matches the experimentally measured value. We estimate the relative folding times between a random chain and molten globule, and between molten globule and the native state, and we find that the ratio is consistentwith the experimentally measured values. We also propose a number of novel experimental characteristics that could be measured in future experiments.
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- Sieradzan, Adam K.
(författare)
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Introduction of Periodic Boundary Conditions into UNRES Force Field
- 2015
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Ingår i: Journal of Computational Chemistry. - : Wiley. - 0192-8651 .- 1096-987X. ; 36:12, s. 940-946
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Tidskriftsartikel (refereegranskat)abstract
- In this article, implementation of periodic boundary conditions (PBC) into physics-based coarse-grained UNited RESidue (UNRES) force field is presented, which replaces droplet-like restraints previously used. Droplet-like restraints are necessary to keep multichain systems together and prevent them from dissolving to infinitely low concentration. As an alternative for droplet-like restrains cuboid PBCs with imaging of the molecules were introduced. Owing to this modification, artificial forces which arose from restraints keeping a droplet together were eliminated what leads to more realistic trajectories. Due to computational reasons cutoff and smoothing functions were introduced on the long range interactions. The UNRES force field with PBC was tested by performing microcanonical simulations. Moreover, to asses the behavior of the thermostat in PBCs Langevin and Berendsen thermostats were studied. The influence of PBCs on association pattern was compared with droplet-like restraints on the hetero tetramer 1 protein system.
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| 9. |
- Sieradzan, Adam K., et al.
(författare)
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Investigation of Phosphorylation-Induced Folding of an Intrinsically Disordered Protein by Coarse-Grained Molecular Dynamics
- 2021
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 17:5, s. 3203-3220
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Tidskriftsartikel (refereegranskat)abstract
- Apart from being the most common mechanism of regulating protein function and transmitting signals throughout the cell, phosphorylation has an ability to induce disorder-to-order transition in an intrinsically disordered protein. In particular, it was shown that folding of the intrinsically disordered protein, eIF4E-binding protein isoform 2 (4E-BP2), can be induced by multisite phosphorylation. Here, the principles that govern the folding of phosphorylated 4E-BP2 (pT37pT46 4E-BP2(18-62)) are investigated by analyzing canonical and replica exchange molecular dynamics trajectories, generated with the coarse-grained united-residue force field, in terms of local and global motions and the time dependence of formation of contacts between Cas of selected pairs of residues. The key residues involved in the folding of the pT37pT46 4E-BP2(18-62) are elucidated by this analysis. The correlations between local and global motions are identified. Moreover, for a better understanding of the physics of the formation of the folded state, the experimental structure of the pT37pT46 4E-BP2(18-62) is analyzed in terms of a kink (heteroclinic standing wave solution) of a generalized discrete nonlinear Schrodinger equation. It is shown that without molecular dynamics simulations the kinks are able to identify not only the phosphorylated sites of protein, the key players in folding, but also the reasons for the weak stability of the pT37pT46 4E-BP2(18-62).
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| 10. |
- Sieradzan, Adam K., et al.
(författare)
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Peierls-Nabarro barrier and protein loop propagation
- 2014
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Ingår i: Physical Review E. Statistical, Nonlinear, and Soft Matter Physics. - 1539-3755 .- 1550-2376. ; 90:6, s. 062717-
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Tidskriftsartikel (refereegranskat)abstract
- When a self-localized quasiparticle excitation propagates along a discrete one-dimensional lattice, it becomes subject to a dissipation that converts the kinetic energy into lattice vibrations. Eventually the kinetic energy no longer enables the excitation to cross over the minimum energy barrier between neighboring sites, and the excitation becomes localized within a lattice cell. In the case of a protein, the lattice structure consists of the C-alpha backbone. The self-localized quasiparticle excitation is the elemental building block of loops. It can be modeled by a kink that solves a variant of the discrete nonlinear Schrodinger equation. We study the propagation of such a kink in the case of the protein G related albumin-binding domain, using the united residue coarse-grained molecular-dynamics force field. We estimate the height of the energy barriers that the kink needs to cross over in order to propagate along the backbone lattice. We analyze how these barriers give rise to both stresses and reliefs, which control the kink movement. For this, we deform a natively folded protein structure by parallel translating the kink along the backbone away from its native position. We release the transposed kink, and we follow how it propagates along the backbone toward the native location. We observe that the dissipative forces that are exerted on the kink by the various energy barriers have a pivotal role in determining how a protein folds toward its native state.
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