| 1. |
- Kachlishvili, Khatuna, et al.
(författare)
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New Insights into Folding, Misfolding, and Nonfolding Dynamics of a WW Domain
- 2020
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 124:19, s. 3855-3872
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Tidskriftsartikel (refereegranskat)abstract
- Intermediate states in protein folding are associated with formation of amyloid fibrils, which are responsible for a number of neurodegenerative diseases. Therefore, prevention of the aggregation of folding intermediates is one of the most important problems to overcome. Recently, we studied the origins and prevention of formation of intermediate states with the example of the Formin binding protein 28 (FBP28) WW domain. We demonstrated that the replacement of Leu26 by Asp26 or Trp26 (in similar to 15% of the folding trajectories) can alter the folding scenario from three-state folding, a major folding scenario for the FBP28 WW domain (WT) and its mutants, toward two-state or downhill folding at temperatures below the melting point. Here, for a better understanding of the physics of the formation/elimination of intermediates, (i) the dynamics and energetics of formation of beta-strands in folding, misfolding, and nonfolding trajectories of these mutants (L26D and L26W) is investigated; (ii) the experimental structures of WT, L26D, and L26W are analyzed in terms of a kink (heteroclinic standing wave solution) of a generalized discrete nonlinear Schrodinger equation. We show that the formation of each beta-strand in folding trajectories is accompanied by the emergence of kinks in internal coordinate space as well as a decrease in local free energy. In particular, the decrease in downhill folding trajectory is similar to 7 kcal/mol, while it varies between 31 and 48 kcal/mol for the three-state folding trajectory. The kink analyses of the experimental structures give new insights into formation of intermediates, which may become a useful tool for preventing aggregation.
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| 2. |
- 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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| 3. |
- Krokhotin, Andrey, et al.
(författare)
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Coexistence of phases in a protein heterodimer
- 2012
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 137:3, s. 035101-
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Tidskriftsartikel (refereegranskat)abstract
- A heterodimer consisting of two or more different kinds of proteins can display an enormous number of distinct molecular architectures. The conformational entropy is an essential ingredient in the Helmholtz free energy and, consequently, these heterodimers can have a very complex phase structure. Here, it is proposed that there is a state of proteins, in which the different components of a heterodimer exist in different phases. For this purpose, the structures in the protein data bank (PDB) have been analyzed, with radius of gyration as the order parameter. Two major classes of heterodimers with their protein components coexisting in different phases have been identified. An example is the PDB structure 3DXC. This is a transcriptionally active dimer. One of the components is an isoform of the intra-cellular domain of the Alzheimer-disease related amyloid precursor protein (AICD), and the other is a nuclear multidomain adaptor protein in the Fe65 family. It is concluded from the radius of gyration that neither of the two components in this dimer is in its own collapsed phase, corresponding to a biologically active protein. The UNRES energy function has been utilized to confirm that, if the two components are separated from each other, each of them collapses. The results presented in this work show that heterodimers whose protein components coexist in different phases, can have intriguing physical properties with potentially important biological consequences.
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| 4. |
- Krokhotin, Andrey, et al.
(författare)
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Kinks, loops, and protein folding, with protein A as an example
- 2014
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 140:2, s. 025101-
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Tidskriftsartikel (refereegranskat)abstract
- The dynamics and energetics of formation of loops in the 46-residue N-terminal fragment of the B-domain of staphylococcal protein A has been studied. Numerical simulations have been performed using coarse-grained molecular dynamics with the united-residue (UNRES) force field. The results have been analyzed in terms of a kink (heteroclinic standing wave solution) of a generalized discrete nonlinear Schrödinger (DNLS) equation. In the case of proteins, the DNLS equation arises from a Cα-trace-based energy function. Three individual kink profiles were identified in the experimental three-α-helix structure of protein A, in the range of the Glu16-Asn29, Leu20-Asn29, and Gln33-Asn44 residues, respectively; these correspond to two loops in the native structure. UNRES simulations were started from the full right-handed α-helix to obtain a clear picture of kink formation, which would otherwise be blurred by helix formation. All three kinks emerged during coarse-grained simulations. It was found that the formation of each is accompanied by a local free energy increase; this is expressed as the change of UNRES energy which has the physical sense of the potential of mean force of a polypeptide chain. The increase is about 7 kcal/mol. This value can thus be considered as the free energy barrier to kink formation in full α-helical segments of polypeptide chains. During the simulations, the kinks emerge, disappear, propagate, and annihilate each other many times. It was found that the formation of a kink is initiated by an abrupt change in the orientation of a pair of consecutive side chains in the loop region. This resembles the formation of a Bloch wall along a spin chain, where the Cα backbone corresponds to the chain, and the amino acid side chains are interpreted as the spin variables. This observation suggests that nearest-neighbor side chain–side chain interactions are responsible for initiation of loop formation. It was also found that the individual kinks are reflected as clear peaks in the principal modes of the analyzed trajectory of protein A, the shapes of which resemble the directional derivatives of the kinks along the chain. These observations suggest that the kinks of the DNLS equation determine the functionally important motions of proteins.
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| 5. |
- 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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| 6. |
- 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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| 7. |
- 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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