| 1. |
- Keasar, Chen, et al.
(author)
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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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In: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 8
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Journal article (peer-reviewed)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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| 2. |
- Kohut, Gergely, et al.
(author)
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The molecular mechanism of structural changes in the antimicrobial peptide CM15 upon complex formation with drug molecule suramin: A computational analysis
- 2019
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In: Physical Chemistry Chemical Physics. - : Royal Society of Chemistry (RSC). - 1463-9084 .- 1463-9076. ; 21:20, s. 10644-10659
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Journal article (peer-reviewed)abstract
- Dynamic increase of resistant bacterial infectious diseases continuously requires development of novel compounds against them. The molecular level understanding of the mechanism and interactions of natural host-defense peptides or antimicrobial peptides (AMPs) is an important step towards rational design and development of compounds inspired by their function. A particular set of these peptides have disordered structure, the ordering of which may modify their antimicrobial properties. Recent experiments demonstrate that such conformational transitions of AMPs could be mediated by the presence of small organic compounds, such as approved drug molecules. However, the molecular mechanisms underlying these structural changes are unclear. In this study, we apply molecular docking and molecular dynamics-based approaches to rigorously analyze the interactions between the drug suramin and the AMP CM15, a synthetic unstructured hybrid peptide. We characterize the energetic properties of putative CM15-suramin complexes revealing particular impacts of CM15 residues as well as the parts of suramin on these interactions. We find that α-helical content of the peptide is increased in the presence of suramin, which is in agreement with the experimental data. Kinetics analysis from canonical molecular dynamics and metadynamics simulations suggest that the effect of suramin does not promote the formation of α-helix but rather results from its ability to stabilize the α-helical population in the conformational pool of the peptide. Potentially, understanding the physico-chemical basis underlying the interactions between drug molecules and disordered AMPs will prove useful in strategies for antimicrobial compound development. Further on, the given computational protocol for the analysis of such flexible systems provide a basis for future theoretical investigation of similar biomolecular complexes.
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| 3. |
- Lensink, Marc F., et al.
(author)
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Impact of AlphaFold on structure prediction of protein complexes: The CASP15-CAPRI experiment
- 2023
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In: Proteins. - : WILEY. - 0887-3585 .- 1097-0134.
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Journal article (peer-reviewed)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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| 4. |
- Irbäck, Anders, et al.
(author)
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All-atom Monte Carlo simulations of protein folding and aggregation
- 2013
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In: 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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Book chapter (peer-reviewed)
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| 5. |
- Kohut, Gergely, et al.
(author)
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Protein-Ligand Interaction Energy-Based Entropy Calculations: Fundamental Challenges For Flexible Systems
- 2018
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In: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 122:32, s. 7821-7827
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Journal article (peer-reviewed)abstract
- Entropy calculations represent one of the most challenging steps in obtaining the binding free energy in biomolecular systems. A novel computationally effective approach (IE) was recently proposed to calculate the entropy based on the computation of protein ligand interaction energy directly from molecular dynamics (MD) simulations. We present a study focused on the application of this method to flexible molecular systems and compare its performance with well-established normal mode (NM) and quasiharmonic (QH) entropy calculation approaches. Our results demonstrated that the IE method is intended for calculating entropy change for binding partners in fixed conformations, as by the original definition of IE, and is not applicable to the molecular complexes in which the interacting partners undergo significant conformational changes during the binding process.
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| 6. |
- Krokhotin, Andrey, et al.
(author)
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Coexistence of phases in a protein heterodimer
- 2012
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In: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 137:3, s. 035101-
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Journal article (peer-reviewed)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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| 7. |
- Krokhotin, Andrey, et al.
(author)
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Kinks, loops, and protein folding, with protein A as an example
- 2014
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In: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 140:2, s. 025101-
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Journal article (peer-reviewed)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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| 8. |
- Liwo, Adam, et al.
(author)
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Long-Time Dynamics of Selected Molecular-Motor Components Using a Physics-Based Coarse-Grained Approach
- 2023
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In: Biomolecules. - : MDPI. - 2218-273X. ; 13:6
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Journal article (peer-reviewed)abstract
- Molecular motors are essential for the movement and transportation of macromolecules in living organisms. Among them, rotatory motors are particularly efficient. In this study, we investigated the long-term dynamics of the designed left-handed alpha/alpha toroid (PDB: 4YY2), the RBM2 flagellum protein ring from Salmonella (PDB: 6SD5), and the V-type Na+-ATPase rotor in Enterococcus hirae (PDB: 2BL2) using microcanonical and canonical molecular dynamics simulations with the coarse-grained UNRES force field, including a lipid-membrane model, on a millisecond laboratory time scale. Our results demonstrate that rotational motion can occur with zero total angular momentum in the microcanonical regime and that thermal motions can be converted into net rotation in the canonical regime, as previously observed in simulations of smaller cyclic molecules. For 6SD5 and 2BL2, net rotation (with a ratcheting pattern) occurring only about the pivot of the respective system was observed in canonical simulations. The extent and direction of the rotation depended on the initial conditions. This result suggests that rotatory molecular motors can convert thermal oscillations into net rotational motion. The energy from ATP hydrolysis is required probably to set the direction and extent of rotation. Our findings highlight the importance of molecular-motor structures in facilitating movement and transportation within living organisms.
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| 9. |
- Liwo, Jozef A., et al.
(author)
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Origin of the Architecture of Biological Macromolecules - A Mean-Field Perspective
- 2014
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In: Biophysical Journal. - : Elsevier BV. - 0006-3495 .- 1542-0086. ; 106:2, s. 256A-256A
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Journal article (other academic/artistic)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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| 10. |
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