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Jacques Meyer - One of the best experts on this subject based on the ideXlab platform.
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iron sulfur Protein Folds iron sulfur chemistry and evolution
Journal of Biological Inorganic Chemistry, 2008Co-Authors: Jacques MeyerAbstract:An inventory of unique local Protein Folds around Fe–S clusters has been derived from the analysis of Protein structure databases. Nearly 50 such Folds have been identified, and over 90% of them harbor low-potential [2Fe–2S]2+,+ or [4Fe–4S]2+,+ clusters. In contrast, high-potential Fe–S clusters, notwithstanding their structural diversity, occur in only three different Protein Folds. These observations suggest that the extant population of Fe–S Protein Folds has to a large extent been shaped in the reducing iron- and sulfur-rich environment that is believed to have predominated on this planet until approximately two billion years ago. High-potential active sites are then surmised to be rarer because they emerged later, in a more oxidizing biosphere, in conditions where iron and sulfide had become poorly available, Fe–S clusters were less stable, and in addition faced competition from heme iron and copper active sites. Among the low-potential Fe–S active sites, Protein Folds hosting [4Fe–4S]2+,+ clusters outnumber those with [2Fe–2S]2+,+ ones by a factor of 3 at least. This is in keeping with the higher chemical stability and versatility of the tetranuclear clusters, compared with the binuclear ones. It is therefore suggested that, at least while novel Fe–S sites are evolving within Proteins, the intrinsic chemical stability of the inorganic moiety may be more important than the stabilizing effect of the polypeptide chain. The discovery rate of novel Fe–S-containing Protein Folds underwent a sharp increase around 1995, and has remained stable to this day. The current trend suggests that the mapping of the Fe–S fold space is not near completion, in agreement with predictions made for Protein Folds in general. Altogether, the data collected and analyzed here suggest that the extant structural landscape of Fe–S Proteins has been shaped to a large extent by primeval geochemical conditions on one hand, and iron–sulfur chemistry on the other.
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Iron–sulfur Protein Folds, iron–sulfur chemistry, and evolution
Journal of Biological Inorganic Chemistry, 2008Co-Authors: Jacques MeyerAbstract:An inventory of unique local Protein Folds around Fe–S clusters has been derived from the analysis of Protein structure databases. Nearly 50 such Folds have been identified, and over 90% of them harbor low-potential [2Fe–2S]2+,+ or [4Fe–4S]2+,+ clusters. In contrast, high-potential Fe–S clusters, notwithstanding their structural diversity, occur in only three different Protein Folds. These observations suggest that the extant population of Fe–S Protein Folds has to a large extent been shaped in the reducing iron- and sulfur-rich environment that is believed to have predominated on this planet until approximately two billion years ago. High-potential active sites are then surmised to be rarer because they emerged later, in a more oxidizing biosphere, in conditions where iron and sulfide had become poorly available, Fe–S clusters were less stable, and in addition faced competition from heme iron and copper active sites. Among the low-potential Fe–S active sites, Protein Folds hosting [4Fe–4S]2+,+ clusters outnumber those with [2Fe–2S]2+,+ ones by a factor of 3 at least. This is in keeping with the higher chemical stability and versatility of the tetranuclear clusters, compared with the binuclear ones. It is therefore suggested that, at least while novel Fe–S sites are evolving within Proteins, the intrinsic chemical stability of the inorganic moiety may be more important than the stabilizing effect of the polypeptide chain. The discovery rate of novel Fe–S-containing Protein Folds underwent a sharp increase around 1995, and has remained stable to this day. The current trend suggests that the mapping of the Fe–S fold space is not near completion, in agreement with predictions made for Protein Folds in general. Altogether, the data collected and analyzed here suggest that the extant structural landscape of Fe–S Proteins has been shaped to a large extent by primeval geochemical conditions on one hand, and iron–sulfur chemistry on the other.
Robert B Best - One of the best experts on this subject based on the ideXlab platform.
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exploring the sequence fitness landscape of a bridge between Protein Folds
PLOS Computational Biology, 2020Co-Authors: Pengfei Tian, Robert B BestAbstract:Most foldable Protein sequences adopt only a single native fold. Recent Protein design studies have, however, created Protein sequences which fold into different structures apon changes of environment, or single point mutation, the best characterized example being the switch between the Folds of the GA and GB binding domains of streptococcal Protein G. To obtain further insight into the design of sequences which can switch Folds, we have used a computational model for the fitness landscape of a single fold, built from the observed sequence variation of Protein homologues. We have recently shown that such coevolutionary models can be used to design novel foldable sequences. By appropriately combining two of these models to describe the joint fitness landscape of GA and GB, we are able to describe the propensity of a given sequence for each of the two Folds. We have successfully tested the combined model against the known series of designed GA/GB hybrids. Using Monte Carlo simulations on this landscape, we are able to identify pathways of mutations connecting the two Folds. In the absence of a requirement for domain stability, the most frequent paths go via sequences in which neither domain is stably folded, reminiscent of the propensity for certain intrinsically disordered Proteins to fold into different structures according to context. Even if the folded state is required to be stable, we find that there is nonetheless still a wide range of sequences which are close to the transition region and therefore likely fold switches, consistent with recent estimates that fold switching may be more widespread than had been thought.
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a small single domain Protein Folds through the same pathway on and off the ribosome
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Emily J Guinn, Robert B Best, Pengfei Tian, Mia Shin, Susan MarquseeAbstract:In vivo, Proteins fold and function in a complex environment subject to many stresses that can modulate a Protein's energy landscape. One aspect of the environment pertinent to Protein folding is the ribosome, since Proteins have the opportunity to fold while still bound to the ribosome during translation. We use a combination of force and chemical denaturant (chemomechanical unfolding), as well as point mutations, to characterize the folding mechanism of the src SH3 domain both as a stalled ribosome nascent chain and free in solution. Our results indicate that src SH3 Folds through the same pathway on and off the ribosome. Molecular simulations also indicate that the ribosome does not affect the folding pathway for this small Protein. Taken together, we conclude that the ribosome does not alter the folding mechanism of this small Protein. These results, if general, suggest the ribosome may exert a bigger influence on the folding of multidomain Proteins or Protein domains that can partially fold before the entire domain sequence is outside the ribosome exit tunnel.
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a small single domain Protein Folds through the same pathway on and off the ribosome
bioRxiv, 2018Co-Authors: Emily J Guinn, Robert B Best, Pengfei Tian, Mia Shin, Susan MarquseeAbstract:In vivo, Proteins fold and function in a complex environment where they are subject to many stresses that can modulate Protein energy landscapes. One aspect of the environment pertinent to Protein folding is the ribosome, since Proteins have the opportunity to fold while still bound to the ribosome during translation. We use a combination of force and chemical denaturant (chemo-mechanical unfolding), as well as point mutations, to characterize the folding mechanism of the src SH3 domain both as a stalled ribosome nascent chain and free in solution. Our results indicate that src SH3 Folds through the same pathway on and off the ribosome. Molecular simulations also indicate that the ribosome does not affect the folding pathway for this small Protein. Taken together, we conclude that the ribosome does not alter the folding mechanism of this small Protein, which appears to fold at the mouth of the ribosome as the Protein emerges from the exit tunnel. These results, if general, suggest the ribosome may exert a bigger influence on the folding of multi-domain Proteins or Protein domains that can partially fold before the entire domain sequence is outside the ribosome exit tunnel.
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bootstrapping new Protein Folds
Biophysical Journal, 2014Co-Authors: Robert B BestAbstract:A unifying feature of the large number of Protein structures is that they fall into a large number of Folds, each with the same overall backbone structure. The total number of Folds in the entire Protein universe is estimated to be only in the thousands (1). This clearly indicates that new function can be developed by adapting existing Folds. But how did we arrive at today’s set of Folds, and how easily might new Folds be created, allowing for the development of further new functions?
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a slow Protein Folds quickly in the end
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Robert B BestAbstract:Until just a few years ago, it was not clear whether it would be possible to fold Proteins using all-atom molecular dynamics simulations with explicit solvent molecules, despite the insights that these simulations had yielded into other biological problems. This was not just because of the computational challenge of reaching folding time scales, typically microseconds to seconds or longer, but also because it was not generally accepted that the empirical energy functions (“force fields”) used were sufficiently accurate to locate the folded state as a global free-energy minimum. This has changed dramatically in the last 2 y, with the development by Shaw and coworkers of a special-purpose supercomputer, Anton, capable of running biomolecular MD simulations on a microsecond or even millisecond timescale (1). This group showed that, with only minor adjustments to existing force fields (2⇓–4), it was possible to fold 12 small, “fast-folding” Proteins (1), which adopt their native structure in microseconds. At the time, it was still not clear, however, whether it would be possible to do the same for larger, slower-folding Proteins (5, 6). In PNAS, Piana et al. report simulations of ubiquitin folding, which occurs in milliseconds (7). Their results not only extend the computationally accessible time scale for calculating equilibrium folding trajectories by 2–3 orders of magnitude but have a number of implications that can only be deduced from a comparison of fast and slow folding Proteins.
Tom L Blundell - One of the best experts on this subject based on the ideXlab platform.
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alignment and searching for common Protein Folds using a data bank of structural templates
Journal of Molecular Biology, 1993Co-Authors: Mark S Johnson, John P Overington, Tom L BlundellAbstract:Abstract We introduce an approach to Protein comparisons in which tertiary-structure information is exploited in the alignment of a Protein sequence of known tertiary structure, or an aligned set of sequences of known homologous structures, with one or more sequences. The local tertiary environments of residues in the one or more three-dimensional structures (defined in terms of residue accessibility to solvent, secondary structure and hydrogen bonding) are used to select position-specific amino acid substitution scores and produce a scoring template suitable for aligning sequences or searching sequence data banks. The amino acid substitution score have been accumulated from 72 families of Protein structure in which the observed substitutions have been classified according to features of the local structure. Hence, the value attributed to a particular amino acid interchange in the template is not a constant, but is dependent upon the environmental context in which that substitution has occurred. We have used these structural templates to align Proteins, as well as to search an amino acid sequence data bank for Proteins having a similar fold, Indeed, a database of templates that corresponds to both unique structures and aligned homologous structures from the Brookhaven Protein Data Bank has been produce. A new sequence can be searched against the database of templates in order to identify a similar tertiary fold even if the sequence is not significantly similar to any Proteins of known three-dimensional structure.
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environment specific amino acid substitution tables tertiary templates and prediction of Protein Folds
Protein Science, 1992Co-Authors: John P Overington, Dan Donnelly, Mark S Johnson, Andrej Sali, Tom L BlundellAbstract:The local environment of an amino acid in a folded Protein determines the acceptability of mutations at that position. In order to characterize and quantify these structural constraints, we have made a comparative analysis of families of homologous Proteins. Residues in each structure are classified according to amino acid type, secondary structure, accessibility of the side chain, and existence of hydrogen bonds from the side chains. Analysis of the pattern of observed substitutions as a function of local environment shows that there are distinct patterns, especially for buried polar residues. The substitution data tables are available on diskette with Protein Science. Given the fold of a Protein, one is able to predict sequences compatible with the fold (profiles or templates) and potentially to discriminate between a correctly folded and misfolded Protein. Conversely, analysis of residue variation across a family of aligned sequences in terms of substitution profiles can allow prediction of secondary structure or tertiary environment.
David T Jones - One of the best experts on this subject based on the ideXlab platform.
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design of metalloProteins and novel Protein Folds using variational autoencoders
Scientific Reports, 2018Co-Authors: David T Jones, Joe G Greener, Lewis MoffatAbstract:The design of novel Proteins has many applications but remains an attritional process with success in isolated cases. Meanwhile, deep learning technologies have exploded in popularity in recent years and are increasingly applicable to biology due to the rise in available data. We attempt to link Protein design and deep learning by using variational autoencoders to generate Protein sequences conditioned on desired properties. Potential copper and calcium binding sites are added to non-metal binding Proteins without human intervention and compared to a hidden Markov model. In another use case, a grammar of Protein structures is developed and used to produce sequences for a novel Protein topology. One candidate structure is found to be stable by molecular dynamics simulation. The ability of our model to confine the vast search space of Protein sequences and to scale easily has the potential to assist in a variety of Protein design tasks.
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assembling novel Protein Folds from super secondary structural fragments
Proteins, 2003Co-Authors: David T Jones, Liam J McguffinAbstract:The results of applying a fragment-based Protein tertiary structure prediction method to the prediction of 14 CASP5 target domains are described. The method is based on the assembly of supersecondary structural fragments taken from highly resolved Protein structures using a simulated annealing algorithm. A number of good predictions for Proteins with novel Folds were produced, although not always as the first model. For two fold recognition targets, FRAGFOLD produced the most accurate model in both cases, despite the fact that the predictions were not based on a template structure. Although clear progress has been made in improving FRAGFOLD since CASP4, the ranking of final models still seems to be the main problem that needs to be addressed before the next CASP experiment.
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predicting novel Protein Folds by using fragfold
Proteins, 2001Co-Authors: David T JonesAbstract:The results of applying a fragment-based Protein tertiary structure prediction method to the prediction of 8 CASP4 targets are described. The method is based on the assembly of supersecondary structural fragments taken from highly resolved Protein structures using a simulated annealing algorithm. Despite the significant degree of success in this case, there is clearly much more developmental work required before predictions with the accuracy of a good homology model, or even a good fold recognition model, can be made with use of this kind of approach.
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successful recognition of Protein Folds using threading methods biased by sequence similarity and predicted secondary structure
Proteins, 1999Co-Authors: David T Jones, Michael L Tress, Kevin Bryson, Caroline HadleyAbstract:Analysis of our fold recognition results in the 3rd Critical Assessment in Structure Prediction (CASP3) experiment, using the programs THREADER 2 and GenTHREADER, shows an encouraging level of overall success. Of the 23 submitted predictions, 20 targets showed no clear sequence similarity to Proteins of known 3D structure. These 20 targets can be divided into 22 domains, of which, 20 domains either entirely match a previously known fold, or partially match a substantial region of a known fold. Of these 20 domains, we correctly assigned the Folds in 10 cases.
John P Overington - One of the best experts on this subject based on the ideXlab platform.
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alignment and searching for common Protein Folds using a data bank of structural templates
Journal of Molecular Biology, 1993Co-Authors: Mark S Johnson, John P Overington, Tom L BlundellAbstract:Abstract We introduce an approach to Protein comparisons in which tertiary-structure information is exploited in the alignment of a Protein sequence of known tertiary structure, or an aligned set of sequences of known homologous structures, with one or more sequences. The local tertiary environments of residues in the one or more three-dimensional structures (defined in terms of residue accessibility to solvent, secondary structure and hydrogen bonding) are used to select position-specific amino acid substitution scores and produce a scoring template suitable for aligning sequences or searching sequence data banks. The amino acid substitution score have been accumulated from 72 families of Protein structure in which the observed substitutions have been classified according to features of the local structure. Hence, the value attributed to a particular amino acid interchange in the template is not a constant, but is dependent upon the environmental context in which that substitution has occurred. We have used these structural templates to align Proteins, as well as to search an amino acid sequence data bank for Proteins having a similar fold, Indeed, a database of templates that corresponds to both unique structures and aligned homologous structures from the Brookhaven Protein Data Bank has been produce. A new sequence can be searched against the database of templates in order to identify a similar tertiary fold even if the sequence is not significantly similar to any Proteins of known three-dimensional structure.
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environment specific amino acid substitution tables tertiary templates and prediction of Protein Folds
Protein Science, 1992Co-Authors: John P Overington, Dan Donnelly, Mark S Johnson, Andrej Sali, Tom L BlundellAbstract:The local environment of an amino acid in a folded Protein determines the acceptability of mutations at that position. In order to characterize and quantify these structural constraints, we have made a comparative analysis of families of homologous Proteins. Residues in each structure are classified according to amino acid type, secondary structure, accessibility of the side chain, and existence of hydrogen bonds from the side chains. Analysis of the pattern of observed substitutions as a function of local environment shows that there are distinct patterns, especially for buried polar residues. The substitution data tables are available on diskette with Protein Science. Given the fold of a Protein, one is able to predict sequences compatible with the fold (profiles or templates) and potentially to discriminate between a correctly folded and misfolded Protein. Conversely, analysis of residue variation across a family of aligned sequences in terms of substitution profiles can allow prediction of secondary structure or tertiary environment.
