Folding & design最新文献

{"title":"How representative are the known structures of the proteins in a complete genome? A comprehensive structural census","authors":"Mark Gerstein","doi":"10.1016/S1359-0278(98)00066-2","DOIUrl":"10.1016/S1359-0278(98)00066-2","url":null,"abstract":"<div><p><strong>Background:</strong> Determining how representative the known structures are of the proteins encoded by a complete genome is important for assessing to what extent our current picture of protein stability and folding is overly influenced by biases in the structure databank (PDB). It is also important for improving database-based methods of structure prediction and genome annotation.</p><p><strong>Results:</strong> The known structures are compared to the proteins encoded by eight complete microbial genomes in terms of simple statistics such as sequence length, composition and secondary structure. The known structures are represented by a collection of nonhomologous domains from the PDB and a smaller list of ‘biophysical proteins’ on which folding experiments have concentrated. The proteins encoded by the genomes are considered as a whole and divided into various regions, such as known-structure homologue, low complexity (nonglobular), transmembrane or linker. Various tests are performed to assess the significance of the reported differences, in both a practical and a statistical sense.</p><p><strong>Conclusions:</strong>The proteins encoded by the genomes are significantly different from those in the PDB. Their sequence lengths, which follow an extreme value distribution, are longer than the PDB proteins and much longer than the biophysical proteins. Their composition differs from the PDB proteins in having more Lys, Ile, Asn and Gln and less Cys and Trp. This is true overall and especially for the regions corresponding to soluble proteins of as yet unknown fold. Secondary-structure prediction on these uncharacterized regions indicates that they contain on average more helical structure than the PDB; differences about this mean are small, with yeast having slightly more sheet structure and <em>Haemophilus influenzae</em> and <em>Helicobacter pylori</em> more helical structure. Further information is available through the GeneCensus system at <span>http://bioinfo.mbb.yale.edu/genome</span><svg><path></path></svg>.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 6","pages":"Pages 497-512"},"PeriodicalIF":0.0,"publicationDate":"1998-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00066-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20794998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discrete molecular dynamics studies of the folding of a protein-like model","authors":"Nikolay V. Dokholyan ,&nbsp;Sergey V. Buldyrev ,&nbsp;H Eugene Stanley ,&nbsp;Eugene I. Shakhnovich","doi":"10.1016/S1359-0278(98)00072-8","DOIUrl":"10.1016/S1359-0278(98)00072-8","url":null,"abstract":"<div><p><strong>Background:</strong> Many attempts have been made to resolve in time the folding of model proteins in computer simulations. Different computational approaches have emerged. Some of these approaches suffer from insensitivity to the geometrical properties of the proteins (lattice models), whereas others are computationally heavy (traditional molecular dynamics).</p><p><strong>Results:</strong> We used the recently proposed approach of Zhou and Karplus to study the folding of a protein model based on the discrete time molecular dynamics algorithm. We show that this algorithm resolves with respect to time the folding ⇌ unfolding transition. In addition, we demonstrate the ability to study the core of the model protein.</p><p><strong>Conclusions:</strong>The algorithm along with the model of interresidue interactions can serve as a tool for studying the thermodynamics and kinetics of protein models.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 6","pages":"Pages 577-587"},"PeriodicalIF":0.0,"publicationDate":"1998-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00072-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20795522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Folding nucleus: specific of multiple? insights from lattice models and experiments","authors":"Eugene I. Shakhnovich","doi":"10.1016/S1359-0278(98)00056-X","DOIUrl":"https://doi.org/10.1016/S1359-0278(98)00056-X","url":null,"abstract":"<div><p>In this commentary, I compare and discuss different views on the nucleation mechanisms in protein folding</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 6","pages":"Pages R108-R111"},"PeriodicalIF":0.0,"publicationDate":"1998-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00056-X","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92111337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two models of the influenza A M2 channel domain: verification by comparison","authors":"Lucy R. Forrest ,&nbsp;William F. DeGrado ,&nbsp;G.R. Dieckmann ,&nbsp;Mark S.P. Sansom","doi":"10.1016/S1359-0278(98)00061-3","DOIUrl":"10.1016/S1359-0278(98)00061-3","url":null,"abstract":"<div><p><strong>Background:</strong> The influenza M2 protein is a simple membrane protein, containing a single transmembrane helix. It is representative of a very large family of single-transmembrane helix proteins. The functional protein is a tetramer, with the four transmembrane helices forming a proton-permeable channel across the bilayer. Two independently derived models of the M2 channel domain are compared, in order to assess the success of applying molecular modelling approaches to simple membrane proteins.</p><p><strong>Results:</strong> The C<em>α</em> RSMD between the two models is 1.7 å. Both models are composed of a left-handed bundle of helices, with the helices tilted roughly 15° relative to the (presumed) bilayer normal. The two models have similar pore radius profiles, with a pore cavity lined by the Ser31 and Gly34 residues and a pore constriction formed by the ring of His37 residues.</p><p><strong>Conclusions:</strong>Independent studies of M2 have converged on the same structural model for the channel domain. This model is in agreement with solid state NMR data. In particular, both model and NMR data indicate that the M2 helices are tilted relative to the bilayer normal and form a left-handed bundle. Such convergence suggests that, at least for simple membrane proteins, restraints-directed modelling might yield plausible models worthy of further computational and experimental investigation.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 6","pages":"Pages 443-448"},"PeriodicalIF":0.0,"publicationDate":"1998-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00061-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20795715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How and why phosphotyrosine-containing peptides bind to the SH2 and PTB domains","authors":"Yingyao Zhou ,&nbsp;Ruben Abagyan","doi":"10.1016/S1359-0278(98)00067-4","DOIUrl":"10.1016/S1359-0278(98)00067-4","url":null,"abstract":"<div><p><strong>Background:</strong> Specific recognition of phosphotyrosine-containing protein segments by Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domains plays an important role in intracellular signal transduction. Although many SH2/PTB-domain-containing receptor–peptide complex structures have been solved, little has been done to study the problem computationally. Prediction of the binding geometry and the binding constant of any peptide–protein pair is an extremely important problem.</p><p><strong>Results:</strong> A procedure to predict binding energies of phosphotyrosine-containing peptides with SH2/PTB domains was developed. The average deviation between experimentally measured binding energies and theoretical evaluations was 1.8 kcal/mol. Binding states of unphosphorylated peptides were also predicted reasonably well. <em>Ab initio</em> predictions of binding geometry of fully flexible peptides correctly identified conformations of two pentapeptides and a hexapeptide complexed with a v-Src SH2 domain receptor with root mean square deviations (rmsds) of 0.3 å, 1.2 å and 1.5 å, respectively.</p><p><strong>Conclusions:</strong>The binding energies of phosphotyrosine-containing complexes can be effectively predicted using the procedure developed here. It was also possible to predict the bound conformations of flexible short peptides correctly from random starting conformations.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 6","pages":"Pages 513-522"},"PeriodicalIF":0.0,"publicationDate":"1998-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00067-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20795004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knowledge-based structure prediction of MHC class I bound peptides: a study of 23 complexes","authors":"Ora Schueler-Furman ,&nbsp;Ron Elber ,&nbsp;Hanah Margalit","doi":"10.1016/S1359-0278(98)00070-4","DOIUrl":"10.1016/S1359-0278(98)00070-4","url":null,"abstract":"<div><p><strong>Background:</strong> The binding of T-cell antigenic peptides to MHC molecules is a prerequisite for their immunogenicity. The ability to identify binding peptides based on the protein sequence is of great importance to the rational design of peptide vaccines. As the requirements for peptide binding cannot be fully explained by the peptide sequence <em>per se</em>, structural considerations should be taken into account and are expected to improve predictive algorithms. The first step in such an algorithm requires accurate and fast modeling of the peptide structure in the MHC-binding groove.</p><p><strong>Results:</strong> We have used 23 solved peptide–MHC class I complexes as a source of structural information in the development of a modeling algorithm. The peptide backbones and MHC structures were used as the templates for prediction. Sidechain conformations were built based on a rotamer library, using the ‘dead end elimination’ approach. A simple energy function selects the favorable combination of rotamers for a given sequence. It further selects the correct backbone structure from a limited library. The influence of different parameters on the prediction quality was assessed. With a specific rotamer library that incorporates information from the peptide sidechains in the solved complexes, the algorithm correctly identifies 85% (92%) of all (buried) sidechains and selects the correct backbones. Under cross-validation, 70% (78%) of all (buried) residues are correctly predicted and most of all backbones. The interaction between peptide sidechains has a negligible effect on the prediction quality.</p><p><strong>Conclusions:</strong>The structure of the peptide sidechains follows from the interactions with the MHC and the peptide backbone, as the prediction is hardly influenced by sidechain interactions. The proposed methodology was able to select the correct backbone from a limited set. The impairment in performance under cross-validation suggests that, currently, the specific rotamer library is not satisfactorily representative. The predictions might improve with an increase in the data.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 6","pages":"Pages 549-564"},"PeriodicalIF":0.0,"publicationDate":"1998-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00070-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20795005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rational design and functional expression of a constitutively active single-chain NS4A–NS3 proteinase","authors":"Alessandra Pasquo ,&nbsp;Maria Chiara Nardi ,&nbsp;Nazzareno Dimasi ,&nbsp;Licia Tomei ,&nbsp;Christian Steinkühler ,&nbsp;Paola Delmastro ,&nbsp;Anna Tramontano ,&nbsp;Raffaele De Francesco","doi":"10.1016/S1359-0278(98)00060-1","DOIUrl":"10.1016/S1359-0278(98)00060-1","url":null,"abstract":"<div><p><strong>Background:</strong> The proteinase domain of the hepatitis C virus NS3 protein is involved in the maturation of the viral polyprotein. A central hydrophobic domain of the NS4A protein is required as a cofactor for its proteolytic activity. The three-dimensional structure of the proteinase domain alone and complexed with an NS4A-derived peptide has been solved recently and revealed that the N terminus of the proteinase is in near proximity to the C terminus of the cofactor. To study the molecular basis of the enzyme activation by its cofactor and to overcome the difficulties of structural and functional investigation associated with a two-species complex, we rationally designed a link to bridge the two molecules in order to have a single polypeptide construct.</p><p><strong>Results:</strong> The engineered construct led to the production of a stable, monomeric protein with proteolytic activity that is independent from the addition of a synthetic peptide representing the cofactor domain of the NS4A protein. The protein is active on both protein and synthetic peptide substrates. Spectroscopic and kinetic analysis of the recombinant NS4A–NS3 single-chain proteinase demonstrated features superimposable with the isolated NS3 proteinase domain complexed with the NS4A cofactor.</p><p><strong>Conclusions:</strong>We designed a very tight connection between the NS3 and NS4A polypeptide chains with the rationale that this would allow a more stable structure to be formed. The engineered single-chain enzyme was indistinguishable from the NS3 proteinase complexed with its NS4A cofactor in all enzymatic and physico-chemical properties investigated.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 6","pages":"Pages 433-441"},"PeriodicalIF":0.0,"publicationDate":"1998-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00060-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20795713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The importance of hydration for the kinetics and thermodynamics of protein folding: simplified lattice models","authors":"Jon M. Sorenson ,&nbsp;Teresa Head-Gordon","doi":"10.1016/S1359-0278(98)00068-6","DOIUrl":"10.1016/S1359-0278(98)00068-6","url":null,"abstract":"<div><p><strong>Background:</strong> Recent studies have proposed various sources for the origin of cooperativity in simplified protein folding models. Important contributions to cooperativity that have been discussed include backbone hydrogen bonding, sidechain packing and hydrophobic interactions. Related work has also focused on which interactions are responsible for making the free energy of the native structure a pronounced global minimum in the free energy landscape. In addition, two-flavor bead models have been found to exhibit poor folding cooperativity and often lack unique native structures. We propose a simple multibody description of hydration with expectations that it might modify the free energy surface in such a way as to increase the cooperativity of folding and improve the performance of two-flavor models.</p><p><strong>Results:</strong> We study the thermodynamics and kinetics of folding for designed 36-mer sequences on a cubic lattice using both our solvation model and the corresponding model without solvation terms. Degeneracies of the native states are studied by enumerating the maximally compact states. The histogram Monte Carlo method is used to obtain folding temperatures, densities of states and heat capacity curves. Folding kinetics are examined by accumulating mean first-passage times versus temperature. Sequences in the proposed solvation model are found to have more unique ground states, fold faster and fold with more cooperativity than sequences in the nonsolvation model.</p><p><strong>Conclusions:</strong>We find that the addition of a multibody description of solvation can improve the poor performance of two-flavor lattice models and provide an additional source for more cooperative folding. Our results suggest that a better description of solvation will be important for future theoretical protein folding studies.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 6","pages":"Pages 523-534"},"PeriodicalIF":0.0,"publicationDate":"1998-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00068-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20795002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic comparison of artificial-chaperone-assisted and unassisted refolding of urea-denatured carbonic anhydrase B","authors":"Peter E. Hanson ,&nbsp;Samuel H. Gellman","doi":"10.1016/S1359-0278(98)00063-7","DOIUrl":"10.1016/S1359-0278(98)00063-7","url":null,"abstract":"<div><p><strong>Background:</strong> We have previously described a method for the refolding of chemically denatured proteins in which small molecules (‘artificial chaperones’, a detergent and cyclodextrin) assist renaturation. In a previous analysis of lysozyme refolding from the GdmCl-denatured, DTT-reduced state, we found that enzymatic activity is regained at indistinguishable rates for unassisted (absence of additives) and artificial-chaperone-assisted refolding. While unassisted and artificial-chaperone-assisted refolding rates could also be directly compared for GdmCl-denatured bovine carbonic anhydrase B (CAB), only cationic detergents could be used as assistants. We therefore set out to determine whether artificial chaperones could assist the refolding of urea-denatured CAB, whether the charge and structure of the detergent used affects refolding assistance, and, if so, whether the assistance is mechanistically similar to that observed for GdmCl-denatured CAB.</p><p><strong>Results:</strong> Our results indicate that CAB can be refolded from the urea-denatured state via the artificial chaperone process, using both anionic and cationic detergents. There is a distinctive product-determining step early in the artificial-chaperone-assisted refolding mechanism, but the rate-determining steps of the unassisted and artificial-chaperone-assisted processes are indistinguishable.</p><p><strong>Conclusions:</strong>Because the rate-determining steps of unassisted and artificial-chaperone-assisted refolding are indistinguishable, we conclude that the rate-determining step of CAB refolding is unaffected by the use of artificial chaperones. Our observations also suggest that denatured CAB undergoes a slow partial folding in concentrated urea solution.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 6","pages":"Pages 457-468"},"PeriodicalIF":0.0,"publicationDate":"1998-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00063-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20795714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure with Folding & Design","authors":"","doi":"10.1016/S1359-0278(98)00058-3","DOIUrl":"https://doi.org/10.1016/S1359-0278(98)00058-3","url":null,"abstract":"","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 6","pages":"Page 589"},"PeriodicalIF":0.0,"publicationDate":"1998-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00058-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136553691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}