Folding & design最新文献

{"title":"A free energy analysis by unfolding applied to 125-mers on a cubic lattice","authors":"Myung S Chung ,&nbsp;Andrew F Neuwald ,&nbsp;W John Wilbur","doi":"10.1016/S1359-0278(98)00008-X","DOIUrl":"10.1016/S1359-0278(98)00008-X","url":null,"abstract":"<div><p><strong>Background</strong>: A common approach to the protein folding problem involves computer simulation of folding using lattice models of amino acid sequences. Key factors for good performance in such models are the correct choice of the temperature and the average interaction energy between residues. In order to push the lattice approach to its limit it is important to have a method to adjust these parameters for optimal folding that is not limited by our ability to successfully simulate folding in a reasonable time.</p><p><strong>Results</strong>: In this study, we adopt a simple cubic-lattice model and present a method for calculating the free energy of a chain as a function of the number of native contacts. This does not require that we are able to fold the sequence by simulation and it provides a method of estimating the folding transition temperature. For a given set of parameters, the free energy analysis also allows an estimate of foldability. By applying the method to sequences with 27 and 125 residues, we show that optimal folding occurs near the folding transition temperature and at either zero or small negative average interaction energy. We find ourselves able to fold only 125-mers that have significant short-range native contacts.</p><p><strong>Conclusions</strong>: A free energy analysis during unfolding is a useful tool for the study of foldability and should be applicable to a variety of folding models. In this way we are able to fold some 125-mer designed sequences and our results confirm the finding that short-range contacts contribute to foldability.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 1","pages":"Pages 51-65"},"PeriodicalIF":0.0,"publicationDate":"1998-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00008-X","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20425493","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":"A new procedure for constructing peptides into a given C","authors":"Yanli Wang ,&nbsp;Hassan I Huq ,&nbsp;Xavier F de la Cruz ,&nbsp;Byungkook Lee","doi":"10.1016/S1359-0278(98)00003-0","DOIUrl":"10.1016/S1359-0278(98)00003-0","url":null,"abstract":"<div><p><strong>Background</strong>: In <em>ab initio</em> protein folding studies, it is often advantageous to build the C<em>α</em> chain first and then to construct the full structure by filling in the peptide groups and the sidechains. Many algorithms have been reported for constructing peptide groups on the C<em>α</em> chain, but most are unsuitable for use in such studies; some are too slow for screening a large number of trial C<em>α</em> chains and others use only the local geometry and ignore the effects of specific non-neighbor interactions, which can be crucial for proper folding. We needed a fast procedure for constructing the peptide groups that does not ignore the effects of long-range, specific interactions.</p><p><strong>Results</strong>: We first found rich correlations between the peptide orientation angle and both the local C<em>α</em>-chain geometry and the type of the flanking amino acid residues. These correlations can be used to greatly limit the range of possible peptide orientation angles. We devised a simple peptide construction procedure in which all orientations within this reduced range are systematically examined and the orientation is selected that minimizes a suitable energy function that includes long-range, specific interactions. When tested on known structures, the method is found to be among the fastest of known methods and attains an accuracy comparable with or better than most methods.</p><p><strong>Conclusions</strong>: The new method is fast and takes into account both the local and non-local specific interactions. It therefore appears to be suitable for use in itab initio protein folding studies, wherein a large number of C<em>α</em> chains are screened.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 1","pages":"Pages 1-10"},"PeriodicalIF":0.0,"publicationDate":"1998-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00003-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20428725","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 intermediates versus molten globule models for protein folding: characterization of partially folded intermediates of apomyoglobin","authors":"Anthony L Fink ,&nbsp;Keith A Oberg ,&nbsp;Sangita Seshadri","doi":"10.1016/S1359-0278(98)00005-4","DOIUrl":"10.1016/S1359-0278(98)00005-4","url":null,"abstract":"<div><p><strong>Background</strong>: Although small proteins may fold in an apparent two-state manner, most studies of protein folding reveal transient intermediates. The ‘molten globule’ has been proposed to be a general intermediate in protein folding. Relatively little is known about the structure of partially folded intermediates, however.</p><p><strong>Results</strong>: Three different partially folded intermediates of apomyoglobin, having 35%, 50% and 60% helix, were characterized at low pH in the presence of different anions. It was found that increasing helical structure correlated with decreasing size and increasing stability to urea. Similar intermediates have been observed transiently during the folding of apomyoglobin.</p><p><strong>Conclusions</strong>: The results are consistent with a model for folding in which structural units coalesce to form a core of relatively native-like structure, the remainder of the protein being relatively disordered. For a given protein there will be certain partially folded conformations of particularly low free energy that are preferentially populated under both equilibrium and transient folding conditions. The conformation and topology of the intermediates will be specific to a given protein, so there are no ‘general’ intermediates, such as the molten globule, in folding.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 1","pages":"Pages 19-25"},"PeriodicalIF":0.0,"publicationDate":"1998-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00005-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20428727","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":"Paper alert","authors":"Lynne Regan ,&nbsp;Luis Serrano ,&nbsp;Andrej Šali ,&nbsp;Amnon Horovitz ,&nbsp;Charles Wilson","doi":"10.1016/S1359-0278(98)00010-8","DOIUrl":"https://doi.org/10.1016/S1359-0278(98)00010-8","url":null,"abstract":"","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 1","pages":"Pages R25-R28"},"PeriodicalIF":0.0,"publicationDate":"1998-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00010-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"137366141","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":"Protein design: a perspective from simple tractable models.","authors":"E I Shakhnovich","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 3","pages":"R45-58"},"PeriodicalIF":0.0,"publicationDate":"1998-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20587726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paper alert","authors":"Lynne Regan ,&nbsp;Luis Serrano ,&nbsp;Andrej Šali ,&nbsp;Amnon Horovitz ,&nbsp;Charles Wilson","doi":"10.1016/S1359-0278(97)00053-9","DOIUrl":"https://doi.org/10.1016/S1359-0278(97)00053-9","url":null,"abstract":"","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"2 6","pages":"Pages R105-R108"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(97)00053-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136849082","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":"Functional diversity of PH domains: an exhaustive modelling study","authors":"Niklas Blomberg ,&nbsp;Michael Nilges","doi":"10.1016/S1359-0278(97)00048-5","DOIUrl":"10.1016/S1359-0278(97)00048-5","url":null,"abstract":"<div><h3>Background:</h3><p>Pleckstrin homology (PH) domains are found in many proteins involved in signal transduction or cytoskeletal organization. The general function for the domain is still unclear; phospholipid binding of some PH domains and a strong electrostatic polarization in the experimental structures suggest a role in localization on membranes. We have analyzed the electrostatic properties and the spatial amino acid distribution from homology models of the entire PH domain family.</p></div><div><h3>Results:</h3><p>Despite the sequence divergence, the quality of the models is sufficient for our study. Most PH domains have an electrostatic polarization similar to the experimental structures. But roughly half of the PH domains linked to a Dbl homology domain have very different electrostatic properties. We also found a striking electrostatic complementarity in some internal PH domain repeats. The analysis of the spatial distribution of amino acids identified residues in the phospholipid-binding site of the spectrin and dynamin PH domains as specific for these domains.</p></div><div><h3>Conclusions:</h3><p>The mostly conserved electrostatic polarization supports a general function in binding to phospholipid membranes. But the presence of PH domains with opposite polarity suggests that ligands and functions have diverged during evolution. We also demonstrate homology modelling as a general sequence analysis tool that can yield significantly more information than conventional analysis.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"2 6","pages":"Pages 343-355"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(97)00048-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20354402","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":"Solution conformation of an essential region of the p53 transactivation domain","authors":"Maria Victoria E Botuyan ,&nbsp;Jamil Momand ,&nbsp;Yuan Chen","doi":"10.1016/S1359-0278(97)00047-3","DOIUrl":"10.1016/S1359-0278(97)00047-3","url":null,"abstract":"<div><h3>Background:</h3><p>The peptide segment surrounding residues Leu22 and Trp23 of the p53 transactivation domain plays a critical role in the transactivation activity of p53. This region binds basal transcriptional components such as the TATA-box binding protein associated factors TAF_II40 and TAF_II60 as well as the mdm-2 and adenovirus type 5 E1B 55 kDa oncoproteins.</p></div><div><h3>Results:</h3><p>The structure of residues 14–28 of p53 was studied by nuclear magnetic resonance spectroscopy and found to prefer a two-<em>β</em>-turn structure stabilized by a hydrophobic cluster consisting of residues known to be important for transactivation and binding to p53-binding proteins. A peptide segment in which Leu22 and Trp23 were replaced by Gln and Ser displays a random structure.</p></div><div><h3>Conclusions:</h3><p>This structural propensity observed in the wild-type p53 peptide is important for understanding the mechanism of transcriptional activation, because very few structural data are available on transactivation domains to date. These results should aid in the design of therapeutics that could competitively inhibit binding of p53 to the oncogene product mdm-2.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"2 6","pages":"Pages 331-342"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(97)00047-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20354401","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":"X-ray crystallography reveals stringent conservation of protein fold after removal of the only disulfide bridge from a stabilized immunoglobulin variable domain","authors":"Isabel Usón ,&nbsp;M Teresa Bes ,&nbsp;George M Sheldrick ,&nbsp;Thomas R Schneider ,&nbsp;Thomas Hartsch ,&nbsp;Hans-Joachim Fritz","doi":"10.1016/S1359-0278(97)00049-7","DOIUrl":"10.1016/S1359-0278(97)00049-7","url":null,"abstract":"<div><h3>Background:</h3><p>Immunoglobulin domains owe a crucial fraction of their conformational stability to an invariant central disulfide bridge, the closure of which requires oxidation. Under the reducing conditions prevailing in cell cytoplasm, accumulation of soluble immunoglobulin is prohibited by its inability to acquire and maintain the native conformation. Previously, we have shown that disulfide-free immunoglobulins can be produced in <em>Escherichia coli</em> and purified from cytoplasmic extracts.</p></div><div><h3>Results:</h3><p>Immunoglobulin REI_v is the variable domain of a human <em>κ</em> light chain. The disulfide-free variant REI_v-C23V/Y32H was crystallized and its structure analyzed by X-ray crystallography (2.8 Å resolution). The conformation of the variant is nearly identical to that of the wild-type protein and the conformationally stabilized variant REI_v-T39K. This constitutes the first crystal structure of an immunoglobulin fragment without a disulfide bridge. The lack of the disulfide bridge produces no obvious local change in structure (compared with the wild type), whereas the Y32H mutation allows the formation of an additional hydrogen bond. There is a further change in the structure that is seen in the dimer in which Tyr49 has flipped out of the dimer interface in the mutant.</p></div><div><h3>Conclusions:</h3><p>Immunoglobulin derivatives without a central disulfide bridge but with stringently conserved wild-type conformation can be constructed in a practical two-step approach. First, the protein is endowed with additional folding stability by the introduction of one or more stabilizing amino acid exchanges; second, the disulfide bridge is destroyed by substitution of one of the two invariant cysteines. Such derivatives can be accumulated in soluble form in the cytoplasmic compartment of the <em>E. coli</em> cell. Higher protein yields and evolutionary refinement of catalytic antibodies by genetic complementation are among the possible advantages.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"2 6","pages":"Pages 357-361"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(97)00049-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20354403","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":"Strain in the folding nucleus of chymotrypsin inhibitor 2","authors":"Andreas G Ladurner ,&nbsp;Laura S Itzhaki ,&nbsp;Alan R Fersht","doi":"10.1016/S1359-0278(97)00050-3","DOIUrl":"10.1016/S1359-0278(97)00050-3","url":null,"abstract":"<div><h3>Background:</h3><p>Chymotrypsin inhibitor 2 (CI2) is a member of the class of fast-folding small proteins, which is very suitable for testing theories of folding. CI2 folds around a diffuse extended nucleus consisting of the single <em>α</em> helix and a set of hydrophobic residues. In particular, Ala16 has been predicted and independently found to interact with Leu49 and Ile57, hydrophobic residues that are highly conserved among homologues. We have characterised in detail the interactions between these residues in the folding nucleus of the protein by using double-mutant cycles.</p></div><div><h3>Results:</h3><p>Surprisingly, we find that there is some destabilising strain in the transition state for folding of the wild-type protein between Ala16 and Ile57. Further, we find that the strain is larger in the native state of the protein. This is shown directly in the unfolding kinetics, which clearly show a release of strain. The net result of this is that the presence of both residues speeds up folding. Ala16 and Leu49 interact favourably in the transition state, but have no net interaction energy in the native state.</p></div><div><h3>Conclusions:</h3><p>Part of the folding nucleus of the protein fits together more snugly in the transition state than it does in the native state. Interactions between some of the closely packed residues in the folding nucleus of CI2 may perhaps be optimised for the rate of folding and not for stability.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"2 6","pages":"Pages 363-368"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(97)00050-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20354404","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}