Folding & designPub Date : 1998-10-01DOI: 10.1016/S1359-0278(98)00050-9
Robert J. Petrella , Themis Lazaridis , Martin Karplus
{"title":"Protein sidechain conformer prediction: a test of the energy function","authors":"Robert J. Petrella , Themis Lazaridis , Martin Karplus","doi":"10.1016/S1359-0278(98)00050-9","DOIUrl":"10.1016/S1359-0278(98)00050-9","url":null,"abstract":"<div><p><strong>Background:</strong> Homology modeling is an important technique for making use of the rapidly increasing number of protein sequences in the absence of structural information. The major problems in such modeling, once the alignment has been made, concern the positions of loops and the orientations of sidechains. Although progress has been made in recent years for sidechain prediction, current methods appear to have a limit on the order of 70% in their accuracy. It is important to have an understanding of this limitation, which for energy-based methods could arise from inaccuracies of the potential function.</p><p><strong>Results:</strong> A test of the <span>charmm</span> function for sidechain prediction was performed. To eliminate the multiple-residue search problem, the minimum energy positions of individual sidechains in ten proteins were calculated in the presence of all other sidechains in their crystal orientations. This test provides a necessary condition that any energy function useful for sidechain placement must satisfy. For <em>χ</em><sub>1</sub> × <em>χ</em><sub>2</sub> rotations, the accuracies were 77.4% and 89.5%, respectively, and in the presence of crystal waters were 86.5% and 94.9%, respectively. If there was an error, the crystal structure usually corresponded to an alternative local minimum on the calculated energy map. Prediction accuracy correlated with the size of the energy gap between primary and secondary minima.</p><p><strong>Conclusions:</strong>The results indicate that the errors in current sidechain prediction schemes cannot be attributed to the potential energy function <em>per se</em>. The test used here establishes a necessary condition that any proposed energy-based sidechain prediction method, as well as many statistically based methods, must satisfy.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 5","pages":"Pages 353-377"},"PeriodicalIF":0.0,"publicationDate":"1998-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00050-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20718397","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}
Folding & designPub Date : 1998-08-01DOI: 10.1016/S1359-0278(98)00036-4
Arthur G. Street , Stephen L. Mayo
{"title":"Pairwise calculation of protein solvent-accessible surface areas","authors":"Arthur G. Street , Stephen L. Mayo","doi":"10.1016/S1359-0278(98)00036-4","DOIUrl":"10.1016/S1359-0278(98)00036-4","url":null,"abstract":"<div><p><strong>Background:</strong> The tractability of many algorithms for determining the energy state of a system depends on the pairwise nature of an energy expression. Some energy terms, such as the standard implementation of the van der Waals potential, satisfy this criterion whereas others do not. One class of important potentials that are not pairwise involves benefits and penalties for burying hydrophobic and/or polar surface areas. It has been found previously that, in some cases, a pairwise approximation to these surface areas correlates with the true surface areas. We set out to generalize the applicability of this approximation.</p><p><strong>Results:</strong> We develop a pairwise expression with one scalable parameter that closely reproduces both the true buried and the true exposed solvent-accessible surface areas. We then refit our previously published coiled-coil stability data to give solvation parameters of 26 cal/mol å<sup>2</sup> favoring hydrophobic burial and 100 cal/mol å<sup>2</sup> opposing polar burial.</p><p><strong>Conclusions:</strong>An accurate pairwise approximation to calculate exposed and buried protein solvent-accessible surface area is achieved.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 4","pages":"Pages 253-258"},"PeriodicalIF":0.0,"publicationDate":"1998-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00036-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20625081","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}
Folding & designPub Date : 1998-08-01DOI: 10.1016/S1359-0278(98)00039-X
Valentina E. Bychkova , Alexandra E. Dujsekina , Andrea Fantuzzi , Oleg B. Ptitsyn , Gian-Luigi Rossi
{"title":"Release of retinol and denaturation of its plasma carrier, retinol-binding protein","authors":"Valentina E. Bychkova , Alexandra E. Dujsekina , Andrea Fantuzzi , Oleg B. Ptitsyn , Gian-Luigi Rossi","doi":"10.1016/S1359-0278(98)00039-X","DOIUrl":"10.1016/S1359-0278(98)00039-X","url":null,"abstract":"<div><p><strong>Background:</strong> Retinol is tightly packed inside the structure of its plasma carrier (retinol-binding protein, RBP). It was found that retinol release from RBP to aqueous solutions is facilitated by either very low pH or very high temperatures (i.e. by non-physiological conditions that cause protein denaturation). It was also found that alcohols induce protein conformational transitions to denatured states. On this basis, it may be suggested that retinol release <em>in vivo</em> is facilitated by the partial unfolding of the carrier resulting from the concerted action of the moderate local decrease of pH and the moderate local decrease of dielectric constant in proximity to the target membranes.</p><p><strong>Results:</strong> <em>In vitro</em>, at 37°C, retinol is removed from its plasma carrier by the concerted action of the moderately low pH and the moderately low dielectric constant of solutions containing a low ionic strength buffer and methanol in variable proportions. Release of retinol is accompanied by a conformational transition of RBP from the native to the molten-globule state.</p><p><strong>Conclusions:</strong>The physiological function of RBP – targeted delivery of retinol – is mimicked <em>in vitro</em> by the facilitated release of retinol (associated with a partial unfolding of the protein carrier) in solutions exhibiting pH and dielectric constant values that are within the range of values expected in the <em>in vivo</em> microenvironment.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 4","pages":"Pages 285-291"},"PeriodicalIF":0.0,"publicationDate":"1998-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00039-X","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20625083","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}
Folding & designPub Date : 1998-08-01DOI: 10.1016/S1359-0278(98)00035-2
Stephen W. Michnick , Eugene Shakhnovich
{"title":"A strategy for detecting the conservation of folding-nucleus residues in protein superfamilies","authors":"Stephen W. Michnick , Eugene Shakhnovich","doi":"10.1016/S1359-0278(98)00035-2","DOIUrl":"10.1016/S1359-0278(98)00035-2","url":null,"abstract":"<div><p><strong>Background:</strong> Nucleation-growth theory predicts that fast-folding peptide sequences fold to their native structure via structures in a transition-state ensemble that share a small number of native contacts (the folding nucleus). Experimental and theoretical studies of proteins suggest that residues participating in folding nuclei are conserved among homologs. We attempted to determine if this is true in proteins with highly diverged sequences but identical folds (superfamilies).</p><p><strong>Results:</strong> We describe a strategy based on comparisons of residue conservation in natural superfamily sequences with simulated sequences (generated with a Monte-Carlo sequence design strategy) for the same proteins. The basic assumptions of the strategy were that natural sequences will conserve residues needed for folding and stability plus function, the simulated sequences contain no functional conservation, and nucleus residues make native contacts with each other. Based on these assumptions, we identified seven potential nucleus residues in ubiquitin superfamily members. Non-nucleus conserved residues were also identified; these are proposed to be involved in stabilizing native interactions. We found that all superfamily members conserved the same potential nucleus residue positions, except those for which the structural topology is significantly different.</p><p><strong>Conclusions:</strong>Our results suggest that the conservation of the nucleus of a specific fold can be predicted by comparing designed simulated sequences with natural highly diverged sequences that fold to the same structure. We suggest that such a strategy could be used to help plan protein folding and design experiments, to identify new superfamily members, and to subdivide superfamilies further into classes having a similar folding mechanism.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 4","pages":"Pages 239-251"},"PeriodicalIF":0.0,"publicationDate":"1998-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00035-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20626461","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}
Folding & designPub Date : 1998-08-01DOI: 10.1016/S1359-0278(98)00033-9
Sophie E. Jackson
{"title":"How do small single-domain proteins fold?","authors":"Sophie E. Jackson","doi":"10.1016/S1359-0278(98)00033-9","DOIUrl":"10.1016/S1359-0278(98)00033-9","url":null,"abstract":"<div><p>Many small, monomeric proteins fold with simple two-state kinetics and show wide variation in folding rates, from microseconds to seconds. Thus, stable intermediates are not a prerequisite for the fast, efficient folding of proteins and may in fact be kinetic traps and slow the folding process. Using recent studies, can we begin to search for trends which may lead to a better understanding of the protein folding process?</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 4","pages":"Pages R81-R91"},"PeriodicalIF":0.0,"publicationDate":"1998-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00033-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20625086","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}
Folding & designPub Date : 1998-08-01DOI: 10.1016/S1359-0278(98)00034-0
Leszek Rychlewski , Baohong Zhang , Adam Godzik
{"title":"Fold and function predictions for Mycoplasma genitalium proteins","authors":"Leszek Rychlewski , Baohong Zhang , Adam Godzik","doi":"10.1016/S1359-0278(98)00034-0","DOIUrl":"10.1016/S1359-0278(98)00034-0","url":null,"abstract":"<div><p><strong>Background:</strong> Uncharacterized proteins from newly sequenced genomes provide perfect targets for fold and function prediction.</p><p><strong>Results:</strong> For 38% of the entire genome of <em>Mycoplasma genitalium</em>, sequence similarity to a protein with a known structure can be recognized using a new sequence alignment algorithm. When comparing genomes of <em>M. genitalium</em> and <em>Escherichia coli</em>, > 80% of <em>M. genitalium</em> proteins have a significant sequence similarity to a protein in <em>E. coli</em> and there are > 40 examples that have not been recognized before. For all cases of proteins with significant profile similarities, there are strong analogies in their functions, if the functions of both proteins are known. The results presented here and other recent results strongly support the argument that such proteins are actually homologous. Assuming this homology allows one to make tentative functional assignments for > 50 previously uncharacterized proteins, including such intriguing cases as the putative <em>β</em>-lactam antibiotic resistance protein in <em>M. genitalium.</em></p><p><strong>Conclusions:</strong>Using a new profile-to-profile alignment algorithm, the three-dimensional fold can be predicted for almost 40% of proteins from a genome of the small bacterium <em>M. genitalium</em>, and tentative function can be assigned to almost 80% of the entire genome. Some predictions lead to new insights about known functions or point to hitherto unexpected features of <em>M.genitalium</em></p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 4","pages":"Pages 229-238"},"PeriodicalIF":0.0,"publicationDate":"1998-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00034-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20626459","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}
Folding & designPub Date : 1998-08-01DOI: 10.1016/S1359-0278(98)00032-7
Chung-Jung Tsai , Dong Xu , Ruth Nussinov
{"title":"Protein folding via binding and vice versa","authors":"Chung-Jung Tsai , Dong Xu , Ruth Nussinov","doi":"10.1016/S1359-0278(98)00032-7","DOIUrl":"10.1016/S1359-0278(98)00032-7","url":null,"abstract":"<div><p>The terms intermolecular and intramolecular recognition are often used when referring to binding and folding, highlighting the common ground between the two processes. Most studies, however, are aimed at either one process or the other. Here, we show how knowledge from binding can aid in understanding folding and <em>vice versa.</em></p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 4","pages":"Pages R71-R80"},"PeriodicalIF":0.0,"publicationDate":"1998-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00032-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20626462","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}
Folding & designPub Date : 1998-08-01DOI: 10.1016/S1359-0278(98)00038-8
Alberta Jaqueline Padilla-Zu´ñiga , Arturo Rojo-Domi´nguez
{"title":"Non-homology knowledge-based prediction of the papain prosegment folding pattern: a description of plausible folding and activation mechanisms","authors":"Alberta Jaqueline Padilla-Zu´ñiga , Arturo Rojo-Domi´nguez","doi":"10.1016/S1359-0278(98)00038-8","DOIUrl":"10.1016/S1359-0278(98)00038-8","url":null,"abstract":"<div><p><strong>Background:</strong> A detailed knowledge of three-dimensional conformations is necessary in order to understand the close relationship between protein structure and function. Among current methodologies, homology modeling is an important tool for obtaining reliable geometries and it provides a direct alternative to X-ray or NMR techniques. In contrast, predictive methods with no three-dimensional template (non-homology) still require further validation and systematization.</p><p><strong>Results:</strong> Here, we present a non-homology knowledge-based strategy for the structural prediction of the proregion of a cysteine proteinase zymogen. This method analyzes individual sequences and multiple alignments of homologous sequences, making use of different published algorithms and incorporating all available structure-related information to obtain improved predictions. Our strategy yielded acceptable secondary structure and general three-dimensional assignments when compared with crystallographic data from homologous proteins.</p><p><strong>Conclusions:</strong>We discuss our successes and failures as a contribution to non-homology prediction development. In addition, based on the information analyzed and generated in this work, we propose plausible folding and activation mechanisms for thiol-proteinase precursors that attempt to shed light on the molecular basis of prosegment functions.</p></div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 4","pages":"Pages 271-284"},"PeriodicalIF":0.0,"publicationDate":"1998-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1359-0278(98)00038-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20625082","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}
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