Folding & design最新文献_第3页

Residual structure in the Alzheimer's disease peptide: probing the origin of a central hydrophobic cluster 阿尔茨海默病肽的残留结构:探测中心疏水簇的起源

Folding & design Pub Date : 1998-10-01 DOI: 10.1016/S1359-0278(98)00054-6

Shengsheng Zhang , Nicole Casey , Jonathan P. Lee

{"title":"Residual structure in the Alzheimer's disease peptide: probing the origin of a central hydrophobic cluster","authors":"Shengsheng Zhang , Nicole Casey , Jonathan P. Lee","doi":"10.1016/S1359-0278(98)00054-6","DOIUrl":"10.1016/S1359-0278(98)00054-6","url":null,"abstract":"<div>Background: Structure–function studies on the Alzheimer's disease peptide show that a central hydrophobic cluster – Aβ(17–21), LVFFA – is a prominent structural feature linked to plaque competence. The origin and stability of this cluster was probed in a 17-residue fragment which includes flanking residues that potentially help stabilize the cluster.Results: After residue substitution, the measurement of pKas, amide exchange rates and other NMR data show that any coulombic interactions between His14 and Glu22 are not required for the stability of the central hydrophobic cluster. In contrast, a single substitution within the cluster disrupts its integrity and causes the largest pKa shift for flanking residues, while increasing the solvent accessibility of the backbone.Conclusions:The integrity of the structurally dominant cluster relies primarily upon local hydrophobic interactions, rather than on interactions between the sidechains of charged flanking residues. Moreover, the conformational disposition of the cluster affects the pKas of flanking residues, underscoring its structural dominance.</div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 5","pages":"Pages 413-422"},"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)00054-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20718403","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}

引用次数: 46

Anatomy by computer experiment of the exchange of a water molecule buried in human apolipoprotein E 人体载脂蛋白E水分子交换的计算机解剖实验

Folding & design Pub Date : 1998-10-01 DOI: 10.1016/S1359-0278(98)00049-2

Martine Prévost

{"title":"Anatomy by computer experiment of the exchange of a water molecule buried in human apolipoprotein E","authors":"Martine Prévost","doi":"10.1016/S1359-0278(98)00049-2","DOIUrl":"10.1016/S1359-0278(98)00049-2","url":null,"abstract":"<div>Background: NMR experiments show that even water molecules that are well ordered in a crystal structure exchange with the external solvent. Despite crucial progress on the understanding of the exchange of crystal-buried water molecules, the detailed pathways followed by a water molecule to escape from or penetrate into the protein interior are unknown.Results: The exchange of a crystal water molecule buried in the low-density lipoprotein receptor-binding domain of human apolipoprotein E with a water molecule from the external solvent was detected and monitored in a molecular dynamics simulation. This simulation shows that the escape of the crystal water molecule from the protein interior and the penetration of the water molecule from the bulk occur by a single-pathway mechanism involving conformational fluctuations of arginine and tryptophan sidechains. Along the pathway the exchanging water molecule interacts specifically with protein atoms by way of a varying pattern of hydrogen bonds.Conclusions:The exchange pathway revealed by the molecular dynamics trajectory suggests a mechanism by which hydrogen bonds work in relay to permit either the penetration or the expulsion of a water molecule. This result may have important implications not only on the process of water exchange but also to probe ligand binding to proteins.</div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 5","pages":"Pages 345-351"},"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)00049-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20718399","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}

引用次数: 6

A structural role for glycosylation: lessons from the hp model 糖基化的结构作用:来自hp模型的教训

Folding & design Pub Date : 1998-10-01 DOI: 10.1016/S1359-0278(98)00046-7

Daniel Hoffmann , Holger Flörke

{"title":"A structural role for glycosylation: lessons from the hp model","authors":"Daniel Hoffmann , Holger Flörke","doi":"10.1016/S1359-0278(98)00046-7","DOIUrl":"10.1016/S1359-0278(98)00046-7","url":null,"abstract":"<div>Background: Protein glycosylation, the covalent attachment of carbohydrates, is very common, but in many cases the biological function of glycosylation is not well understood. Recently, fluorescence energy transfer experiments have shown that glycosylation can strongly change the global conformational distributions of peptides. We intend to show the physical mechanism behind this structural effect using a theoretical model.Results: The framework of the hp model of Dill and coworkers is used to describe peptides and their glycosylated counterparts. Conformations are completely enumerated and exact results are obtained for the effect of glycosylation. On glycosylation, the model peptides experience conformational changes similar to those seen in experiments. This effect is highly specific for the sequence of amino acids and also depends on the size of the glycan. Experimentally testable predictions are made for related peptides.Conclusions:Glycans can, by means of entropic contributions, modulate the free energy landscape of polypeptides and thereby specifically stabilize polypeptide conformations. With respect to glycoproteins, the results suggest that the loss of chain entropy during protein folding is partly balanced by an increase in carbohydrate entropy.</div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 5","pages":"Pages 337-343"},"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)00046-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20718398","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}

引用次数: 23

Ubiquitin superfolds: intrinsic and attachable regulators of cellular activities? 泛素超折叠:细胞活动的内在和附加调节剂?

Folding & design Pub Date : 1998-10-01 DOI: 10.1016/S1359-0278(98)00047-9

R John Mayer , Michael Landon , Robert Layfield

引用次数: 16

Proteolytic selection for protein folding using filamentous bacteriophages 利用丝状噬菌体进行蛋白质折叠的蛋白水解选择

Folding & design Pub Date : 1998-10-01 DOI: 10.1016/S1359-0278(98)00044-3

Peter Kristensen , Greg Winter

{"title":"Proteolytic selection for protein folding using filamentous bacteriophages","authors":"Peter Kristensen , Greg Winter","doi":"10.1016/S1359-0278(98)00044-3","DOIUrl":"10.1016/S1359-0278(98)00044-3","url":null,"abstract":"<div>Background: Filamentous bacteriophages have been used for the selection of folded peptide and protein ‘ligands’ by binding the phage to ‘receptor’-coated solid phase. Here, using proteolysis, we have developed a technique for the selection of folded and stable proteins that is independent of their binding activities.Results: When a 21-residue peptide comprising a protease cleavage site was introduced into the flexible linker between the second and third domains of the minor coat protein p3 of filamentous bacteriophage, the phages could be cleaved by trypsin and were rendered non-infective. By contrast, phages displaying mutant barnases at this site were resistant to proteolysis, but were cleaved and their infectivity was destroyed as the temperature was raised. By mixing phages bearing two barnase mutants of differing stability, and adding protease at a temperature at which one mutant was resistant and the other was sensitive, we were able to enrich by 1.6 ×104-fold for phages bearing the more stable barnase.Conclusions:The approach provides a means for the selection of folded and stable proteins, and may be applicable to the selection of de novo proteins.</div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 5","pages":"Pages 321-328"},"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)00044-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20719123","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}

引用次数: 257

Probing the folding pathway of a β-clam protein with single-tryptophan constructs 用单色氨酸构建体探索β-蛤蛋白的折叠途径

Folding & design Pub Date : 1998-10-01 DOI: 10.1016/S1359-0278(98)00053-4

Patricia L. Clark , Benjamin F. Weston , Lila M. Gierasch

{"title":"Probing the folding pathway of a β-clam protein with single-tryptophan constructs","authors":"Patricia L. Clark , Benjamin F. Weston , Lila M. Gierasch","doi":"10.1016/S1359-0278(98)00053-4","DOIUrl":"https://doi.org/10.1016/S1359-0278(98)00053-4","url":null,"abstract":"<div>Background: Cellular retinoic acid binding protein I (CRABPI) is a small, predominantly β-sheet protein with a simple architecture and no disulfides or cofactors. Folding of mutants containing only one of the three native tryptophans has been examined using stopped-flow fluorescence and circular dichroism at multiple wavelengths.Results: Within 10 ms, the tryptophan fluorescence of all three mutants shows a blue shift, and stopped-flow circular dichroism shows significant secondary structure content. The local environment of Trp7, a completely buried residue located near the intersection of the N and C termini, develops on a 100 ms time scale. Spectral signatures of the other two tryptophan residues (87 and 109) become native-like in a 1 s kinetic phase.Conclusions:Formation of the native β structure of CRABPI is initiated by rapid hydrophobic collapse, during which local segments of chain adopt significant secondary structure. Subsequently, transient yet specific interactions of amino acid residues restrict the arrangement of the chain topology and initiate long-range associations such as the docking of the N and C termini. The development of native tertiary environments, including the specific packing of the β-sheet sidechains, occurs in a final, highly cooperative step simultaneous with stable interstrand hydrogen bonding.</div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 5","pages":"Pages 401-412"},"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)00053-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90027812","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}

引用次数: 51

Empirical modifications to the Amber/OPLS potential for predicting the solution conformations of cyclic peptides by vacuum calculations 用真空计算预测环肽溶液构象的琥珀/OPLS电位的经验修正

Folding & design Pub Date : 1998-10-01 DOI: 10.1016/S1359-0278(98)00051-0

Chen Keasar , Rakefet Rosenfeld

{"title":"Empirical modifications to the Amber/OPLS potential for predicting the solution conformations of cyclic peptides by vacuum calculations","authors":"Chen Keasar , Rakefet Rosenfeld","doi":"10.1016/S1359-0278(98)00051-0","DOIUrl":"10.1016/S1359-0278(98)00051-0","url":null,"abstract":"<div>Background: Peptides have ubiquitous roles in all biological systems and are thus of interest in both basic and applied research. The rational design of bioactive peptides could be greatly enhanced by an efficient method for accurately predicting the conformations that these molecules can adopt in solution. As a design process inevitably requires testing numerous molecules, an efficient method would require the calculations to be performed in vacuum.Results: Attempts to predict the conformations of cyclic peptides using a simulated annealing protocol with the Amber/OPLS potential in vacuum resulted, not unexpectedly, in overly packed, non-native conformations. We therefore empirically modified the potential by several cycles of structure prediction and function refinement until a good fit between experimental and predicted conformations was obtained. Three major modifications to the potential were required in order to reproduce the solution structures of cyclic peptides: explicit torsional energies for the peptide backbone torsional angles; explicit hydrogen-bonding energies for backbone hydrogen bonds; and a penalty for close approaches between uncharged and charged atoms.Conclusions:Using the modified potential, we predicted the solution conformations of cyclic peptides in the size range of 5–10 residues with reasonable accuracy.</div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 5","pages":"Pages 379-388"},"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)00051-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20718401","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}

引用次数: 7

Efficient dynamics in the space of contact maps 接触映射空间中的有效动力学

Folding & design Pub Date : 1998-10-01 DOI: 10.1016/S1359-0278(98)00045-5

Michele Vendruscolo , Eytan Domany

{"title":"Efficient dynamics in the space of contact maps","authors":"Michele Vendruscolo , Eytan Domany","doi":"10.1016/S1359-0278(98)00045-5","DOIUrl":"10.1016/S1359-0278(98)00045-5","url":null,"abstract":"<div>Background: Two problems are of major importance in protein fold prediction: how to generate plausible conformations, and how to choose an energy function to identify the native state. Contact maps are a simple representation of protein structure and offer a promising framework to address these two issues.Results: In this work we develop Monte Carlo dynamics in contact map space. The procedure is divided into four steps: non-local dynamics, in which large-scale “cluster” moves are performed (clusters are in approximate correspondence with secondary structure elements); local dynamics, in which secondary structure location is optimized; reconstruction, in which the physicality of the contact map is restored; and refinement, which consists of a further Monte Carlo energy minimization in real space. We demonstrate that such a dynamical procedure is effective in producing uncorrelated low-energy states.Conclusions:The procedure introduced in this paper very effectively generates a representative ensemble of conformations. We are able to show that existing sets of pairwise contact energy parameters are not suitable to single out the native state within this ensemble. The remaining outstanding issue in protein folding is to find an energy function that can discriminate the native state from decoys.</div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 5","pages":"Pages 329-336"},"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)00045-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20719124","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}

引用次数: 38

A simple model for evolution of proteins towards the global minimum of free energy 蛋白质向全球自由能最小值进化的简单模型

Folding & design Pub Date : 1998-10-01 DOI: 10.1016/S1359-0278(98)00052-2

Tamar Kaffe-Abramovich , Ron Unger

{"title":"A simple model for evolution of proteins towards the global minimum of free energy","authors":"Tamar Kaffe-Abramovich , Ron Unger","doi":"10.1016/S1359-0278(98)00052-2","DOIUrl":"10.1016/S1359-0278(98)00052-2","url":null,"abstract":"<div>Background: Proteins seem to have their native structure in a global minimum of free energy. No mechanism is known, however, for ensuring this property. Furthermore, computational complexity studies suggest that such a mechanism is not feasible. These seemingly contradictory observations can be reconciled by the suggestion that evolutionary selection can yield proteins whose native conformation is in the global minimum of free energy. The aim of this study is to investigate such evolutionary processes in a simple model of protein folding.Results: Three possible evolutionary processes are explored.First, if the free energy of the chain is kept below a fixed threshold there is no improvement towards the global minimum. Second, if free energy is minimized directly, sequences emerge whose native conformation is in the global minimum of free energy. Third, when evolutionary pressure is applied within a small set of close homologs, sequences emerge whose functional conformation is in the global minimum of free energy.Conclusions:Although minimizing free energy does select for sequences whose functional conformation is in the global free energy minimum, we argue that for most proteins, which typically have free energy values of only 5–15 kcal/mol, such evolutionary pressure cannot be considered biologically plausible. In contrast, by repeatedly forcing sequences to avoid drifting towards competing “non-native” conformations, sequences emerge whose native conformation becomes very close to the global minimum of free energy. We argue that such a mechanism is both efficient and biologically plausible.</div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 5","pages":"Pages 389-399"},"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)00052-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20718400","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}

引用次数: 9

Prion protein fragments spanning helix 1 and both strands of β sheet (residues 125–170) show evidence for predominantly helical propensity by CD and NMR 朊病毒蛋白片段横跨螺旋1和β片的两条链(残基125-170)，通过CD和NMR显示出主要的螺旋倾向

Folding & design Pub Date : 1998-10-01 DOI: 10.1016/S1359-0278(98)00043-1

Gary J. Sharman , Nigel Kenward , Huw E. Williams , Michael Landon , R John Mayer , Mark S. Searle

{"title":"Prion protein fragments spanning helix 1 and both strands of β sheet (residues 125–170) show evidence for predominantly helical propensity by CD and NMR","authors":"Gary J. Sharman , Nigel Kenward , Huw E. Williams , Michael Landon , R John Mayer , Mark S. Searle","doi":"10.1016/S1359-0278(98)00043-1","DOIUrl":"10.1016/S1359-0278(98)00043-1","url":null,"abstract":"<div>Background: Transmissible spongiform encephalopathies are a group of neurodegenerative disorders of man and animals that are believed to be caused by an α-helical to β-sheet conformational change in the prion protein, PrP. Recently determined NMR structures of recombinant PrP (residues 121–231 and 90–231) have identified a short two-stranded anti-parallel β sheet in the normal cellular form of the protein (PrPC). This β sheet has been suggested to be involved in seeding the conformational transition to the disease-associated form (PrPSc) via a partially unfolded intermediate state.Results: We describe CD and NMR studies of three peptides (125–170, 142–170 and 156–170) that span the β-sheet and helix 1 region of PrP, forming a large part of the putative PrPSc–PrPC binding site that has been proposed to be important for self-seeding replication of PrPSc. The data suggest that all three peptides in water have predominantly helical propensities, which are enhanced in aqueous methanol (as judged by deviations from random-coil Hα chemical shifts and 3JHα–NH values). Although the helical propensity is most marked in the region corresponding to helix 1 (144–154), it is also apparent for residues spanning the two β-strand sequences.Conclusions:We have attempted to model the conformational properties of a partially unfolded state of PrP using peptide fragments spanning the region 125–170. We find no evidence in the sequence for any intrinsic conformational preference for the formation of extended β-like structure that might be involved in promoting the PrPC–PrPSc conformational transition.</div>","PeriodicalId":79488,"journal":{"name":"Folding & design","volume":"3 5","pages":"Pages 313-320"},"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)00043-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20718396","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}

引用次数: 21