Structure and folding of disulfide-rich miniproteins: Insights from molecular dynamics simulations and MM-PBSA free energy calculations
The fold of small disulfide‐rich proteins largely relies on two or more disulfide bridges that are main components of the hydrophobic core. Because of the small size of these proteins and their high cystine content, the cysteine connectivity has been difficult to ascertain in some cases, leading to...
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Published in | Proteins, structure, function, and bioinformatics Vol. 73; no. 1; pp. 87 - 103 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Hoboken
Wiley Subscription Services, Inc., A Wiley Company
01.10.2008
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Subjects | |
Online Access | Get full text |
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Summary: | The fold of small disulfide‐rich proteins largely relies on two or more disulfide bridges that are main components of the hydrophobic core. Because of the small size of these proteins and their high cystine content, the cysteine connectivity has been difficult to ascertain in some cases, leading to uncertainties and debates in the literature. Here, we use molecular dynamics simulations and MM‐PBSA free energy calculations to compare similar folds with different disulfide pairings in two disulfide‐rich miniprotein families, namely the knottins and the short‐chain scorpion toxins, for which the connectivity has been discussed. We first show that the MM‐PBSA approach is able to discriminate the correct knotted topology of knottins from the laddered one. Interestingly, a comparison of the free energy components for kalata B1 and MCoTI‐II suggests that cyclotides and squash inhibitors, although sharing the same scaffold, are stabilized through different interactions. Application to short‐chain scorpion toxins suggests that the conventional cysteine pairing found in many homologous toxins is significantly more stable than the unconventional pairing reported for maurotoxin and for spinoxin. This would mean that native maurotoxin and spinoxin are not at the lowest free energy minimum and might result from kinetically rather than thermodynamically driven oxidative folding processes. For both knottins and toxins, the correct or conventional disulfide connectivities provide lower flexibilities and smaller deviations from the initial conformations. Overall, our work suggests that molecular dynamics simulations and the MM‐PBSA approach to estimate free energies are useful tools to analyze and compare disulfide bridge connectivities in miniproteins. Proteins 2008. © 2008 Wiley‐Liss, Inc. |
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Bibliography: | istex:CA7DE4516A000DE9C301E320ACC84F506820AB3E ArticleID:PROT22054 ark:/67375/WNG-5DMWXLC5-H Cecil Combelles's current address is Institut Charles Gerhardt, CNRS, Université Montpellier 2, cc 1501, Place Eugène Bataillon, 34095 Montpellier, France. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0887-3585 1097-0134 |
DOI: | 10.1002/prot.22054 |