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Computational De Novo Design of a Self-Assembling Peptide with Predefined Structure
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
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2015 (Engelska)Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 427, nr 2, s. 550-562Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Protein and peptide self-assembly is a powerful design principle for engineering of new biomolecules. More sophisticated biomaterials could be built if both the structure of the overall assembly and that of the self-assembling building block could be controlled. To approach this problem, we developed a computational design protocol to enable de novo design of self-assembling peptides with predefined structure. The protocol was used to design a peptide building block with a beta alpha beta fold that self-assembles into fibrillar structures. The peptide associates into a double beta-sheet structure with tightly packed a-helices decorating the exterior of the fibrils. Using circular dichroism, Fourier transform infrared spectroscopy, electron microscopy and X-ray fiber diffraction, we demonstrate that the peptide adopts the designed conformation. The results demonstrate that computational protein design can be used to engineer protein and peptide assemblies with predefined three-dimensional structures, which can serve as scaffolds for the development of functional biomaterials. Rationally designed proteins and peptides could also be used to investigate the subtle energetic and entropic tradeoffs in natural self-assembly processes and the relation between assembly structure and assembly mechanism. We demonstrate that the de novo designed peptide self-assembles with a mechanism that is more complicated than expected, in a process where small changes in solution conditions can lead to significant differences in assembly properties and conformation. These results highlight that formation of structured protein/peptide assemblies is often dependent on the formation of weak but highly precise intermolecular interactions.

Ort, förlag, år, upplaga, sidor
2015. Vol. 427, nr 2, s. 550-562
Nyckelord [en]
self-assembly, computational protein design, protein structure, Fourier transform infrared spectroscopy, de novo design
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
biokemi
Identifikatorer
URN: urn:nbn:se:su:diva-115297DOI: 10.1016/j.jmb.2014.12.002ISI: 000348888200029PubMedID: 25498388OAI: oai:DiVA.org:su-115297DiVA, id: diva2:799909
Anmärkning

AuthorCount:6;

Tillgänglig från: 2015-03-31 Skapad: 2015-03-18 Senast uppdaterad: 2020-03-04Bibliografiskt granskad
Ingår i avhandling
1. Infrared spectroscopy: a tool for protein characterization
Öppna denna publikation i ny flik eller fönster >>Infrared spectroscopy: a tool for protein characterization
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Infrared (IR) spectroscopy, which belongs to vibrational spectroscopy, detects the vibrations of molecules, for example, proteins. The absorption of the peptide group gives rise to 9 characteristic bands in the infrared region, named A, B, I-VII, with a decreasing energy or wavenumber (cm-1). Among the 9 bands, amide I, which is mainly caused by C=O stretching vibration, is most sensitive to backbone structure and environment, and therefore can be used for structural analysis. In this thesis, a membrane protein sarcoplasmic reticulum Ca2+-ATPase (SERCA1a) and a self-assembling peptide was studied with IR spectroscopy.  

In the first two papers, IR spectroscopy was used to assess the quality of a recombinant SERCA1a. A yeast-based expression system was applied to express recombinant SERCA1a, and the reaction cycle as well as the structure was analysed with IR spectroscopy. Different reaction intermediates were accumulated under different buffer conditions upon the release of ATP. The results showed that the recombinant protein shared similar IR features compared to the native protein. However, two SERCA1a preparations showed a difference around 1640 cm-1 in the amide I region. Using curve fitting, the band was assigned to β structure, and further investigation indicated that the difference in this region originates from protein aggregation. In the third paper, a co-fitting approach was tested and showed to be a more reliable method for structural analysis, and it can be applied in the biological IR spectroscopy. In the fourth paper, a peptide was computational designed and was predicted to self-assemble to amyloid fibrils, the formation of the fibril was confirmed with both electron microscopy and X-ray diffraction. IR spectroscopy was used to analyze further the structural details and the results support our structural predication. 

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2016
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
biokemi
Identifikatorer
urn:nbn:se:su:diva-128761 (URN)978-91-7649-407-3 (ISBN)
Disputation
2016-05-27, Magnéli Hall, Arrhenius Laboratory, Svante arrhenius väg 16 B, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2016-05-02 Skapad: 2016-04-04 Senast uppdaterad: 2017-02-20Bibliografiskt granskad

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Li, ChengeBarth, Andreas
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Institutionen för biokemi och biofysik
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