NDLI: Dynamics of locking of peptides onto growing amyloid fibrils

Content Provider	PubMed Central
Author	Reddy, Govardhan Straub, John E. Thirumalai, D.
Abstract	Sequence-dependent variations in the growth mechanism and stability of amyloid fibrils, which are implicated in a number of neurodegenerative diseases, are poorly understood. We have carried out extensive all-atom molecular dynamics simulations to monitor the structural changes that occur upon addition of random coil (RC) monomer fragments from the yeast prion Sup35 and Aβ-peptide onto a preformed fibril. Using the atomic resolution structures of the microcrystals as the starting points, we show that the RC → β-strand transition for the Sup35 fragment occurs abruptly over a very narrow time interval, whereas the acquisition of strand content is less dramatic for the hydrophobic-rich Aβ-peptide. Expulsion of water, resulting in the formation of a dry interface between 2 adjacent sheets of the Sup35 fibril, occurs in 2 stages. Ejection of a small number of discrete water molecules in the second stage follows a rapid decrease in the number of water molecules in the first stage. Stability of the Sup35 fibril is increased by a network of hydrogen bonds involving both backbone and side chains, whereas the marginal stability of the Aβ-fibrils is largely due to the formation of weak dispersion interaction between the hydrophobic side chains. The importance of the network of hydrogen bonds is further illustrated by mutational studies, which show that substitution of the Asn and Gln residues to Ala compromises the Sup35 fibril stability. Despite the similarity in the architecture of the amyloid fibrils, the growth mechanism and stability of the fibrils depend dramatically on the sequence.
Related Links	http://dx.doi.org/10.1073/pnas.0902473106
Ending Page	11953
Page Count	6
Starting Page	11948
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	29
Volume Number	106
Language	English
Publisher	National Academy of Sciences
Publisher Date	2009-07-21
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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