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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-17807

Paoli, B; Seeber, M; Backus, E H; Ihalainen, J A; Hamm, P; Caflisch, A (2009). Bulky Side Chains and Non-native Salt Bridges Slow down the Folding of a Cross-Linked Helical Peptide: A Combined Molecular Dynamics and Time-Resolved Infrared Spectroscopy Study. Journal of Physical Chemistry. B, 113(13):4435-4442.

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Abstract

Multiple 4-mus molecular dynamics (MD) simulations are used to study the folding process of the cross-linked alpha-helical peptide Ac-EACAR(5)EAAAR(10)EAACR(15)Q-NH(2) (EAAAR peptide). The folding kinetics are single exponential at 330 K, while they are complex at 281 K with a clear deviation from single-exponential behavior, in agreement with time-resolved infrared (IR) spectroscopy measurements. Network analysis of the conformation space sampled by the MD simulations reveals four main folding channels which start from conformations with partially formed helical structure and non-native salt-bridges in a kinetically partitioned unfolded state. The independent folding pathways explain the comparable quality of models based on stretched exponential and multiexponential fitting of the kinetic traces at low temperature. The rearrangement of bulky side chains, and in particular their reorientation with respect to the cross-linker, makes the EAAAR peptide a slower folder at 281 K than a similar peptide devoid of the three glutamate side chains. On the basis of this simulation result, extracted from a total MD sampling of 1.0 ms, a mutant with additional bulky side chains (three methionines replacing alanines at positions 2, 7, and 12) is suggested to fold slower than the EAAAR peptide. This prediction is confirmed by time-resolved IR spectroscopy.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Biochemistry
07 Faculty of Science > Institute of Biochemistry

07 Faculty of Science > Institute of Physical Chemistry
DDC:570 Life sciences; biology
540 Chemistry
Language:English
Date:02 April 2009
Deposited On:07 Apr 2009 11:39
Last Modified:27 Nov 2013 23:06
Publisher:American Chemical Society
ISSN:1520-5207
Additional Information:Full text article
Publisher DOI:10.1021/jp810431s
PubMed ID:19256526
Citations:Web of Science®. Times Cited: 8
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