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Discovering conformational sub-states relevant to protein function

Ramanathan, A and Savol, AJ and Langmead, CJ and Agarwal, PK and Chennubhotla, CS (2011) Discovering conformational sub-states relevant to protein function. PLoS ONE, 6 (1).

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Background: Internal motions enable proteins to explore a range of conformations, even in the vicinity of native state. The role of conformational fluctuations in the designated function of a protein is widely debated. Emerging evidence suggests that sub-groups within the range of conformations (or sub-states) contain properties that may be functionally relevant. However, low populations in these sub-states and the transient nature of conformational transitions between these substates present significant challenges for their identification and characterization. Methods and Findings: To overcome these challenges we have developed a new computational technique, quasianharmonic analysis (QAA). QAA utilizes higher-order statistics of protein motions to identify sub-states in the conformational landscape. Further, the focus on anharmonicity allows identification of conformational fluctuations that enable transitions between sub-states. QAA applied to equilibrium simulations of human ubiquitin and T4 lysozyme reveals functionally relevant sub-states and protein motions involved in molecular recognition. In combination with a reaction pathway sampling method, QAA characterizes conformational sub-states associated with cis/trans peptidyl-prolyl isomerization catalyzed by the enzyme cyclophilin A. In these three proteins, QAA allows identification of conformational sub-states, with critical structural and dynamical features relevant to protein function. Conclusions: Overall, QAA provides a novel framework to intuitively understand the biophysical basis of conformational diversity and its relevance to protein function. © 2011 Ramanathan et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Ramanathan, A
Savol, AJ
Langmead, CJlangmead@pitt.eduLANGMEAD
Agarwal, PK
Chennubhotla, CS
Date: 7 February 2011
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 6
Number: 1
DOI or Unique Handle: 10.1371/journal.pone.0015827
Refereed: Yes
MeSH Headings: Humans; Isomerism; Models, Chemical; Models, Molecular; Molecular Dynamics Simulation; Motion; Muramidase--chemistry; Phase Transition; Protein Binding; Protein Conformation; Proteins--chemistry; Proteins--metabolism; Proteins--physiology; Ubiquitin--chemistry
Other ID: NLM PMC3030567
PubMed Central ID: PMC3030567
PubMed ID: 21297978
Date Deposited: 03 Aug 2012 18:55
Last Modified: 29 Jan 2019 15:55


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