Discovering Conformational Sub-States Relevant to Protein Function

Ramanathan, Arvind; Savol, Andrej J.; Langmead, Christopher J.; Agarwal, Pratul K.; Chennubhotla, Chakra S.

doi:10.1371/journal.pone.0015827

Discovering Conformational Sub-States Relevant to Protein Function

Journal Article · Thu Jan 27 23:00:00 EST 2011 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0015827· OSTI ID:1564803

Ramanathan, Arvind ^[1]; Savol, Andrej J. ^[2]; Langmead, Christopher J. ^[3]; Agarwal, Pratul K. ^[4]; Chennubhotla, Chakra S. ^[5]

Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Carnegie Mellon Univ., Pittsburgh, PA (United States)
Univ. of Pittsburgh, PA (United States); Carnegie Mellon Univ., Pittsburgh, PA (United States)
Carnegie Mellon Univ., Pittsburgh, PA (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Univ. of Pittsburgh, PA (United States)

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 sub-states present significant challenges for their identification and characterization.

Methods and Findings: To overcome these challenges we have developed a new computational technique, quasi-anharmonic 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.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)

Sponsoring Organization:: USDOE Office of Science; National Institute of Health (NIH)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1564803

Journal Information:: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 1 Vol. 6; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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