title: Discovering conformational sub-states relevant to protein function.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Computational Biology Institute and Computer Science and Mathematics Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee, United States of America.
authors.forename: Arvind
authors.initials: A
authors.lastname: Ramanathan
authors.forename: Andrej J
authors.initials: AJ
authors.lastname: Savol
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Langmead
authors.forename: Pratul K
authors.initials: PK
authors.lastname: Agarwal
authors.forename: Chakra S
authors.initials: CS
authors.lastname: Chennubhotla
mesh_terms: D006801:Humans; D007536:Isomerism; D008956:Models, Chemical; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009038:Motion; D009113:Muramidase / Q000737:chemistry; D044367:Phase Transition; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D025801:Ubiquitin / Q000737:chemistry
chemical_list: D011506:Proteins; D025801:Ubiquitin; D009113:Muramidase