Allosteric transitions in the chaperonin GroEL are captured by a dominant normal mode that is most robust to sequence variations

¹ NIH
² National Institutes of Health
³ University of Maryland

^* To whom correspondence should be addressed. E-mail: zhengwj{at}helix.nih.gov.

Submitted on January 24, 2007
Revised on March 7, 2007
Accepted on 4 June 2007

	Abstract

The E. Coli chaperonin GroEL, which helps proteins to fold, consists of two heptameric rings stacked back-to-back. During the reaction cycle GroEL undergoes a series of allosteric transitions triggered by ligand (substrate protein, ATP, and the cochaperonin GroES) binding. Based on an elastic network model of the bullet-shaped double-ring chaperonin GroEL-(ADP)₇-GroES structure (R"T state), we perform a normal mode analysis in order to explore the energetically favorable collective motions encoded in the R"T structure. By comparing each normal mode with the observed conformational changes in the R"TTR" transition, a single dominant normal mode provides a simple description of this highly intricate allosteric transition. A detailed analysis of this relatively high-frequency mode describes the structural and dynamic changes that underlie the positive intra-ring and negative inter-ring cooperativity. The dynamics embedded in the dominant mode entails highly concerted structural motions with approximate preservation of seven fold symmetry within each ring and negatively correlated ones between the two rings. The dominant normal mode (in comparison with the other modes) is robust to parametric perturbations caused by sequence variations, which validates its functional importance. Response of the dominant mode to local changes that mimic mutations using the Structural Perturbation Method technique leads to a wiring diagram that identifies a network of key residues that regulate the allosteric transitions. Many of these residues are located in inter-subunit interfaces, and may therefore play a critical role in transmitting allosteric signals between subunits.

Key Words: GroEL, allostery, elastic network model, normal mode, robustness

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