The chaperonin, GroEL, is a protein complex that facilitates protein folding, the last step in gene expression. It is a 14-subunit double-toroid assembly (two rings, each with 7 subunits) that captures nonnative protein at one end of its central channel. With the help of 7 ATPs and a co-chaperonin GroES, GroEL forms a large dome-shaped chamber into which the nonnative protein is released to fold in isolation. The functional cycle of GroEL is driven by the binding of ATP and involves huge en bloc domain movements around hinge-like connections between the domains.
High-resolution crystal structures from Dr. Sigler's grouphave shown the initial and final states of this cycle and provide critical information which, combined with functional studies, enables us to infer a molecular mechanism for this process. In collaboration with Dr. Sigler's group, we carried out a computational simulation of the reaction pathways of the GroEL conformational changes using a targeted molecular dynamics (TMD) method. The results explain the high degree of positive cooperativity that enables the cis-assembly to form and the negative cooperativity that causes this complex to disassemble as the second complex forms on the opposite ring. Such a detailed stereochemical description of allosteric mechanism has not been provided by experimental approaches. The simulation has also shown its reliability by explaining several inexplicable effects of mutants and correctly predicts the order of domain movements inferred from experiments.
Jianpeng Ma, Terence C. Flynn, Qiang Cui, Andrea Leslie, John E. Walker and Martin Karplus (2002). A Dynamic Analysis of the Rotation Mechanism for Conformational Change in F1-ATPase. Structure 10: 921-931.
Yifei Kong, Yufeng Shen, Tiffany E. Warth and Jianpeng Ma (2002). Conformational Pathways in the Gating of E.coli Mechanosensitive Channel. Proc. Natl. Acad. Sci. USA. 99: 5999-6004.