Allosteric Transitions of Supramolecular Systems Explored by Network Models: Application to Chaperonin GroEL

Identification of pathways involved in the structural transitions of biomolecular systems is often complicated by the transient nature of the conformations visited across energy barriers and the multiplicity of paths accessible in the multidimensional energy landscape. This task becomes even more challenging in exploring molecular systems on the order of megadaltons. Coarse-grained models that lend themselves to analytical solutions appear to be the only possible means of approaching such cases. Motivated by the utility of elastic network models for describing the collective dynamics of biomolecular systems and by the growing theoretical and experimental evidence in support of the intrinsic accessibility of functional substates, we introduce a new method, adaptive anisotropic network model (aANM), for exploring functional transitions. Application to bacterial chaperonin GroEL and comparisons with experimental data, results from action minimization algorithm, and previous simulations support the utility of aANM as a computationally efficient, yet physically plausible, tool for unraveling potential transition pathways sampled by large complexes/assemblies. An important outcome is the assessment of the critical inter-residue interactions formed/broken near the transition state(s), most of which involve conserved residues. Author Summary: Most proteins are biomolecular machines. They perform their function by undergoing changes between different structures. Understanding the mechanism of transition between these structures is of major importance to design methods for controlling such transitions, and thereby modulating protein function. Although there are many computational methods for exploring the transitions of small proteins, the task of exploring the transition pathways becomes prohibitively expensive in the case of supramolecular systems. The bacterial chaperonin GroEL is such a supramolecular machine. It plays an important role in assisting protein folding. During its function, GroEL undergoes structural transitions between multiple forms. Here, we are introducing a new methodology, based on elastic network models, for elucidating the transition mechanisms in such supramolecular systems. Application to GroEL provides us with biologically significant information on critical interactions and sequence of events occurring during the chaperonin machinery and key contacts that make and break at the transition. The method can be readily applied to other supramolecular machines.