ClpB, a member of the AAA+ (ATPases associated with various cellular activities) superfamily, is critical to prevent protein aggregation during severe stress conditions. Protein aggregation can cause severe diseases and abnormalities that can result in harm to humans. The disaggregation mechanism involves removing polypeptide chains from amorphous aggregates and threading them through the central channel of the ClpB homohexameric ring. To-date, two ClpB conformations have been resolved at high resolution using cryogenic electron microscopy, the pre-hydrolysis “ring” and the post-hydrolysis “spiral” structures. This project uses coarse-grained molecular dynamics simulations to probe the spiral conformation. To this end, we optimized the intra- and inter-subunit interactions of the SMOG coarse-grained model to best match the residue fluctuations observed in all-atom simulations. Results of the coarse-grained simulations were compared and contrasted with those obtained in single molecule fluorescence energy transfer experiments.

Coarse-grained molecular dynamics simulation studies of mechanisms of the ClpB disaggregation machine

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