Computational Studies of Functional Dynamics of the ClpB Disaggregase Nanomachine

Abstract

By Akil Fletcher, Chemistry

Advisor: George Stan

Presentation ID: 226

Abstract: Protein aggregation is an event whereby a protein folds into nonfunctional cellular aggregates that leaves the cellular environment disrupted and causes diseases. Protein quality control ensures cell viability against such deleterious pathways through protein degradation, disaggregation, or folding assistance mediated by chaperones and proteases. Nanomachines in the AAA+ (ATPases Associated with diverse cellular Activities) superfamily actively participate in protein remodeling by performing degradation or disaggregation. ClpB (Caseinolytic Peptidase B) is a powerful AAA+ motor protein that converts chemical energy to mechanical energy by ATP hydrolysis to perform large conformational changes. Coarse-grained (CG) models are widely used to study the long-timescale dynamics of proteins involving folding and conformational changes. Coarse graining makes the energy landscape smoother and thereby provides more sampling through the conformational space. We performed coarse-grained molecular dynamics simulations using the SMOG2 all-atom structure-based model to elucidate the functional dynamics of ClpB. During the model optimization, we matched the native fluctuation of the CG model with previously obtained fully solvated all-atom simulations. In our study, we used smFRET (single-molecule Fluorescence Resonance Energy Transfer)-derived distance restraints to probe the dynamics within individual ClpB subunits. The calculated FRET efficiencies are in close agreement with the experimentally obtained FRET efficiencies.