A Molecular Dynamics Study of the Flexibility and Protein-Binding of the Trigger Factor Chaperone in Solution

Abstract

Trigger factor (TF) is a chaperone, found in bacterial cells (and chloroplasts), that interacts with nascent polypeptide chains to guide protein folding, and prevent spontaneous misfolding and aggregation. While its crystal structure has been resolved, the solution structure and dynamics is largely unknown. using all-atom and coarse-grained molecular dynamics (MD) simulations in combination with Markov State Modeling (MSM) on the extended crystal structure of TF in solution, we show that the collective motions of its tertiary domains, hinged about inter-domain linkers with minimal or no loss in secondary structure, leads to a substantially different conformation in solution, with a relatively stable compact collapsed state and several intermediate metastable states. These states are the results of domain-pair formations that are triggered by burial of hydrophobic residues and stabilized by hydrophilic contacts. A hydrophobic probes method, which uses methane-like Lennard-Jones particles to identify hydrophobic patches, is employed to characterize these contacts as well as the surface hydrophobicity of TF. The flexibility and promiscuity of TF facilitate its chaperone action on a variety of substrate proteins; however, its direct influence, or that of chaperones in general, on protein-folding pathways remains poorly understood. We employ steered MD to complement AA-MD simulations to understand the relatively unknown binding mechanism of maltose binding protein (MBP) to TF. We show that, in solution, TF, by conserving secondary structural elements in the folding intermediates of MBP, stabilizes native contacts in MBP and prevents the protein aggregation. Contrary to the current viewpoint, our results also illustrate a crucial role for N-terminal of TF in its binding with protein substrates through hydrophilic interactions.