Binding and Folding of the Small Bacterial Chaperone HdeA

The small pH stress-sensing chaperone HdeA helps pathogenic intermediate in which one monomer is partially unfolded. The absence of a like model to delineate the relationship between dimer interface formation and monomer folding and to better understand the structural details of the chaperone activation mechanism. Free energy surfaces show that dimer interface formation and monomer folding proceed concurrently through an on-pathway dimeric folded dimer to a chaperone-active unfolded monomer to prevent the acid-induced aggregation of periplasmic proteins. Here we use a topology-based Go-like model to delineate the relationship between dimer interface formation and monomer folding and to better understand the structural details of the chaperone activation mechanism. Free energy surfaces show that dimer interface formation and monomer folding proceed concurrently through an on-pathway dimeric preexisting fully fully folded monomer in the proposed binding mechanism is in agreement with HdeA's rapid chaperone response. Binding between unfolded monomers exhibits an enhancement of molecular recognition reminiscent of the fly-casting mechanism. Overall, our simulations further highlight the efficient nature of HdeA's chaperone response and we anticipate that knowledge of a dimeric intermediate will facilitate the interpretation of experimental studies.