Flexibility of the bacterial chaperone trigger factor in microsecond-timescale molecular dynamics simulations

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biophysics

Background:

• Trigger factor (TF) is the primary chaperone interacting with nascent polypeptide chains exiting the ribosome.
• Experimental data suggest TF possesses substantial conformational flexibility.
• Understanding TF's dynamic behavior is crucial for elucidating its role in protein folding.

Purpose of the Study:

• To investigate the atomic-level conformational flexibility of bacterial trigger factor (TF).
• To compare the effects of different molecular dynamics simulation force fields on TF dynamics.
• To rationalize experimental observations of TF's conformational states.

Main Methods:

• Performed two independent 1.5-μs molecular dynamics simulations of TF in explicit solvent.
• Utilized two distinct simulation force fields: OPLS-AA/L and AMBER ff99SB-ILDN.
• Conducted simulations involving force field swapping to assess sampling effects.

Main Results:

• Both simulations demonstrated significant TF flexibility, with large deviations from the crystallographic structure due to domain reorientations.
• Predicted extensive contacts between TF's peptidyl-prolyl isomerase (PPIase) domain and the nascent-chain-binding Arm 1 domain.
• Observed distinct conformational behaviors: rapid compacting in OPLS-AA/L versus sustained dynamics in AMBER ff99SB-ILDN, potentially due to sampling differences.

Conclusions:

• Molecular dynamics simulations provide atomic-level insights into TF's conformational flexibility and domain interactions.
• Discrepancies between force fields highlight the importance of adequate sampling in simulating TF.
• Simulation findings offer potential explanations for experimental observations and inform future modeling of TF function on translating ribosomes.