Predicting the reaction coordinates of millisecond light-induced conformational changes in photoactive yellow protein.
Understanding the dynamics of large-scale conformational changes in proteins still poses a challenge for molecular simulations. We employ transition path sampling of explicit solvent molecular dynamics trajectories to obtain atomistic insight in the reaction network of the millisecond timescale partial unfolding transition in the photocycle of the bacterial sensor photoactive yellow protein. Likelihood maximization analysis predicts the best model for the reaction coordinates of each substep as well as tentative transition states, without further simulation. We find that the unfolding of the alpha-helical region 43-51 is followed by sequential solvent exposure of both Glu46 and the chromophore. Which of these two residues is exposed first is correlated with the presence of a salt bridge that is part of the N-terminal domain. Additional molecular dynamics simulations indicate that the exposure of the chromophore does not result in a productive pathway. We discuss several possibilities for experimental validation of these predictions. Our results open the way for studying millisecond conformational changes in other medium-sized (signaling) proteins.
Vreede
Jocelyne
J
Van't Hoff Institute for Molecular Sciences, University of Amsterdam, Nieuwe Achtergracht 166, 1018 WV Amsterdam, The Netherlands. j.vreede@uva.nl
Juraszek
Jarek
J
Bolhuis
Peter G
PG
D001426:Bacterial Proteins / Q000737:chemistry*; D001499:Bayes Theorem; D018698:Glutamic Acid / Q000737:chemistry; D020607:Halorhodospira halophila / Q000378:metabolism; D006860:Hydrogen Bonding; D008027:Light; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D020283:Photoreceptors, Microbial / Q000737:chemistry*; D011487:Protein Conformation / Q000528:radiation effects*; D017510:Protein Folding / Q000528:radiation effects; D017433:Protein Structure, Secondary / Q000528:radiation effects; D017434:Protein Structure, Tertiary / Q000528:radiation effects; D012996:Solutions; D013816:Thermodynamics; D013997:Time Factors
D001426:Bacterial Proteins; D020283:Photoreceptors, Microbial; D012996:Solutions; C050162:photoactive yellow protein, Bacteria; D018698:Glutamic Acid